Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 18, 23, 34 and 43-49 are pending and being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Oct 21, 2025 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Rejection Withdrawn
The rejection of claims 18, 23, 34 and 43-46 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over WO2009132058 (of record, Dillons hereafter, published Oct 29, 2009; PTO 892) in view of WO2010/104949 publication (of record, Hsu hereafter, published September 16, 2010; PTO 892) and WO2008119567 (of record, Bluemel hereafter, published Oct 2008; PTO 892), Theill et al (US20020081296, published June 27, 2002; PTO 892) and Kufer et al (US20070123479, published May 31, 2007; PTO 892) is withdrawn in view of the claim amendment.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Claims 48-49 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, because the claim purports to invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, but fails to recite a combination of elements as required by that statutory provision and thus cannot rely on the specification to provide the structure, material or acts to support the claimed function. As such, the claim recites a function that has no limits and covers every conceivable means for achieving the stated function, while the specification discloses at most only those means known to the inventor. Accordingly, the disclosure is not commensurate with the scope of the claim.
One cannot reasonably understand the claim phrase “means for binding the extracellular domain of human B cell maturation antigen (BCMA), …means for binding human CD3 epsilon” to have a sufficiently definite meanings as the name for the structure of full-size bispecific antibody. A person of ordinary skill in the art would not have known the structure of full-size bispecific antibody comprising a first binding domain comprises a first means for binding the extracellular domain of BCMA and the structure of a second binding domain comprising means for binding to human CD3 epsilon based on the teachings of the specification and the art at the time of filing. The specification does not describe the structure based on the written description or material or acts for binding the extracellular domain of human B cell maturation antigen (BCMA), …means for binding human CD3 epsilon encompassed by the claimed full-size bispecific antibody.
The specification defines full-size antibody as follow:
[0023] Unless indicated otherwise, the terms "antibody" or "immunoglobulin" are used as general terms to include both the full-size antibody, the individual chains thereof, as well as all parts, domains or fragments thereof.
The full-size antibody encompasses all parts, domains or any fragments thereof. Thus the means-plus-function limitation must be read as covering only the means disclosed in the specification. However, the specification does not disclose any full-size equivalents thereof.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 18, 23, 34 and 43-47 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “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 characteristics and/or other 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 applicant was in possession of the claimed genus.” (see MPEP 2163).
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art. This problem may arise where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), "[claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
"[A] sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780,1790 (Fed. Cir. 2014) ("The '128 and '485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number" of species.
In Amgen Inc, v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc, v. Eli Lily & Co.. 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is "had possession of the claimed subject matter as of the filing date. Demonstrating possession "requires a precise definition" of the invention. To provide this precise definition" for a claim to a genus, a patentee must disclose "a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus" (see Amgen at page 1358).
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products - "a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials", which may be present in "functional terminology when the art has established a correlation between structure and function" (Amgen page 1361).
Claim 18 encompasses any bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a VH and a VL domain and binds to the extracellular domain of human B cell maturation antigen (BCMA), and a second binding domain comprises a VH and a VL domain and binds to human CD3 epsilon, wherein the bispecific binding agent is a full-size antibody.
Claim 23 encompasses the bi specific binding agent of claim 18, wherein the first binding domain is obtained from a mouse antibody or antigen binding fragment thereof.
Claim 34 encompasses a pharmaceutical composition comprising at least one bispecific binding agent of claim 18 and a pharmaceutically acceptable carrier.
Claim 43 encompasses the bispecific binding agent of claim 18, wherein the full-size length antibody is an IgG antibody.
Claim 44 encompasses the bispecific binding agent of claim 18, wherein the full-size antibody is a bivalent antibody.
Claim 45 encompasses the bispecific binding agent of claim 18, wherein the full-size length antibody is a bivalent, IgG antibody.
Claim 46 encompasses the bispecific binding agent of claim 23, wherein the mouse antibody is obtained by immunization of mice with an antigen comprising an extracellular domain of the human BCMA.
Claim 47 encompasses any bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a VH and a VL domain and binds to the extracellular domain of human B cell maturation antigen (BCMA), and a second binding domain comprises a VH and a VL domain and binds to human CD3 epsilon, wherein the bispecific binding agent is a full-size antibody, wherein said first binding domain is obtained from a mouse antibody or antigen binding fragment thereof, and wherein the mouse antibody is obtained by immunization of mice with an antigen comprising an extracellular domain of the human BCMA.
Claim 48 encompasses any bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a first means for binding the extracellular domain of human B cell maturation antigen (BCMA), and a second binding domain comprises a second means for binding human CD3 epsilon, wherein the bispecific binding agent is a full-size antibody.
Claim 49 encompasses the bispecific binding agent of claim 48, wherein the second binding domain comprises a VH and a VL domain.
Regarding antibody, the specification defines as follow:
[0023] Unless indicated otherwise, the terms "antibody" or "immunoglobulin" are used as general terms to include both the full-size antibody, the individual chains thereof, as well as all parts, domains or fragments thereof.
[0075] In the bispecific binding agent of the invention, the two binding domains may be in identical or different formats as described above, e.g. the first binding domain may be an immunoglobulin single variable domain like a V or a VH and the second one a different immunoglobulin single variable domain or a BiTE or a diabody, respectively, or vice versa, the first binding domain may be a full-size antibody and the second one an antibody fragment like a diabody or vice versa, etc.
[0083] The CDRs (complementarity determining regions) of an antibody with BCMA specificity can be obtained by N-terminal sequencing, Edman degradation and mass spectrometry of a commercially available antibody, e.g. Vicky-1 (Santa Cruz, # sc-57037) or Mab193 (R & D, #MAB193), suitable techniques have been reviewed by Steen and Mann, Nature Reviews Molecular Cell Biology, 5:699-711, 2004. Once the framework has been identified and the sequences of the CDRs are known, the encoding DNA sequence is synthesized and grafted onto a framework with similar properties as compared to the parental one by molecular cloning methods as described in Gabbard et al., Protein Engineering, Design & Selection, vol. 22, no. 3, pp. 189-198, 2009. This framework can be part of a full IgG sequence to generate a bispecific full-sized antibody, a single chain Fv fragment to generate an antibody fragment-based molecule or part of the structural region of an antibody to provide an additional specificity. All the thus obtained molecules are tested for binding to BCMA using commercially available recombinant protein representing the extracellular domain of BCMA (R & D, #193-BC-050) in an ELISA assay or by flow cytometry using a cell line e.g. NCI H929 (ATCC, # ATCC CRL-9068) expressing BCMA, both methods being well known to the person skilled in the art.
Thus, the full-size antibody includes bispecific IgG, diabody, BiTE antibody, VHH, the individual chains thereof, as well as all parts, domains or fragments thereof.
Regarding antibody molecule, the specification defines the term antibody molecule as follows:
[0024] The term "antibody molecule" (or immunoglobulin or Ig) encompasses antibodies, in particular human antibodies, antibody fragments, antibody-like molecules and conjugates (e.g. with human serum albumin or in the form of immunoconjugates, e.g. with .sup.131iodine, calicheamicin, auristatin or others) with any of the above mentioned antibody molecules. Antibodies include, but are not limited to, monoclonal, chimerized monoclonal, bi- or multispecific antibodies. The term "antibody" shall encompass complete immunoglobulins comprising two heavy chains and two light chains, e.g. fully human antibodies as they are produced by lymphocytes and for example present in blood sera, monoclonal antibodies secreted by hybridoma cell lines, polypeptides produced by recombinant expression in host cells, which have the binding specificity of immunoglobulins or monoclonal antibodies, and molecules which have been derived from such immunoglobulins, monoclonal antibodies, or polypeptides by further processing or recombinant expression while retaining their binding specificity.
Regarding antibody fragment, the specification discloses:
[0025] Antibody fragments or antibody-like molecules may contain only a portion of the constant region or lack the constant domain as long as they exhibit specific binding to the antigen. The choice of the type and length of the constant region depends, if no effector functions like complement fixation or antibody dependent cellular toxicity are desired, mainly on the desired pharmacological properties of the antibody protein. The antibody molecule will typically be a tetramer consisting of two light chain/heavy chain pairs, but may also be dimeric, i.e. consisting of a light chain/heavy chain pair, e.g. a Fab or Fv fragment, or it may be a monomeric single chain antibody (scFv). Antigen-binding antibody fragments or antibody-like molecules, including single-chain antibodies and linear antibodies, may comprise, on a single polypeptide, the variable region(s) alone or in combination with the entirety or a portion of the following: constant domain of the light chain, CH1, hinge region, CH2, and CH3 domains, e.g. a so-called "SMIP.™." ("Small Modular Immunopharmaceutical"), which is an antibody-like molecule employing a single polypeptide chain as its binding domain Fv, which is linked to single-chain hinge and effector domains devoid of the constant domain CH1 (WO 02/056910). SMIP.RTM.s can be prepared as monomers or dimers, but they do not assume the dimer-of-dimers structure of traditional antibodies. A so-called scorpion, an extension of a SMIP that has two binding specificities, is described in WO 2007/146968.
[0026] VHHs or VHs, as defined below, also fall within the category of antibody-like molecules" or "antibody fragments".
