Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 3, 2026 has been entered.
Claims 18, 23, 34 and 43-49 are pending.
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 statements (IDS) submitted on April 7, 2026, April 3, 2026 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Rejection Withdrawn
The rejection of claims 48-49 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first paragraph, because the claim purports to invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph is withdrawn in view of the claim amendment and the argument at p. 4-6.
The enablement rejection of claims 18, 34, 43-45, 48 and 49 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of the claim amendment.
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 43-49 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 a bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that 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 second antigen-binding VH/VL pair that 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 bispecific binding agent of claim 18, wherein said 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 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 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 a bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that 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 second antigen-binding VH/VL pair that 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 a 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 an antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that binds to human CD3 epsilon.
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.
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 specification discloses 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.
Regarding number of species of full-size antibody comprises a first antigen-binding heavy chain variable domain (VH/light chain variable domain (VL) pair that binds to the extracellular domain of human B cell maturation antigen (BCMA) and a second binding domain comprises a second antigen-binding VH/VL pair that binds to human CD3 epsilon, the specification does not disclose a representative number of species falling within the scope of the genus nor provides a common structure-function relationship sufficient to enable a person of ordinary skill in the art to ‘visualize or recognize’ the members of the genus 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 et 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.
For each claim drawn to a genus, 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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus, See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406, MPEP 2163 II. A. 3 ii.
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.
In this case, the disclosure of just two BCMA specific antibodies Vicky-1 and Mabl93. See, e.g., Specification at 9:15-16. (". . . a BCMA specific antibody, e.g. Vicky- 1 (Santa Cruz, # sc-57037) or Mabl93 (R&D, #MAB 193) .. ."). See, e.g., Specification at 27:1-5 is not representative of the genus of first binding domain comprises any heavy chain variable domain (VH) light chain variable domain (VL) pairs that bind to the extracellular domain of human BCMA encompassed by the claimed full-size bispecific antibody.
Likewise, the disclosure of three monoclonal anti-CD3 antibody UCHT-1, OKT3 and TR-66. See, e.g., id. at 28:20-24 that recognizes human CD3 epsilon is not representative of the genus of second binding domain comprises any second antigen-binding VH/VL pair that binds to human CD3 epsilon encompassed by the claimed full-size bispecific antibody. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
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)).
Therefore, it appears that the instant specification does not adequately disclose the breadth of the bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a first antigen-binding heavy chain variable domain (VH) and light chain variable domain (VL) pair that bind to the extracellular domain of human BCMA and a second antigen-binding heavy chain variable domain (VH) and light chain variable domain (VL) pair that bind to 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 the extracellular domain of human BCMA and human CD3 epsilon at the time the instant application was filed.
Applicants’ arguments filed April 3, 2026 have been fully considered but are not found persuasive.
Applicant respectfully disagrees with the Examiner's assertions. However, solely to expedite examination, Claim 18 is amended herein to recite among other features that a first binding domain comprises a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that binds to the extracellular domain of human B cell maturation antigen (BCMA), and a second binding domain comprises a second antigen-binding VH/VL pair that binds to human CD3 epsilon. Applicant submits that one of ordinary skill in the art can reasonably conclude based on the present Application that Applicant had possession of the subject matter of Claim 18 as amended at the time of filing.
As discussed previously, 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 and that is a full-size antibody. See, e.g., Specification at 6:27-29, 9:6-9, 24:12-17, 27:5-10. Further, the present Application discloses non-limiting examples of antibodies that bind to the extracellular domain of BCMA or CD3 epsilon, and their corresponding VH and VL pairs that bind to the respective targets. See, e.g., id. at 10:9-15, 21:3-9, 25:13-14, 27:1-4, 3:11-21, 13:23- 14:19, 26:9-22. 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 M.P.E.P. #2163 II.A.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)). Further, at least the antibodies to human CD3 epsilon bind to different regions of CD3 epsilon. See '567 publication at 24:25-25:4, 26:9-22. The diversity in the regions to which the known antibodies bind reflects the diversity of the antibodies to human CD3 epsilon.
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. Claim 47 is amended in a similar manner, taking into account any differences in the recited features. Claim 47 as amended is adequately supported by the present Application to satisfy the written description requirement at least for reasons discussed above.
The Examiner asserts that "the full-size antibody includes bispecific IgG, diabody, BiTE antibody, the individual chains thereof, e.g., VH or VL as well as all part, domains or fragments thereof," and that the claims encompass "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 C3 epsilon." Office Action at p. 21.
However, the present Application distinguishes "full-size antibody" from non-full-size arrangements, such as one based on an antibody fragment or domains, a single chain Fv fragment, or a diabody.
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. Specification at 6:27-29 (emphases added).
Thus, the Application discloses that "full-size antibody" denotes a subset of the broader "antibody" or "immunoglobulin" genus.
Further, the Application discloses that "full-size antibody" refers to a specific example of "antibody" or "immunoglobulin," and that "the individual chains [of the full-size antibody]," or "parts, domains, or fragments [of the full-size antibody]" represent only a portion of the full-size antibody. In addition, the present Application discloses examples of structural features that may distinguish a full-size antibody from an antibody fragment-based molecule.
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. Specification at 27:9-12 (emphases added).
Moreover, the currently pending claims recite that the first binding domain includes a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that binds to the extracellular domain of human BCMA, and not a combination of "any VH" and "any VL" that binds to the extracellular domain of human BCMA as asserted by the Examiner. Office Action at p. 11.
Likewise, the currently pending claim recites that the second binding domain includes a second antigen-binding VH/VL pair that binds to human CD3 epsilon, and not a combination of "any VH and VL domain that binds to human CD3 epsilon" as asserted by the Examiner. Id.
Thus, the full-size antibody as recited does not encompass "all antibodies" contrary to the Examiner's assertions, and the first and second binding domains each include the paired combination of VH and VL that binds to the respectively recited targets or fragments [of the full-size antibody]" represent only a portion of the full-size antibody. In addition, the present Application discloses examples of structural features that may distinguish a full-size antibody from an antibody fragment-based molecule.
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. Specification at 27:9-12 (emphases added).
Moreover, the currently pending claims recite that the first binding domain includes a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that binds to the extracellular domain of human BCMA, and not a combination of "any VH" and "any VL" that binds to the extracellular domain of human BCMA as asserted by the Examiner. Office Action at p. 11. Likewise, the currently pending claim recites that the second binding domain includes a second antigen-binding VH/VL pair that binds to human CD3 epsilon, and not a combination of "any VH and VL domain that binds to human CD3 epsilon" as asserted by the Examiner. Id.
Thus, the full-size antibody as recited does not encompass "all antibodies" contrary to the Examiner's assertions, and the first and second binding domains each include the paired combination of VH and VL that binds to the respectively recited targets.
The Examiner analogizes this case to Juno Therapeutics, Inc. v. Kita Pharma., Inc., 10 F.4th 1330 (Fed. Cir. 2021), and asserts that "[i]n 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 that binds to the extracellular domain of human B cell maturation antigen (BCMA) and a VH and a VL domain that that binds to human C3 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 [sic] of bispecific binding agents at the time of filing." Specification at p. 24. However, Juno is distinguishable from the present case for at least the following reasons.
First, the single-chain antibody variable fragments (scFvs) at issue in Juno were part of a chimeric antigen receptor ("CAR") construct, which was a nascent technology involving a new combination of peptide domains. The '190 patent relates to a nucleic acid polymer encoding a three-part CAR for a T cell. It claims priority to a provisional application filed May 28, 2002, a time period that one of the inventors labeled as "the birth of the CART field." Juno, 10 F.4th at 1333 (emphasis added). The court further consistently noted the lack of compliance with the written description requirement for the claims at issue in Juno in the context of a CAR.
Substantial evidence does not support the jury's finding that the '190 patent disclosed sufficient information to show the inventors possessed the claimed genus of functional CD19-specific scFvs as part of their claimed CAR. Id. at 1340 (emphasis added); see also id. at 1338 ("To satisfy written description, however, the inventors needed to convey that they possessed the claimed invention, which encompasses all scFvs, known and unknown, as part of the claimed CAR that bind to a selected target." (emphasis added)).
In contrast, the presently claimed bispecific binding agent relates to a combination of two binding domains, such as that in a bispecific antibody. Applicant submits that bispecific antibodies were well-known in the field at the time of filing of the present Application. For example, Dillon and Kindsvogel (cited by the Office Action) disclose bispecific antibodies. See Dillon at 26:30- 31; Kindsvogel at 27:32-28:6; see Office Action at pp. 42, 44. Applicant submits that Juno is inapposite at least where bispecific binding agents such as bispecific antibodies were known in the art.