Regarding binding domain, the specification discloses:
[0027] The term "binding domain" or "or antigen-binding domain" refers to the regions within the bispecific binding agent that bind to/interact with the structure/antigen/epitope of the respective target molecule, i.e. BCMA or CD3, respectively. It can refer to the complete variable region or specifically to the complementarity determining regions (CDRs) that form the contact surface with the target molecule.
The terms “e.g.”, “i.e.” and “includes but not limited to” the ones that disclosed in the specification. The first binding domain comprise a VH and VL domains or the six CDRs of anti-BCMA antibodies are not limited to the anti-BCMA antibodies Vicky-1 from Santa Cruz, # sc-57037 or Mab 193 (R&D, #MAB 193) and the second binding domain comprising a VH and a VL domains that binds to the first twenty seven N-terminus residues of human CD3 is not limited to a monoclonal anfi-CD3 antibody OKT3 from ATCC CRL 8001) or another anti-CD3 antibody like WT32, anti-leu-4, UCHT-1, 8PY-3TA or SPV-T3B.
However, the specification does not provide adequate written description support for the broad genus of any full-size bispecific binding agent comprising a first binding domain comprises any VH and any VL domain that binds to the extracellular domain of human B cell maturation antigen (BCMA) and a second binding domain comprises any VH and VL domain that binds to human CD3 epsilon. In particular, the specification does not describe with sufficient relevant identifying characteristics such as: i. Complete structure, i.e., amino acid sequence of heavy and light chains variable domains (VH and VL), ii. Partial structure, i.e., six CDRs that correlated with binding to the extracellular domain of human B cell maturation antigen (BCMA) and human CD3 epsilon. There is no limitation on the structure of the VH and VL that bind to extracellular domain of human B cell maturation antigen (BCMA) and human CD3 epsilon. There is no information in the specification how much variation in the VH and VL is permissible for it still bind human B cell maturation antigen (BCMA) and human CD3 epsilon. Without such as description, one of ordinary skill in the art would be unable to distinguish which full-length antibody would fall within the scope encompassed by the claim and which do not.
The claims use functional language to claim a genus because it claims all antibodies that bind to extracellular domain of human B cell maturation antigen (BCMA) and human CD3 epsilon. See Juno Therapeutics, Inc. v. Kite Pharm., Inc., 10F.4th 1330, 1335 (Fed. Cir. 2021) (discussing “genus claims using functional language, like the binding function of the claimed binding agent. “Generally, a genus can be sufficiently disclosed by either a representative number of species falling within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. (citation omitted). “For genus claims using functional language, … the written description ‘must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” Id (quoting Ariad Pharms., 598 F.3d at 1349).
A “representative number of species” means any such number of species that adequately describes the entire genus. Thus, when there is a substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Jansen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014). Satisfactory disclosure of a “representative number” depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. See MPEP §2163 (9th ed. Rev. 07-2022 Feb. 2023).
The specification discloses:
[0033] Covalent linking of two monoclonal antibodies is described in Anderson, Blood 80 (1992), 2826-34. In the context of this invention, one of the antibodies is specific for BCMA and the other one for CD3. By way of example, a BCMA specific antibody, e.g. Vicky-1 (Santa Cruz, # sc-57037) or Mab193 (R & D, #MAB193) is chemically linked to a monoclonal anti-CD3 antibody, e.g. OKT3 (ATCC CRL 8001) or another anti-CD3 antibody like WT32, anti-leu-4, UCHT-1, SPV-3TA or SPV-T3B.
The specification exemplifies:
[0156] Generating a Bispecific BCMA/CD3 Single Chain Binding Agent
[0157] a) Generation of Anti-BCMA and Anti-CD3 Binding Domains
[0158] The DNA fragment encoding the CD3-specific binding domain is obtained by amplification from a synthetic DNA construct encoding the VH and VL region separated by an 18 amino acid linker, as disclosed in WO 2004106383, using primers similar to the ones described there, generating a BsrGl restriction site at the VH end and a BspEl restriction site at the VL end. The DNA sequence encoding the BCMA-binding domain is obtained by amplification from VH and VL DNA molecules synthesized upon sequencing a commercially available antibody. Alternatively, cDNA constructs are used that are obtained from the VH and VL RNA from a BCMA specific hybridoma, using suitable primers generating a BspEl restriction site at the VL 5' end and a SalI restriction site at the 3' VH end.
[0159] b) Cloning of Anti-CD3.times.Anti-BCMA Constructs
[0160] Cloning is done in VH anti-CD3-VL anti CD3.times.VH anti-BCMA-VL anti-BCMA orientation. The anti-CD3 construct is cleaved with the restriction enzymes BsrGl and BspEl and subsequently cloned into the bluescript KS vector (Stratagene, La Jolla, Calif.), containing the amino acid sequence of an eukaryotic secretory signal (leader) peptide as a EcoRl/BsrGI-fragment. After cleavage with EcoRl and BspEl, the resulting DNA fragment comprising the respective anti-CD3 scFv with the leader peptide is cloned into an EcoRl/BspEl-cleaved plasmid pEFDHFR and the BCMA fragments are cloned into the BspEl/SalI-cleaved vector. Alternatively, cloning is done in the other orientation.
[0161] c) Expression and Characterization of the Bispecific Single Chain Binding Agent
[0162] After confirmation of the desired sequence by DNA sequencing, the construct obtained in b) is transfected, e.g. into dehydrofolate reductase negative CHO cells, and expressed for characterisation as described in WO 2004/106383. For example, for binding to Jurkat cells (ATCC, # TIB-152) for CD3 and NCI H929 (ATCC CRL-9068) for BCMA a flow cytometry experiment is performed. The cells are incubated with the supernatant of BCMA/CD3 bi-specific construct expressing cells for approximately 1 h at 4.degree. C., washed 2.times. in FACS buffer (phosphate-buffered saline containing 1% fetal calf serum (FCS) and 0.05% sodium azide) and bound construct is detected via the 6.times.HIS tag incorporated in the expression vector pEFDHFR using a HIS antibody e.g. (Dianova, DIA910). For the detection of bound anti-HIS antibody the cells are washed as described above and incubated with e.g. goat anti-mouse-FITC-conjugated antibody (BD 550003) or with anti-mouse-PE conjugated antibody (IgG) (Sigma, P8547) and analysed e.g. on a FACS Canto (BD). The functional activity of the constructs is then analysed using a flow cytometry based assay after the constructs have been purified by a two-step purification process including immobilized metal affinity chromatography (IMAC) and gel filtration as described in WO 2004/106383, but using a CHO cell line transfected with a DNA construct expressing full-length BCMA on the surface.
The disclosure of only two species of antibodies Vicky-1 and Mab193 that bind to human BCMA and OKT3 and UCHT1 that binds to human CD3 epsilon encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the genus”. See Enzo Biochem, Inc v Gen-Probe Inc., 323 F.3d 956, 966-67 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343, 1350 (Fed. Cir. 2004). For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See Regents of the Univ. of Calif. V. Eli Lilly, 119 F.3d 1559, 1568 (Fed. Cir. 1997). Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety of scope of the genus,” or by establishment of “a reasonable structure-function correlation.” See AbbVie, 759 F.3d at 1300-01. “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date.” Id. At 1301.
“[T]he test for sufficiency of written description is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter a of the time of filing.” Ariad Pharms., 598 F.36 at 1351. Ariad explains that “the test requires an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art.” Id.
Nevertheless, “[the ‘written description’ requirement must be applied in the context of the particular invention and ]the state of the knowledge.” Capon v. Eshhar, 418 F.3d 1349, 1358-61 (Fed. Cir. 2005).
For Example, in Juno, the Federal Circuit found that the written description requirement was not met. 10 F.4th at 1342. Although single-chain antibody variable fragments (scFvs) in general were known, the realm of possible scFvs that bind to CD19 (a protein that appears on the surface of certain cells) was vast and the number of known CD19-specific scFvs was small (five at most). Id. The patent at issue there provided no details about which scFvs bind to CD19 in a way that distinguishes them from scFvs that do not bind to CD19. Id.
In this case, the specification does not disclose a representative number of species of full-size bispecific binding agent or full-length IgG antibody or bivalent full-size antibody comprising a VH and a VL domain that binds to the extracellular domain of human B cell maturation antigen (BCMA) and a VH and a VL domain that hinds to human CD3 epsilon nor provides a structure-function relationship sufficient to enable a person of ordinary skill in the art to ‘visualize or recognize’ the members of the germs of bispecific binding agents at the time of filing.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. (of record) taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 2003 Nov 14;334(1): 103-118), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular. Given that hundreds of unique antibody structures may bind a single antigen or epitope of an antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and two species cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in AbbVie).
Further, numerous publications acknowledging that the conformation of CDRs as well as frameworks influence binding.
MacCalium et al. (of record, J. Mol. Biol, 262: 732-745, 1996; PTO 892), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate a number of residues outside the standard CDR definitions make antigen contacts ( see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.).
De Pascalis el al. (of record. Journal of Immunology 169: 3076-3084, 2002; PTO 892) teach that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential .for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in ah six CDRs were used for the constructs (see page 3080, left cot.).