Second, Juno is distinguishable from the present case at least because the present Application discloses numerous examples of the first and second binding domains. As discussed above, the present Application discloses non-limiting examples of the first binding domain that binds to the extracellular domain of BCMA, including Vicky-1, Mabl93, and Ryan's antagonistic BCMA-specific antibody. Further, the present Application discloses non-limiting examples of the second binding domain that binds to human CD3 epsilon, including CD3-binding molecules in the '567 publication, UCHT-1, OKT3, and TR-66. In contrast, the patent in Juno was found to disclose only a single scFv specific for the recited target, CD19. See Juno, 10 F.4* at 1340.
Thus, given that antibodies to the extracellular domain of human BCMA and antibodies to human CD3 epsilon were each already individually known, and that bispecific antibodies were a well-known technology, the disclosure of specific examples of binding domains having the recited features 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.
Claim 18 encompasses a bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that 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 second antigen-binding VH/VL pair that 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 bispecific binding agent of claim 18, wherein said 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 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 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 a bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that 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 second antigen-binding VH/VL pair that 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 a 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 an antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that binds to human CD3 epsilon.
The specification discloses:
EXAMPLE
[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 WO2004106383, 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 describe the structure, e.g., amino acid sequence of the first antigen-binding heavy chain variable domain (VH) and light chain variable domain (VL) pair that binds to the extracellular domain of human B cell maturation antigen (BCMA) and the structure, e.g., amino acid sequence of the first antigen-binding heavy chain variable domain (VH) and light chain variable domain (VL) pair that binds to human CD3 epsilon encompassed by the claimed genus of bispecific binding agent is a full-size antibody. There is not no objective evidence of any bispecific full-size IgG antibody (claim 43), bispecific full-size bivalent IgG antibody (claim 45) that binds to the extracellular domain of human B cell maturation antigen (BCMA) and the structure, e.g., amino acid sequence of the first antigen-binding heavy chain variable domain (VH) and light chain variable domain (VL) pair that binds to human CD3 epsilon.
Contrary to applicant’s assertion that the present Application discloses non-limiting examples of the first binding domain that binds to the extracellular domain of BCMA, including Vicky-1, Mabl93, and Ryan's antagonistic BCMA-specific antibody and non-limiting examples of the second binding domain that binds to human CD3 epsilon, including CD3-binding molecules in the '567 publication, UCHT-1, OKT3, and TR-66, the specification does not describe the structure, e.g., amino acid sequence of the first antigen-binding heavy chain variable domain (VH) and light chain variable domain (VL) pair that binds to the extracellular domain of human B cell maturation antigen (BCMA) and the structure, e.g., amino acid sequence of the first antigen-binding heavy chain variable domain (VH) and light chain variable domain (VL) pair that binds to human CD3 epsilon encompassed by the claimed genus of bispecific binding agent is a full-size antibody.
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 et 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 a first binding domain comprising a VH and VL pair that bind to the extracellular domain of human BCMA and a second antigen-binding VH and VL pair that binds to 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.
While the specification identified two commercially available antibodies that may be used to form the first binding domain that binds to the extracellular domain of human BCMA, such as Vicky-1 (Santa Cruz cat. No. 57037) and Mab193 (R&D cat. No. MAB193), and three antibodies that may be used to form the second binding domain that binds to human CD3 epsilon such as UCHT-1, OKT3, or TR-66, six combinations (2 x 3) are not representative of the genus. These species fails to convey evidence of possession of the entire genus. The specification does not describe the structure, e.g., amino acid sequence of VH and VL common to members of the genus that correlated with binding to extracellular domain of human BCMA and human CD3 epsilon. Thus, 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.
While the specification discloses:
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, e.g. as described in Harlow and Lane (Antibodies, A Laboratory Manual (1988), Cold Spring Harbor). The anti-CD3 antibody sequences can be derived from published sequences, e.g. as disclosed in U.S. Pat. No. 7,381,803 or in WO 2008/119567.
However, 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.
In response to the argument that the single-chain antibody variable fragments (scFvs) at issue in Juno were part of a chimeric antigen receptor ("CAR") construct, which was a nascent technology involving a new combination of peptide domains, analogous to Juno, instant specification provides no details about which VH and VL in the VH(BCMA)-VL(BCMA)-VH(CD3)-VL(CD3), VH(CD3)-VL(CD3)-VH(BCMA)-VL(BCMA) or VH CD3)-VL(CD3)-VL(BCMA)-VH(BCMA) in the scFvs that bind to the extracellular domain of BCMA and which VH and VL in the scFvs that bind to human CD3 epsilon in a way that distinguishes them from scFvs that do not bind to the extracellular domain of BCMA and which VH and VL in the scFvs that bind to human CD3 epsilon. Applicant’s disclosure does not support the claimed genus of bispecific scFvs that binds to the extracellular domain of human BCMA and human CD3 epsilon as part of the claimed bispecific binding agent wherein the bispecific binding agent is a full size antibody or wherein the full size antibody is IgG antibody (claim 43) or bivalent IgG antibody (claim 45).
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.
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 Kalled et al (newly cited, published September 16, 2010; PTO 892), Chevrier et al (newly cited, US20090148462, published June 11, 2009; PTO 892), Koenig et al (of record, US20080095766, published April 24, 2008; PTO 892) and Chames et al (of record, 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.
Claim 18 encompasses a bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that 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 second antigen-binding VH/VL pair that 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 (claim 23) or wherein the full-size antibody is an IgG antibody (claim 43) or wherein the full-size antibody is a bivalent antibody (claim 44) or wherein the full-size antibody is a bivalent, IgG antibody (claim 45)
Claim 34 encompasses a pharmaceutical composition comprising at least one bispecific binding agent of claim 18 and a pharmaceutically acceptable carrier.
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 a bispecific binding agent comprising at least two binding domains, wherein a first binding domain comprises a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that 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 second antigen-binding VH/VL pair that 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 a 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 an antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that binds to human CD3 epsilon.
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. For example, traditional production of full length bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain- light chain pairs, where the two chains have different specificities. A different approach, antibody variable domains with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region(CH1) containing the site necessary for light chain binding, present in at least one of the fusions. DNAs-encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. This provides for great flexibility in adjusting the mutual proportions of the three polypeptide fragments in embodiments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yields. In a preferred embodiment of this approach, 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. It was found that this asymmetric structure facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, as the presence of an immunoglobulin light chain in only one half of the bispecific molecule provides for a facile way of separation. The interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. 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. In another approach, 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. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (scFv) dimers has also been reported 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 teaches that high levels of BCMA on B cells of patients exhibiting autoimmune activity, such as those diagnosed with SLE, see entire document, abstract, in particular. Bispecific antibodies having one arm specific for BCMA on B cell and the other arm specific for CD3 may redirect T cells to B cell to treat various autoimmune disease.
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, Kalled teaches various antibodies, e.g., A7D12.2, C11D5.3, C12A3.2, C13F12.1 that bind to extracellular domain (see para. [038]) of human B cell maturation antigen (BCMA, also known as TNFRSF17 and CD269), see entire document, p. 2, in particular. The VH and VL pairs are shown in Table 3 at p. 15, Table 1, at p. 6. Examples of anti-BCMA mAbs, include clone C4E2.2, clone VICKY-1, 6D10, and clone 335004, see p. 7, para. [016]. Kalled teaches that the antibodies or antigen binding fragment may be used to treat B cell-related disorders, include autoimmune diseases, e.g., SLE, or B cell lymphoma, cancer in which cancer cells express BCMA, e.g., lymphomatoid granulomatosis, see p. 19, para. [046], [047].
Chevrier teaches neutrokine-alpha receptor BCMA, also known as TR18, is a protein of 184 amino acid residues (SEQ ID NO: 8), the extracellular domain comprising amino acids 1 to 51 of SEQ ID NO: 8), see para. [0231] to [0232], [0234]. Chevrier teaches anti-BCMA antibodies, including multispecific antibodies, see para. [0259], [0261]. Chevrier teaches BCMA antibodies may act as agonists or antagonists of the BCMA polypeptides, see para. [0264]. Receptor-specific BCMA antibodies which both prevent ligand binding and receptor activation as well as BCMA antibodies that recognize the receptor-ligand complex, and, preferably, do not specifically recognize the unbound receptor or the unbound ligand may be used in the methods of the invention, see para. [0265]. Chevrier teaches that there is widespread belief in the scientific community that antagonists of Neutrokine-alpha have therapeutic potential in the treatment of autoimmune diseases, including but not limited to Systemic lupus erythematosus (SLE or "lupus"), see para. [0005] to [0006]. The anti-Neutrokine-alpha antibody, e.g., anti-BCMA antibody works by reducing B cell numbers and/or B cell activity, see para. [0029] to [0030].
Like Dillon, Kalled and Chevrier do not teach the second binding domain comprises a VH and a VL domain that binds to human CD3 epsilon as per claim 18.