Vajdos et al. (of record, J. Mol. Biol. 320, 415-428, 2002; PTO 892) state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect tire CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.).
Wu et al. (of record, J. Mol. Biol. 294, 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
Finally, Dufner (of record, Trends Biotechnol. 24(11):523-529, 2006; PTO 892) teaches: “specific structural information - on the antibody to be optimized, its antigen and their interaction- is rarely available or lacks the high resolution required to determine accurately important details such as side-chain conformations, hydrogen-bonding patterns and the position of water molecules (p. 527, Col. 2, 1). Thus, one of skill in the art cannot envision or recognize the structure of the genus of bispecific full-size antibodies comprising any VH and VL, any fragment or any part thereof that bind to the extracellular domain of human BCMA and human CD3 epsilon as broadly as claimed.
A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit this functional property.
In AbbVie v. Centocor (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all IL-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must 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.” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
While the specification discloses bispecific binding agent can be obtained by screening phage library, see p. 20, line 1, possession may not be shown by merely described how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) As such, the specification merely asks one of skill in the art to come up with the structure of the claimed bispecific antibody. Thus, the specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A description of what a material does, rather than of what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. The Federal Circuit has held that “a sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the germs so that one of skill in the art can "visualize or recognize" the members of the genus" (Id. at 1.350, quoting Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1568-69 (Fed. Cir. 1997)).
Thus, the specification does not disclose a representative number of species of bispecific full-size antibody or bispecific bivalent IgG full-length antibody that binds to the extracellular domain of human BCMA and human CD3 epsilon, nor sufficient structure/function relationship correlative to the recited functional properties.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the bispecific full-length antibody or bispecific bivalent IgG full-length antibody that binds to human BCMA and human CD3 epsilon. A skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all the said bispecific full-length antibody or bispecific bivalent IgG full-length antibody that binds to human BCMA and human CD3 epsilon at the time the instant application was filed.
Applicants’ arguments filed Oct 21, 2025 have been fully considered but are not found persuasive.
Applicants’ position is that Claim 18 is amended to recite, among other features, that the bispecific binding agent is a full-size antibody. Applicant submits that one of ordinary skill in the art can reasonably conclude in view of the present Application that Applicant had possession of the bispecific binding agent as recited in Claim 18 as amended at the time of filing.
Specifically, the present Application discloses a bispecific binding agent that includes a first binding domain that binds to BCMA, and a second binding domain that binds to CD3:
In a first aspect, the bispecific binding agent is in the format of a bispecific antibody molecule or a fragment thereof which has at least two binding domains, comprising a first binding domain and a second binding domain, wherein said first binding domain binds to BCMA and wherein said second binding domain binds to CD3. Specification at 9:6-9. Further, the present Application discloses that in some embodiments, "antibody" refers to a full-size antibody.
Unless indicated otherwise, the terms "antibody" or "immunoglobulin" are used as general terms to include both the full-size antibody, the individual chains thereof, as well as all parts, domains or fragments thereof." Id. at 6:27-29; see also id at 24:12-17, 27:5-10 ("This framework can be part of a full IgG sequence to generate a bispecific full-sized antibody."). The present Application also discloses that in some embodiments, the bispecific binding agent binds to "an epitope of BCMA that is located in the extracellular domain." Id at 25:13-14.
Regarding the VH and VL domains, the present Application discloses variable regions of the light chain and heavy chain of an antibody that binds to BCMA:
The anti-BCMA antibody sequences can be derived from protein sequencing of the variable regions of the light and heavy chains of a BCMA-specific antibody, e.g. a commercially available one or an antibody obtained by methods as described herein, or they can be obtained by sequencing the RNA of a hybridoma generated by immunization with BCMA, using conventional methods ... Id. at 10:9-13; see also id. at 21:3-9 ("... the variable regions of the VH and VL genes of a BCMA specific antibody .. ."). The present disclosure also provides non-limiting examples of anti-BCMA antibodies, such as Vicky-1 and Mabl93, having suitable sequence-based features for a binding domain that binds to BCMA. See id. at 27:1-4. Moreover, the present Application discloses published examples of BCMA-specific antibodies. See id. at 3:11-21.
Regarding CD3, the present Application discloses variable regions of the light chain and the heavy chain of an antibody that binds to CD3, including human CD3 epsilon. See, e.g., id. at 13:23-14:19, 26:9-22. Further, the present Application discloses non-limiting examples of anti- CD3 antibodies that bind to human CD3 epsilon, such as OKT3 and UCHT1. See id. at 13:23- 14:19, 26:20-22. The present disclosure also provides suitable anti-CD3 antibody sequences that were published in, for example, WO 2008/119567. See id. at 10:14-15.
Thus, antibodies to BCMA, including those that bind to the extracellular domain of human BCMA, or antibodies to human CD3 epsilon, and the relevant structural features thereof, were each already individually known. See MP.E.P. §2163 ILA.2 ("Information which is well known in the art need not be described in detail in the specification." citing Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986)). At least for these reasons, amended Claim 18, as well as each claim dependent therefrom, is adequately supported by the present Application to satisfy the written description requirement.
The Office Action asserts that "[for claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus." Office Action at p. 3. The Office Action further lists examples of "a genus of antibodies with particular functional properties" including "high affinity, neutralization activity, competing with a reference antibody for binding." Id. at pp. 3-4. However, the presently pending claims do not recite functional properties such as binding affinity, neutralization activity, or competitive binding with a reference antibody (that is, a functional result that is more than simply binding to a target). The claims simply recite two biding domains that bind to two targets: the extracellular domain of human BCMA and human CD3 epsilon. Thus, the claims do not recite an activity or property that would trigger a written description analysis for disclosure of a representative number of species or the structural features common to members of the species, contrary to the Examiner's assertions.
Further, even if the claims were to require disclosure of a representative number of species or the structural features common to members of the species, the present Application provides the requisite disclosure, at least by disclosing the structural features common to members of the species. Specifically, the structural features common to members of the claimed bispecific binding agent include, within the bispecific binding agent, a combination of the first binding domain that binds to the extracellular domain of human BCMA and the second binding domain that binds to human CD3 epsilon. See, e.g., Specification at 2:3-16. The present Application discloses non-limiting examples of a bispecific binding agent that is a full-size antibody. See, e.g., id. at 9:20- 27, 11:10-25. As discussed above, antibodies to the extracellular domain of human BCMA and antibodies to human CD3 epsilon were each already individually known. Thus, at least the disclosure of the structural features common to members of the claimed bispecific binding agent in the present Application satisfies the written description requirement.
In view of the above, withdrawal of this rejection is respectfully requested.
In response, the amendment to claim 18 is acknowledged.
Regarding antibody, the specification defines as follow:
[0023] Unless indicated otherwise, the terms "antibody" or "immunoglobulin" are used as general terms to include both the full-size antibody, the individual chains thereof, as well as all parts, domains or fragments thereof.
[0075] In the bispecific binding agent of the invention, the two binding domains may be in identical or different formats as described above, e.g. the first binding domain may be an immunoglobulin single variable domain like a V or a VH and the second one a different immunoglobulin single variable domain or a BiTE or a diabody, respectively, or vice versa, the first binding domain may be a full-size antibody and the second one an antibody fragment like a diabody or vice versa, etc.
[0083] The CDRs (complementarity determining regions) of an antibody with BCMA specificity can be obtained by N-terminal sequencing, Edman degradation and mass spectrometry of a commercially available antibody, e.g. Vicky-1 (Santa Cruz, # sc-57037) or Mab193 (R & D, #MAB193), suitable techniques have been reviewed by Steen and Mann, Nature Reviews Molecular Cell Biology, 5:699-711, 2004. Once the framework has been identified and the sequences of the CDRs are known, the encoding DNA sequence is synthesized and grafted onto a framework with similar properties as compared to the parental one by molecular cloning methods as described in Gabbard et al., Protein Engineering, Design & Selection, vol. 22, no. 3, pp. 189-198, 2009. This framework can be part of a full IgG sequence to generate a bispecific full-sized antibody, a single chain Fv fragment to generate an antibody fragment-based molecule or part of the structural region of an antibody to provide an additional specificity. All the thus obtained molecules are tested for binding to BCMA using commercially available recombinant protein representing the extracellular domain of BCMA (R & D, #193-BC-050) in an ELISA assay or by flow cytometry using a cell line e.g. NCI H929 (ATCC, # ATCC CRL-9068) expressing BCMA, both methods being well known to the person skilled in the art.
Thus, the full-size antibody includes bispecific IgG, diabody, BiTE antibody, the individual chains thereof, e.g., VH or VL, as well as all parts, domains or fragments thereof.
Claims 18, 23, 43-45 use functional language to claim a genus because it claims all antibodies, e.g., IgG, (scFv)2, diabody, VHH, the individual chains thereof, as well as all parts, domains or fragments thereof that bind to extracellular domain of human B cell maturation antigen (BCMA) and human CD3 epsilon. See Juno Therapeutics, Inc. v. Kite Pharm., Inc., 10F.4th 1330, 1335 (Fed. Cir. 2021) (discussing “genus claims using functional language, like the binding function of the claimed binding agent. “Generally, a genus can be sufficiently disclosed by either a representative number of species falling within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. (citation omitted). “For genus claims using functional language, … the written description ‘must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” Id (quoting Ariad Pharms., 598 F.3d at 1349).
A “representative number of species” means any such number of species that adequately describes the entire genus. Thus, when there is a substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Jansen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014). Satisfactory disclosure of a “representative number” depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. See MPEP §2163 (9th ed. Rev. 07-2022 Feb. 2023).
The specification exemplifies:
[0156] Generating a Bispecific BCMA/CD3 Single Chain Binding Agent
[0157] a) Generation of Anti-BCMA and Anti-CD3 Binding Domains
[0158] The DNA fragment encoding the CD3-specific binding domain is obtained by amplification from a synthetic DNA construct encoding the VH and VL region separated by an 18 amino acid linker, as disclosed in WO 2004106383, using primers similar to the ones described there, generating a BsrGl restriction site at the VH end and a BspEl restriction site at the VL end. The DNA sequence encoding the BCMA-binding domain is obtained by amplification from VH and VL DNA molecules synthesized upon sequencing a commercially available antibody. Alternatively, cDNA constructs are used that are obtained from the VH and VL RNA from a BCMA specific hybridoma, using suitable primers generating a BspEl restriction site at the VL 5' end and a SalI restriction site at the 3' VH end.
[0159] b) Cloning of Anti-CD3.times.Anti-BCMA Constructs
[0160] Cloning is done in VH anti-CD3-VL anti CD3.times.VH anti-BCMA-VL anti-BCMA orientation. The anti-CD3 construct is cleaved with the restriction enzymes BsrGl and BspEl and subsequently cloned into the bluescript KS vector (Stratagene, La Jolla, Calif.), containing the amino acid sequence of an eukaryotic secretory signal (leader) peptide as a EcoRl/BsrGI-fragment. After cleavage with EcoRl and BspEl, the resulting DNA fragment comprising the respective anti-CD3 scFv with the leader peptide is cloned into an EcoRl/BspEl-cleaved plasmid pEFDHFR and the BCMA fragments are cloned into the BspEl/SalI-cleaved vector. Alternatively, cloning is done in the other orientation.
[0161] c) Expression and Characterization of the Bispecific Single Chain Binding Agent
[0162] After confirmation of the desired sequence by DNA sequencing, the construct obtained in b) is transfected, e.g. into dehydrofolate reductase negative CHO cells, and expressed for characterisation as described in WO 2004/106383. For example, for binding to Jurkat cells (ATCC, # TIB-152) for CD3 and NCI H929 (ATCC CRL-9068) for BCMA a flow cytometry experiment is performed. The cells are incubated with the supernatant of BCMA/CD3 bi-specific construct expressing cells for approximately 1 h at 4.degree. C., washed 2.times. in FACS buffer (phosphate-buffered saline containing 1% fetal calf serum (FCS) and 0.05% sodium azide) and bound construct is detected via the 6.times.HIS tag incorporated in the expression vector pEFDHFR using a HIS antibody e.g. (Dianova, DIA910). For the detection of bound anti-HIS antibody the cells are washed as described above and incubated with e.g. goat anti-mouse-FITC-conjugated antibody (BD 550003) or with anti-mouse-PE conjugated antibody (IgG) (Sigma, P8547) and analysed e.g. on a FACS Canto (BD). The functional activity of the constructs is then analysed using a flow cytometry based assay after the constructs have been purified by a two-step purification process including immobilized metal affinity chromatography (IMAC) and gel filtration as described in WO 2004/106383, but using a CHO cell line transfected with a DNA construct expressing full-length BCMA on the surface.
The specification discloses:
[0033] Covalent linking of two monoclonal antibodies is described in Anderson, Blood 80 (1992), 2826-34. In the context of this invention, one of the antibodies is specific for BCMA and the other one for CD3.By way of example, a BCMA specific antibody, e.g. Vicky-1 (Santa Cruz, # sc-57037) or Mab193 (R & D, #MAB193) is chemically linked to a monoclonal anti-CD3 antibody, e.g. OKT3 (ATCC CRL 8001) or another anti-CD3 antibody like WT32, anti-leu-4, UCHT-1, SPV-3TA or SPV-T3B.
The disclosure of only two species of antibodies Vicky-1 and Mab193 that bind to human BCMA and two species of OKT3 and UCHT1 that bind to human CD3 epsilon encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the genus” of full-size bispecific antibodies. See Enzo Biochem, Inc v Gen-Probe Inc., 323 F.3d 956, 966-67 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343, 1350 (Fed. Cir. 2004). For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See Regents of the Univ. of Calif. V. Eli Lilly, 119 F.3d 1559, 1568 (Fed. Cir. 1997). Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety of scope of the genus,” or by establishment of “a reasonable structure-function correlation.” See AbbVie, 759 F.3d at 1300-01. “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date.” Id. At 1301.
“[T]he test for sufficiency of written description is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter a of the time of filing.” Ariad Pharms., 598 F.36 at 1351. Ariad explains that “the test requires an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art.” Id.
Nevertheless, “[the ‘written description’ requirement must be applied in the context of the particular invention and ]the state of the knowledge.” Capon v. Eshhar, 418 F.3d 1349, 1358-61 (Fed. Cir. 2005).
For Example, in Juno, the Federal Circuit found that the written description requirement was not met. 10 F.4th at 1342. Although single-chain antibody variable fragments (scFvs) in general were known, the realm of possible scFvs that bind to CD19 (a protein that appears on the surface of certain cells) was vast and the number of known CD19-specific scFvs was small (five at most). Id. The patent at issue there provided no details about which scFvs bind to CD19 in a way that distinguishes them from scFvs that do not bind to CD19. Id.
In this case, the specification does not disclose a representative number of species of full-size bispecific binding agent or full-length IgG antibody or bivalent full-size antibody comprising a VH and a VL domain that binds to the extracellular domain of human B cell maturation antigen (BCMA) and a VH and a VL domain that hinds to human CD3 epsilon nor provides a structure-function relationship sufficient to enable a person of ordinary skill in the art to ‘visualize or recognize’ the members of the germs of bispecific binding agents at the time of filing.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. (of record) taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 2003 Nov 14;334(1): 103-118), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular. Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in AbbVie).
Further, numerous publications acknowledging that the conformation of CDRs as well as frameworks influence binding.
MacCalium et al. (of record, J. Mol. Biol, 262: 732-745, 1996; PTO 892), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate a number of residues outside the standard CDR definitions make antigen contacts ( see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.).
De Pascalis el al. (of record. Journal of Immunology 169: 3076-3084, 2002; PTO 892) teach that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential .for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in ah six CDRs were used for the constructs (see page 3080, left cot.).
Vajdos et al. (of record, J. Mol. Biol. 320, 415-428, 2002; PTO 892) state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect tire CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.).
Wu et al. (of record, J. Mol. Biol. 294, 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
Finally, Dufner (of record, Trends Biotechnol. 24(11):523-529, 2006; PTO 892) teaches: “specific structural information - on the antibody to be optimized, its antigen and their interaction- is rarely available or lacks the high resolution required to determine accurately important details such as side-chain conformations, hydrogen-bonding patterns and the position of water molecules (p. 527, Col. 2, 1). Thus, one of skill in the art cannot envision or recognize the structure of the genus of bispecific full-size antibodies comprising any VH and VL, any fragment or any part thereof that bind to the extracellular domain of human BCMA and human CD3 epsilon as broadly as claimed.
A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit this functional property.
Regarding VH and VL, the specification does not describe the amino acid sequences of VH and VL domains that bind the extracellular domain of human B cell maturation antigen (BCMA) and the amino acid sequences of VH and VL domains that bind to human CD3 epsilon. There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed full-size antibody comprising at least two binding domains wherein the first binding domain comprises any VH and any VL domains and binds to any epitope located in the extracellular domain of human BCMA and a second binding domain comprises any VH and VL domains and binds to human CD3 epsilon to demonstrate possession. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005). “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69. Thus, the instant disclosure, including the claims fail to disclose a representative number of species falling with the scope of the genus or structural common to the members of the genus to enable one of ordinary skill in the art to visualize or recognize member of the genus of full-size antibodies at the time of filing.
While the specification discloses method of obtaining monoclonal antibody by immunization with BCMA (claims 46-47) and sequencing the RNA of a hybridoma, possession may not be shown by merely described how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
For these reasons, the rejection is maintained.
Claims 18, 34, 43-45, 48 and 49 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 bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises any VH and any VL domain and binds to the extracellular domain of human B cell maturation antigen (BCMA), and a second binding domain comprises any VH and any VL domain and binds to human CD3 epsilon, wherein the bispecific binding agent is a full-length antibody, wherein the full-length antibody is obtained by immunization of mice with the extracellular domain of BCMA and human CD3 epsilon, does not reasonably provide enablement for any bispecific binding agent as set forth in claims 18, 34, 43-45, 48 and 49. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (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, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 18 encompasses any bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a VH and a VL domain and binds to the extracellular domain of human B cell maturation antigen (BCMA), and a second binding domain comprises a VH and a VL domain and binds to human CD3 epsilon, wherein the bispecific binding agent is a full-size antibody.
Claim 23 encompasses the bi specific binding agent of claim 18, wherein the first binding domain is obtained from a mouse antibody or antigen binding fragment thereof.
Claim 34 encompasses a pharmaceutical composition comprising at least one bispecific binding agent of claim 18 and a pharmaceutically acceptable carrier.
Claim 43 encompasses the bispecific binding agent of claim 18, wherein the full-size length antibody is an IgG antibody.
Claim 44 encompasses the bispecific binding agent of claim 18, wherein the full-size antibody is a bivalent antibody.
Claim 45 encompasses the bispecific binding agent of claim 18, wherein the full-size length antibody is a bivalent, IgG antibody.
Claim 46 encompasses the bispecific binding agent of claim 23, wherein the mouse antibody is obtained by immunization of mice with an antigen comprising an extracellular domain of the human BCMA.
Claim 47 encompasses any bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a VH and a VL domain and binds to the extracellular domain of human B cell maturation antigen (BCMA), and a second binding domain comprises a VH and a VL domain and binds to human CD3 epsilon, wherein the bispecific binding agent is a full-size antibody, wherein said first binding domain is obtained from a mouse antibody or antigen binding fragment thereof, and wherein the mouse antibody is obtained by immunization of mice with an antigen comprising an extracellular domain of the human BCMA.
Claim 48 encompasses any bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a first means for binding the extracellular domain of human B cell maturation antigen (BCMA), and a second binding domain comprises a second means for binding human CD3 epsilon, wherein the bispecific binding agent is a full-size antibody.
Claim 49 encompasses the bispecific binding agent of claim 48, wherein the second binding domain comprises a VH and a VL domain.
Regarding antibody, the specification defines as follow:
[0023] Unless indicated otherwise, the terms "antibody" or "immunoglobulin" are used as general terms to include both the full-size antibody, the individual chains thereof, as well as all parts, domains or fragments thereof.
[0075] In the bispecific binding agent of the invention, the two binding domains may be in identical or different formats as described above, e.g. the first binding domain may be an immunoglobulin single variable domain like a V or a VH and the second one a different immunoglobulin single variable domain or a BiTE or a diabody, respectively, or vice versa, the first binding domain may be a full-size antibody and the second one an antibody fragment like a diabody or vice versa, etc.
[0083] The CDRs (complementarity determining regions) of an antibody with BCMA specificity can be obtained by N-terminal sequencing, Edman degradation and mass spectrometry of a commercially available antibody, e.g. Vicky-1 (Santa Cruz, # sc-57037) or Mab193 (R & D, #MAB193), suitable techniques have been reviewed by Steen and Mann, Nature Reviews Molecular Cell Biology, 5:699-711, 2004. Once the framework has been identified and the sequences of the CDRs are known, the encoding DNA sequence is synthesized and grafted onto a framework with similar properties as compared to the parental one by molecular cloning methods as described in Gabbard et al., Protein Engineering, Design & Selection, vol. 22, no. 3, pp. 189-198, 2009. This framework can be part of a full IgG sequence to generate a bispecific full-sized antibody, a single chain Fv fragment to generate an antibody fragment-based molecule or part of the structural region of an antibody to provide an additional specificity. All the thus obtained molecules are tested for binding to BCMA using commercially available recombinant protein representing the extracellular domain of BCMA (R & D, #193-BC-050) in an ELISA assay or by flow cytometry using a cell line e.g. NCI H929 (ATCC, # ATCC CRL-9068) expressing BCMA, both methods being well known to the person skilled in the art.
Thus, the full-size antibody includes bispecific IgG, diabody, BiTE antibody, VHH, the individual chains thereof, as well as all parts, domains or fragments thereof.
Regarding antibody molecule, the specification defines the term antibody molecule as follows:
[0024] The term "antibody molecule" (or immunoglobulin or Ig) encompasses antibodies, in particular human antibodies, antibody fragments, antibody-like molecules and conjugates (e.g. with human serum albumin or in the form of immunoconjugates, e.g. with .sup.131iodine, calicheamicin, auristatin or others) with any of the above mentioned antibody molecules. Antibodies include, but are not limited to, monoclonal, chimerized monoclonal, bi- or multispecific antibodies. The term "antibody" shall encompass complete immunoglobulins comprising two heavy chains and two light chains, e.g. fully human antibodies as they are produced by lymphocytes and for example present in blood sera, monoclonal antibodies secreted by hybridoma cell lines, polypeptides produced by recombinant expression in host cells, which have the binding specificity of immunoglobulins or monoclonal antibodies, and molecules which have been derived from such immunoglobulins, monoclonal antibodies, or polypeptides by further processing or recombinant expression while retaining their binding specificity.
Regarding antibody fragment, the specification discloses:
[0025] Antibody fragments or antibody-like molecules may contain only a portion of the constant region or lack the constant domain as long as they exhibit specific binding to the antigen. The choice of the type and length of the constant region depends, if no effector functions like complement fixation or antibody dependent cellular toxicity are desired, mainly on the desired pharmacological properties of the antibody protein. The antibody molecule will typically be a tetramer consisting of two light chain/heavy chain pairs, but may also be dimeric, i.e. consisting of a light chain/heavy chain pair, e.g. a Fab or Fv fragment, or it may be a monomeric single chain antibody (scFv). Antigen-binding antibody fragments or antibody-like molecules, including single-chain antibodies and linear antibodies, may comprise, on a single polypeptide, the variable region(s) alone or in combination with the entirety or a portion of the following: constant domain of the light chain, CH1, hinge region, CH2, and CH3 domains, e.g. a so-called "SMIP.™." ("Small Modular Immunopharmaceutical"), which is an antibody-like molecule employing a single polypeptide chain as its binding domain Fv, which is linked to single-chain hinge and effector domains devoid of the constant domain CH1 (WO 02/056910). SMIP.RTM.s can be prepared as monomers or dimers, but they do not assume the dimer-of-dimers structure of traditional antibodies. A so-called scorpion, an extension of a SMIP that has two binding specificities, is described in WO 2007/146968.
[0026] VHHs or VHs, as defined below, also fall within the category of antibody-like molecules" or "antibody fragments".
Regarding binding domain, the specification discloses:
[0027] The term "binding domain" or "or antigen-binding domain" refers to the regions within the bispecific binding agent that bind to/interact with the structure/antigen/epitope of the respective target molecule, i.e. BCMA or CD3, respectively. It can refer to the complete variable region or specifically to the complementarity determining regions (CDRs) that form the contact surface with the target molecule.
The terms “e.g.”, “i.e.” and “includes but not limited to” are not limited to antibodies specifically disclosed in the specification. The first binding domain comprise a VH and VL domains or the six CDRs of anti-BCMA antibodies are not limited to the anti-BCMA antibodies Vicky-1 from Santa Cruz, # sc-57037 or Mab 193 (R&D, #MAB 193) and the second binding domain comprising a VH and a VL domains that binds to the first twenty seven N-terminus residues of human CD3 is not limited to a monoclonal anfi-CD3 antibody OKT3 from ATCC CRL 8001) or another anti-CD3 antibody like WT32, anti-leu-4, UCHT-1, 8PY-3TA or SPV-T3B.
The specification discloses:
[0033] Covalent linking of two monoclonal antibodies is described in Anderson, Blood 80 (1992), 2826-34. In the context of this invention, one of the antibodies is specific for BCMA and the other one for CD3.By way of example, a BCMA specific antibody, e.g. Vicky-1 (Santa Cruz, # sc-57037) or Mab193 (R & D, #MAB193) is chemically linked to a monoclonal anti-CD3 antibody, e.g. OKT3 (ATCC CRL 8001) or another anti-CD3 antibody like WT32, anti-leu-4, UCHT-1, SPV-3TA or SPV-T3B.
The specification exemplifies:
[0156] Generating a Bispecific BCMA/CD3 Single Chain Binding Agent
[0157] a) Generation of Anti-BCMA and Anti-CD3 Binding Domains
[0158] The DNA fragment encoding the CD3-specific binding domain is obtained by amplification from a synthetic DNA construct encoding the VH and VL region separated by an 18 amino acid linker, as disclosed in WO 2004106383, using primers similar to the ones described there, generating a BsrGl restriction site at the VH end and a BspEl restriction site at the VL end. The DNA sequence encoding the BCMA-binding domain is obtained by amplification from VH and VL DNA molecules synthesized upon sequencing a commercially available antibody. Alternatively, cDNA constructs are used that are obtained from the VH and VL RNA from a BCMA specific hybridoma, using suitable primers generating a BspEl restriction site at the VL 5' end and a SalI restriction site at the 3' VH end.
[0159] b) Cloning of Anti-CD3.times.Anti-BCMA Constructs
[0160] Cloning is done in VH anti-CD3-VL anti CD3.times.VH anti-BCMA-VL anti-BCMA orientation. The anti-CD3 construct is cleaved with the restriction enzymes BsrGl and BspEl and subsequently cloned into the bluescript KS vector (Stratagene, La Jolla, Calif.), containing the amino acid sequence of an eukaryotic secretory signal (leader) peptide as a EcoRl/BsrGI-fragment. After cleavage with EcoRl and BspEl, the resulting DNA fragment comprising the respective anti-CD3 scFv with the leader peptide is cloned into an EcoRl/BspEl-cleaved plasmid pEFDHFR and the BCMA fragments are cloned into the BspEl/SalI-cleaved vector. Alternatively, cloning is done in the other orientation.
[0161] c) Expression and Characterization of the Bispecific Single Chain Binding Agent
[0162] After confirmation of the desired sequence by DNA sequencing, the construct obtained in b) is transfected, e.g. into dehydrofolate reductase negative CHO cells, and expressed for characterisation as described in WO 2004/106383. For example, for binding to Jurkat cells (ATCC, # TIB-152) for CD3 and NCI H929 (ATCC CRL-9068) for BCMA a flow cytometry experiment is performed. The cells are incubated with the supernatant of BCMA/CD3 bi-specific construct expressing cells for approximately 1 h at 4.degree. C., washed 2.times. in FACS buffer (phosphate-buffered saline containing 1% fetal calf serum (FCS) and 0.05% sodium azide) and bound construct is detected via the 6.times.HIS tag incorporated in the expression vector pEFDHFR using a HIS antibody e.g. (Dianova, DIA910). For the detection of bound anti-HIS antibody the cells are washed as described above and incubated with e.g. goat anti-mouse-FITC-conjugated antibody (BD 550003) or with anti-mouse-PE conjugated antibody (IgG) (Sigma, P8547) and analysed e.g. on a FACS Canto (BD). The functional activity of the constructs is then analysed using a flow cytometry based assay after the constructs have been purified by a two-step purification process including immobilized metal affinity chromatography (IMAC) and gel filtration as described in WO 2004/106383, but using a CHO cell line transfected with a DNA construct expressing full-length BCMA on the surface.
However, the specification does not teach the structure, e.g., amino acid sequences of the heavy variable (VH) and light chain variable (VL) that correlated with binding to the extracellular domain of human B cell maturation antigen (BCMA) and amino acid sequences of the VH and VL that correlated with binding to human CD3 epsilon encompassed by the genus of full-size antibody. The specification does not teach the structures common to the members of the genus of bispecific antibodies to enable one of skill in the art to make and use without undue experimentation.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (of record, Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 2003 Nov 14;334(1): 103-118), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Regarding full-size antibody that include individual chains thereof, as well as all parts, domains or fragments thereof as defined in the specification, individual chain, e.g., VH or VL or CDR does not bind to any antigen.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRS (all six CDRs) in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites.
For example, Fernández-Quintero et al (Mabs 13(1): e1923122, p. 1-7, 2021; PTO 892) teach the variable domain of heavy and light chain i.e., VH and VL which forms the antigen-binding surface is required for antigen binding, see page 3, in particular. As such, any full-size antibody comprising just heavy chain without the light chain or vice versa or just light chain CDRs without the heavy chain CDR or just heavy chain CDRs without the light chain CDRs cannot bind to the extracellular domain of human B cell maturation antigen (BCMA) and human CD3 epsilon, much less as a pharmaceutical composition for treating any cancer or autoimmune disease in a subject.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR.
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
MacCalium et al. (of record, J. Mol. Biol, 262: 732-745, 1996; PTO 892), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate a number of residues outside the standard CDR definitions make antigen contacts ( see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.).
De Pascalis el al. (of record. Journal of Immunology 169: 3076-3084, 2002; PTO 892) teach that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential .for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in ah six CDRs were used for the constructs (see page 3080, left cot.).
Vajdos et al. (of record, J. Mol. Biol. 320, 415-428, 2002; PTO 892) state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect tire CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.).
Wu et al. (of record, J. Mol. Biol. 294, 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
Finally, Dufner (of record, Trends Biotechnol. 24(11):523-529, 2006; PTO 892) teaches: “specific structural information - on the antibody to be optimized, its antigen and their interaction- is rarely available or lacks the high resolution required to determine accurately important details such as side-chain conformations, hydrogen-bonding patterns and the position of water molecules (p. 527, Col. 2, 1).
There are insufficient working examples. One skilled in the art cannot predict which combination of VH and VL of full-size antibody such as full-size IgG, bivalent antibody, or bivalent IgG antibody that binds to which epitope of the extracellular domain of human BCMA and human CD3 epsilon can be used effectively as a pharmaceutical composition, based only upon the teachings of the specification. Therefore, one skilled in the art cannot practice the invention with a reasonable expectation of success without undue experiment.
Applicant is reminded that reasonable correlation must exist between the scope of the claims and scope of enablement set forth.
In deciding In re Fisher, 166 USPQ 18, 24 (CCPA 1970), the Court indicated the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. “Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC 1997).
Thus, the overly broad scope of the claims would merely serve as an invitation to one skilled in the art to identify VH and VL that is capable of binding to a desired target, e.g., the extracellular domain of human BCMA and human CD3 epsilon, which might be used in producing the claimed bispecific binding agent; yet, defining a substance by its principal biological activity amounts to an alleged conception having no more specificity than that of a wish to know the identity of any material with that biological property. See Colbert v. Lofdahl, 21 USPQ2d 1068, 1071 (BPAI 1991). The same might be said of the bispecific binding agent which is a bispecific full-size antibody or IgG full-size or diabody, or scFv2 antibody comprising a first binding domain comprising a VH and a VL domain that binds to the extracellular domain of human B cell maturation antigen (BCMA) and a second binding domain comprising a VH and VL domain that binds to human CD3 epsilon.
Applicants’ arguments filed Oct 21, 2025 have been fully considered but are not found persuasive.
Applicants’ position is that Claim 18 is amended to recite, among other features, that the bispecific binding agent is a full-size antibody. Applicant submits that amended Claim 18 is enabled by the present Application.
In particular, the presently pending claims recite structural features of the bispecific binding agent, including a first binding domain having a VH and a VL domain and that binds the extracellular domain of human BCMA, and a second binding domain having a VH and a VL domain and that binds to human CD3 epsilon, where the bispecific binding agent is a full-size antibody. As discussed above, the present Application also discloses non-limiting examples of
antibodies to the extracellular domain of human BCMA and antibodies to human CD3 epsilon. See, e.g., Specification at 3:11-21, 10:14-15, 13:23-14:19, 26:20-22, 27:1-4. Further, the present Application discloses non-limiting options for making a bispecific binding agent, including the hybrid hybridoma technique. See, e.g., id. at 9:20-10:19, 11:10-25. At least for these reasons, Applicant submits that one of ordinary skill in the art, in view of the present Application, can make and use the claimed bispecific binding agent without undue experimentation.
The Office Action asserts that "the specification does not teach the structure, e.g., amino acid sequences of the heavy variable (VH) and light chain variable (VL) that correlated with binding to the extracellular domain of human B cell maturation antigen (BCMA) and amino acid sequences of the VH and VL that correlated with binding to human CD3 epsilon." Office Action at p. 16. However, as discussed above, the claims recite the structural features common to members of the claimed bispecific binding agent, namely, the combination of the first binding domain that binds to the extracellular domain of human BCMA and the second binding domain that binds to human CD3 epsilon. Applicants submits that in view of the present Application, one of ordinary skill in the art can make and use a bispecific binding agent as presently claimed, for example, by combining a suitable binding domain of an antibody that binds to the extracellular domain of human BCMA and another binding domain of an antibody that binds to human CD3 epsilon, without undue experimentation.
Further, as discussed during the interview (and without agreeing to the Examiner's characterization of the claims in the Interview Summary dated July 10, 2025), the presently pending claims are distinguishable from those of Amgen v. Sanofi. See Office Action at p. 18.
In view of the above, withdrawal of this rejection is respectfully requested.
In response, the amendment to claim 18 is acknowledged.
Regarding antibody, the specification defines as follow:
[0023] Unless indicated otherwise, the terms "antibody" or "immunoglobulin" are used as general terms to include both the full-size antibody, the individual chains thereof, as well as all parts, domains or fragments thereof.
Thus the antibody include both full-size, any VH or VL, any parts of domains, e.g., any one or more CDRs or any fragments thereof.
[0075] In the bispecific binding agent of the invention, the two binding domains may be in identical or different formats as described above, e.g. the first binding domain may be an immunoglobulin single variable domain like a VL or a VH and the second one a different immunoglobulin single variable domain or a BiTE or a diabody, respectively, or vice versa, the first binding domain may be a full-size antibody and the second one an antibody fragment like a diabody or vice versa, etc.
[0083] The CDRs (complementarity determining regions) of an antibody with BCMA specificity can be obtained by N-terminal sequencing, Edman degradation and mass spectrometry of a commercially available antibody, e.g. Vicky-1 (Santa Cruz, # sc-57037) or Mab193 (R & D, #MAB193), suitable techniques have been reviewed by Steen and Mann, Nature Reviews Molecular Cell Biology, 5:699-711, 2004. Once the framework has been identified and the sequences of the CDRs are known, the encoding DNA sequence is synthesized and grafted onto a framework with similar properties as compared to the parental one by molecular cloning methods as described in Gabbard et al., Protein Engineering, Design & Selection, vol. 22, no. 3, pp. 189-198, 2009. This framework can be part of a full IgG sequence to generate a bispecific full-sized antibody, a single chain Fv fragment to generate an antibody fragment-based molecule or part of the structural region of an antibody to provide an additional specificity. All the thus obtained molecules are tested for binding to BCMA using commercially available recombinant protein representing the extracellular domain of BCMA (R & D, #193-BC-050) in an ELISA assay or by flow cytometry using a cell line e.g. NCI H929 (ATCC, # ATCC CRL-9068) expressing BCMA, both methods being well known to the person skilled in the art.
The specification discloses:
[0033] Covalent linking of two monoclonal antibodies is described in Anderson, Blood 80 (1992), 2826-34. In the context of this invention, one of the antibodies is specific for BCMA and the other one for CD3.By way of example, a BCMA specific antibody, e.g. Vicky-1 (Santa Cruz, # sc-57037) or Mab193 (R & D, #MAB193) is chemically linked to a monoclonal anti-CD3 antibody, e.g. OKT3 (ATCC CRL 8001) or another anti-CD3 antibody like WT32, anti-leu-4, UCHT-1, SPV-3TA or SPV-T3B.
The specification exemplifies:
[0156] Generating a Bispecific BCMA/CD3 Single Chain Binding Agent
[0157] a) Generation of Anti-BCMA and Anti-CD3 Binding Domains
[0158] The DNA fragment encoding the CD3-specific binding domain is obtained by amplification from a synthetic DNA construct encoding the VH and VL region separated by an 18 amino acid linker, as disclosed in WO 2004106383, using primers similar to the ones described there, generating a BsrGl restriction site at the VH end and a BspEl restriction site at the VL end. The DNA sequence encoding the BCMA-binding domain is obtained by amplification from VH and VL DNA molecules synthesized upon sequencing a commercially available antibody. Alternatively, cDNA constructs are used that are obtained from the VH and VL RNA from a BCMA specific hybridoma, using suitable primers generating a BspEl restriction site at the VL 5' end and a SalI restriction site at the 3' VH end.
[0159] b) Cloning of Anti-CD3.times.Anti-BCMA Constructs
[0160] Cloning is done in VH anti-CD3-VL anti CD3.times.VH anti-BCMA-VL anti-BCMA orientation. The anti-CD3 construct is cleaved with the restriction enzymes BsrGl and BspEl and subsequently cloned into the bluescript KS vector (Stratagene, La Jolla, Calif.), containing the amino acid sequence of an eukaryotic secretory signal (leader) peptide as a EcoRl/BsrGI-fragment. After cleavage with EcoRl and BspEl, the resulting DNA fragment comprising the respective anti-CD3 scFv with the leader peptide is cloned into an EcoRl/BspEl-cleaved plasmid pEFDHFR and the BCMA fragments are cloned into the BspEl/SalI-cleaved vector. Alternatively, cloning is done in the other orientation.
[0161] c) Expression and Characterization of the Bispecific Single Chain Binding Agent
[0162] After confirmation of the desired sequence by DNA sequencing, the construct obtained in b) is transfected, e.g. into dehydrofolate reductase negative CHO cells, and expressed for characterisation as described in WO 2004/106383. For example, for binding to Jurkat cells (ATCC, # TIB-152) for CD3 and NCI H929 (ATCC CRL-9068) for BCMA a flow cytometry experiment is performed. The cells are incubated with the supernatant of BCMA/CD3 bi-specific construct expressing cells for approximately 1 h at 4.degree. C., washed 2.times. in FACS buffer (phosphate-buffered saline containing 1% fetal calf serum (FCS) and 0.05% sodium azide) and bound construct is detected via the 6.times.HIS tag incorporated in the expression vector pEFDHFR using a HIS antibody e.g. (Dianova, DIA910). For the detection of bound anti-HIS antibody the cells are washed as described above and incubated with e.g. goat anti-mouse-FITC-conjugated antibody (BD 550003) or with anti-mouse-PE conjugated antibody (IgG) (Sigma, P8547) and analysed e.g. on a FACS Canto (BD). The functional activity of the constructs is then analysed using a flow cytometry based assay after the constructs have been purified by a two-step purification process including immobilized metal affinity chromatography (IMAC) and gel filtration as described in WO 2004/106383, but using a CHO cell line transfected with a DNA construct expressing full-length BCMA on the surface.
However, the specification does not teach the structure, e.g., amino acid sequences of the heavy variable (VH) and light chain variable (VL) domains that correlated with binding to the extracellular domain of human B cell maturation antigen (BCMA) and amino acid sequences of the VH and VL that correlated with binding to human CD3 epsilon encompassed by the genus of antibody, e.g., full-size, any VH or VL, any parts of domains, e.g., any one or more CDRs, any fragments (claims 18, 34, 43-45, 48-49) or any full-size equivalents thereof (claims 48-49) other than the Bispecific Single Chain antibody (scFv), diabody, IgG bivalent antibody. The specification does not teach the structures, VH and VL common to the members of the genus to enable one of skill in the art to make and use without undue experimentation.
Regarding pharmaceutical composition (claim 34), there are insufficient in vivo working examples. It is unpredictable which undisclosed bispecific full-size antibody, any VH or VL, any parts of domains, e.g., any one or more CDRs or any fragments thereof correlated with binding to the extracellular domain of human B cell maturation antigen (BCMA) and human CD3 epsilon, effective as a pharmaceutical composition (claim 34) for treating any and all diseases.
Even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
MacCalium et al. (of record, J. Mol. Biol, 262: 732-745, 1996; PTO 892), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate a number of residues outside the standard CDR definitions make antigen contacts ( see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.).
De Pascalis el al. (of record. Journal of Immunology 169: 3076-3084, 2002; PTO 892) teach that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential .for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in ah six CDRs were used for the constructs (see page 3080, left cot.).
Vajdos et al. (of record, J. Mol. Biol. 320, 415-428, 2002; PTO 892) state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect tire CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.).
Wu et al. (of record, J. Mol. Biol. 294, 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
Finally, Dufner (of record, Trends Biotechnol. 24(11):523-529, 2006; PTO 892) teaches: “specific structural information - on the antibody to be optimized, its antigen and their interaction- is rarely available or lacks the high resolution required to determine accurately important details such as side-chain conformations, hydrogen-bonding patterns and the position of water molecules (p. 527, Col. 2, 1).
In response to the argument that the pending claims are distinguishable from those of Amgen v. Sanofi (Office Action at p. 18) by combining a suitable binding domain of an antibody that binds to the extracellular domain of human BCMA and another binding domain of an antibody that binds to human CD3 epsilon, the pending claims encompass any full-size IgG antibody, the individual chains thereof, as well as all parts, domains or fragments thereof that bind to linear or conformational epitopes of the extracellular domain of human BCMA and human CD3 epsilon. The claims do not the full-size antibody that binds to linear epitope of extracellular domain of human BCMA and human CD3 epsilon.
Enablement is not commensurate with how to make and use any full-size antibody comprising a first domain comprising any VH and/or VL that binds to the extracellular domain of human BCMA and another binding domain comprising any VH and/or VL that binds to human CD3 epsilon still maintains binding to the linear or conformational epitope of the extracellular domain of human BCMA and human CD3 epsilon.
For example, Fernández-Quintero et al (Mabs 13(1): e1923122, p. 1-7, 2021; PTO 892) teach the variable domain of heavy and light chain i.e., VH and VL which forms the antigen-binding surface is required for antigen binding, see page 3, in particular. As such, any fragment thereof comprising just heavy chain without the light chain or vice versa or just light chain CDRs without the heavy chain CDR or just one CDR from heavy chain without the light chain CDRs cannot bind to the extracellular domain of human BCMA and CD3 epsilon, much less for use as a pharmaceutical composition for treating any disease in a subject.
For these reasons, the rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 18, 23, 34 and 43-48 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over WO2009132058 (of record, Dillons hereafter, published Oct 29, 2009; PTO 892) in view of Kindsvogel (WO02066516 publication, newly cited, published August 29, 2002; PTO 892), Koenig et al (US20080095766, published April 24, 2008; PTO 892) and Chames et al (British Journal of Pharmacology 157: 220-233, 2009; PTO 892).
Claim interpretation:
The bispecific binding agent is a full-size antibody comprising at least two binding domains, wherein a first binding domain comprises a VH and a VL domain and binds to the extracellular domain of human B cell maturation antigen (BCMA), and a second binding domain comprises a VH and a VL domain and binds to human CD3 epsilon. The term “full-size” antibody includes IgG bispecific antibody but not limited to covalently linking two monoclonal antibodies or by conventional hybrid-hybridoma techniques.
Regarding claims 18, 44, 48-49, Dillons teaches bispecific antibody having one binding arm that binds to the extracellular domain (EDC) of human BCMA as per claim 18 (see p. 9, lines 17-20, p. 25, lines 9-10, p. 36, p. 38, last line) and the other arm that bind to a triggering molecule on T-cell, e.g., CD3, see p. 26, l. 33 to p27, line 1. Dillons further teaches that the bispecific antibodies can be prepared as full-length antibodies, see p. 27, line 7, in particular. Methods for making bispecific antibodies are known in the art. In one approach, the bispecific antibodies are composed of the bispecific antibodies are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. The preferred interface comprises at least a part of the CH3 domain of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e. g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain (s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e. g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers. Alternatively, the bispecific antibody comprises the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites such as the one described by Hollinger et al, by Hollinger et al, Proc. Natl. Acad. Sci. USA, 90: 6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments, see p. 29, lines 20, in particular.
The bispecific antibodies are composed of a hybrid immunoglobulin heavy chain (VH) and a light chain (VL) with a first binding specificity in one arm, e.g., BCMA, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm, e.g., CD3 on T cell, see para. bridging p. 27 and 28, p. 26, line 33 to 27, line 1. To facilitate pairing of the two heavy chains heterodimer, the interface (CH3 domain) in one of the heavy chains comprises a cavity (one or more small amino acid side chains are replaced with a larger side chains such as tyrosine or tryptophan ( and the other heavy chain comprises a knob by replacing large amino acids with small ones (e.g., alanine or threonine) for increasing the yield of the heterodimer IgG bispecific antibody over the other unwanted end-products such as homodimers, see p. 28. Dillons also teaches BCMA is presented on the surface of B cell and elevated BCMA levels on B cells is associated with various autoimmune diseases, including systemic lupus erythematosus (SLE), see abstract, p.5, p. 45, in particular. Dillons also teaches that bispecific antibodies can include cross-linked antibodies using crosslinking agents known in the art, see p. 28, lines 19-29. The bispecific antibodies may be used to localize CD3 expressing leukocyte to BCMA expressing cells, see p. 27. The specific antibodies are useful for treating autoimmune disease such as systemic lupus erythematosus (SLE), see abstract, p.3-4, in particular.
Regarding claims 23, 46, 47, Dillions teaches the BCMA antibody is monoclonal antibodies produced by conventional method of immunizing a mouse and hybridoma technology according to Harlow, see p. 14-25, p. 37, line 33 to p. 38, line 6-8.
Regarding claim 34, Dillions teaches pharmaceutical formulations having the reference antibodies and acceptable carrier, such as phosphate or citrate buffer, see p. 40, lines 1-9.
Regarding claims 43 and 45, Dillions teaches that the full-size Ig antibody comprises Fc (aka IgG) capable of binding to one or more FcγRI, FcγRII, and FcγRIII for mediated antibody-dependent cell-mediated cytotoxicity (ADCC), see p. 15, in particular.
Claim 44 is included as Dillions’ full-size antibody comprises two antigen-binding sites, which is bivalent as evidenced by Arathoon and known in the art, see Fig. 1C.
Dillon does not teach bispecific binding agent comprising a first binding domain and a second domain, wherein the first binding domain comprises a VH and a VL domain that binds to the extracellular domain of human B cell maturation antigen (BCMA) and the second binding domain comprises a VH and a VL domain that binds to human CD3 epsilon as per claim 18. However, Kindsvogel teaches binding domain, e.g., murine monoclonal antibody, can be a whole antibody or an antibody fragment, e.g., scFv comprising a VH and VL that binds to the extracellular domain of human B cell maturation antigen (BCMA), see p. 4, line 17-22, p. 13, line 36 to p. 14, line 9, in particular. Kindsvogel further teaches multispecific antibody comprises antibody components that have binding sites for two different antigens, see p. 14. lines 24-28. For example, monoclonal or polyclonal antibodies can be produced using at least one polypeptide comprising a cysteine-rich region of either BCMA or TACI, or an immunogenic fragment thereof, see p. 15, line 28-33, p. 17, in particular. The antibodies bind to the extracellular domain of a receptor, e.g., human BCMA comprising the amino acid sequence of SEQ ID NO: 2, see p. 3, lines 12-15, p. 13, lines 6-7, reference claim 15(a). The epitopes can be a contiguous sequence (linear determinants” or conformational, see p. 13, line 24-30. Kindsvogel further teaches that that antibodies are typically raised in animals such as mice by immunization with BCMA by methods known to those skilled in the art, see p. 23-24, in particular. Kindsvogel teaches production of antibody fragments of anti-BCMA by enzymatic cleavage of antibodies with pepsin to produce F(ab’)2 or pepsin to produced Fab fragment, see p. 25. For scFv antibody, Fv fragment, the VH and VL chains are connected by a peptide linker, see p. 25, lines 29 to p. 26. Kindsvogel teaches bispecific antibodies can be made by a variety of conventional methods. For example, Fab’ fragment from different antibodies can be crosslinked, see p. 27-28. Alternatively, bispecific antibodies can be produced by fusing two hybridoma cell lines, one cell line that produces anti-BCMA monoclonal antibody, and one cell line that produces anti-TACI monoclonal antibody. Bispecific molecule of the invention can also be a single chain bispecific molecule, such as a single chain bispecific antibody, a single chain bispecific molecule comprising one single chain antibody and a binding determinant, or a single chain bispecific molecule comprising two binding determinants. The anti-BCMA antibody can be used to treat B-cell malignancy , e.g., multiple myeloma (see p. 39, Examples 2, 4) or autoimmune disease, see p. 42, in particular.
Koenig teaches full-length IgG (aka full-size, para. [0355]) humanized OKT3 antibody that binds to epsilon subunit within the human CD3 complex for treating autoimmune disease wherein the antibody comprising a VH domain having the amino acid sequence of the VH domain of a humanized OKT3, for example, SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9 (FIG. 1B) and a VL domain having the amino acid sequence of the VL domain of a humanized OKT3, for example, SEQ ID NO: 3 or SEQ ID NO:4 (FIG. 1A) and Fc domains that do not bind or have significantly reduced binding to Fc receptors, see entire document, abstract, [0129], [0137], [0180], in particular. Koenig teaches bispecific antibody that bind to CD3 and a heterologous epitope such as a heterologous polypeptide, see para. [0125]. Koenig teaches that the antibody comprising a variant Fc region that that may confer null binding to Fc.gamma.RIIIA, Fc.gamma.RIIIB, and Fc.gamma.RIIA, see para. [0167]. This eliminates symptoms or side effect associated with anti-CD3 epsilon administration, see para. [0183], [0195].
Chames teaches IgG monoclonal antibodies or bsAb (quadroma) are large (about 150 kDa), see p. 223, left col., Table 2, Figure 2, in particular. The large size of mAbs and the presence of the Fc region can be advantageous in terms of pharmacokinetics, such as long serum half-life, see p. 227, left column, lines 1-2, in particular.
In view of the combined teachings of Dillons, Kindsvogel, Koenig and Chames, it would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made to have made a full-size bispecific IgG antibody using Dillons’ or Kindsvogel’s method by fusing two hybridoma cell lines, one cell line that produces anti-BCMA monoclonal antibody comprising a VH and a VL domain that binds to human BCMA of Kindsvogel, and one cell line that produces monoclonal antibody that binds to human CD3 epsilon wherein the antibody comprising a VH and a VL domain of Koenig to arrive at the claimed full-size IgG bispecific bivalent (two binding sites) antibody (bsAb quadroma) that binds to human BCMA and human CD3ε with a reasonable expectation success, e.g., longer serum half-life as taught by Chames for treating various cancers, e.g., Hodgkin’s lymphoma, Burkitt’s lymphoma, B cell lymphoma, multiple myeloma ( see para. [007]) or autoimmune disease as taught by Kindsvogel and/or Koenig.
The person of ordinary skill in the art would have found it obvious to make a full-size IgG bispecific antibody because Dillons teaches that bispecific antibody binding to ECD of human BCMA and CD3ε is useful for treating various autoimmune diseases by targeting CD3 expressing T cells (leukocytes) to BCMA expressing B cells for depleting BCMA expressing B cells.
The person of ordinary skill in the art would have found it obvious to make a full-size IgG bispecific antibody because Koenig teaches that the antibody comprising modified Fc region may confer null binding to Fc.gamma.RIIIA, Fc.gamma.RIIIB, and Fc.gamma.RIIA and eliminate symptoms or side effect associated with cytokine storms, see para. [0183], [0195].
One of ordinary skill in the art would have been motivated to and had a reasonable expectation of success at the time the invention was made to have made a full-size bispecific IgG antibody that binds to human BCMA and human CD3ε because Dillons teaches that the bispecific antibodies can be prepared as full-length antibodies, see p. 27, line 7, in particular.
One of ordinary skill in the art would have been motivated to and had a reasonable expectation of success at the time the invention was made to have made a full-size bispecific IgG antibody that binds to human BCMA and human CD3ε because Kindsvogel teaches that bispecific antibodies can be made by a variety of conventional methods, including by fusing two hybridoma cell lines or crosslinking two Fab’ fragment from different antibodies, see p. 27-28.
The person of ordinary skill in the art would have found it obvious to make a full-size IgG bispecific antibody (bsAb quadroma) because Chames teaches that the large-size of antibody (approximately 150 kDa) having Fc domain is expected to improve stability, longer half-life and better pharmacokinetics, see p. 227, left column, lines 1-2, in particular.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdiqital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641