However, 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 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 CD3ε 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, Kalled, Chevrier, 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 comprising two binding domains using Kalled’s or Chevrier’s VH and VL pair as the first binding domain that binds to the extracellular domain of human BCMA and Koenig’s binding domain comprises a VH and VL pair as the second binding domain that binds to the human CD3 epsilon in any of the methods of Dillon or Chevrier to arrive at the claimed full-size IgG bispecific bivalent (two binding sites) antibody that binds to ECD of human BCMA and human CD3ε with a reasonable expectation success, e.g., longer serum half-life as taught by Chames for treating various diseases such as cancers, e.g., Hodgkin’s lymphoma, Burkitt’s lymphoma, B cell lymphoma, multiple myeloma ( see para. [007]) or autoimmune disease as taught by Dillon, Kalled and Koenig.
The person of ordinary skill in the art would have found it obvious to make a bispecific antibody because Dillons teaches that bispecific antibody binding to ECD of human BCMA and CD3 is useful for treating various autoimmune diseases, e.g., SLE by targeting CD3 expressing T cells (leukocytes) to BCMA expressing B cells for depleting BCMA expressing B cells and Chevrier teaches that anti-BCMA antibody works by reducing B cell numbers and/or B cell activity for treating various autoimmune diseases, see para. [0010], [0029] to [0030].
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 do so because Kalled teaches that the human BCMA specific antibody or antigen binding fragment thereof may be used to treat B cell-related disorders, include autoimmune diseases, e.g., SLE, or B cell lymphoma, cancer in which cancer cells express BCMA, e.g., lymphomatoid granulomatosis (see p. 19, para. [046], [047]).
One of ordinary skill in the art would have been motivated to do so because Chevrier teaches that Receptor-specific BCMA antibodies which both prevent ligand binding and receptor activation as well as BCMA antibodies that recognize the receptor-ligand complex and Koenig teaches full-length IgG (aka full-size, para. [0355]), humanized OKT3 antibody that binds to epsilon subunit within the human CD3 complex to redirect CD3 expressing T cells to cells expressing BCMA for treating autoimmune diseases by reducing B cell numbers and/or B cell activity as taught by Chevrier, see para. [0029] to [0030].
One of ordinary skill in the art would have 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 ECD of human BCMA and human CD3ε because Dallon 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 or single chain by linking VH and VL from different antibodies together, 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 IgG 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. Interdigital 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.
Applicants’ arguments filed April 3, 2026 have been fully considered but are not found persuasive.
Applicant’s position is that the cited references do not support the Examiner's motivation to modify the references to arrive at the claimed bispecific binding agent having binding domains that bind to the extracellular domain of human BCMA and human CD3 epsilon.
In the absence of an expectation by one of ordinary skill in the art that the proposed prior art combination would meet the asserted goal for making the modification, there is no motivation for the proposed combination. See Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1368-69 (Fed. Cir. 2016) (holding that the references "support a conclusion that the claimed efficiency that allegedly motivated the combination would not be achieved and that a person of ordinary skill in this field would not have been motivated to use the [proposed modification].").
First, as discussed previously, Dillon does not disclose any bispecific antibody having the combination of binding specificity to BCMA and to CD3. See Dillon at 26:33-27:4 ("... an anti- B cell marker binding arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e. g. CD2 or CD3), . . . so as to focus cellular defense mechanisms to the B cell.") However, Dillon does not identify any "anti-B cell marker," let alone BCMA, for use in a bispecific context.
Second, one of ordinary skill in the art would not have been motivated to select BCMA as the target of the anti-B cell marker binding arm because the cited references do not provide a reasonable expectation of success in focusing cellular defense mechanisms to B-cells by doing so. See Intelligent Bio-Systems at 1368-69 (holding that in the absence of a reasonable expectation of success for the proposed modification, there is no motivation to make the modification the Examiner is proposing).
Specifically, it was known that a BCMA isoform that is secreted as a soluble receptor inhibits BAFF signaling in mature B-cells. See Maia et al. (PLOS ONE 6(6): e20787) (of record) at p. 8, right col. Because the BCMA isoform inhibits BAFF signaling, one of ordinary skill in the art would reasonably conclude that the soluble receptor includes the extracellular domain of BCMA, and therefore would also bind to a binding domain that binds to the extracellular domain of human BCMA. Further, because BCMA lacks a signal peptide, one would have reasonably concluded that the secreted BCMA isoform is generated from membrane-bound BCMA. See Bossen et al. (Semin Immunol 2006 Oct;18(5):263-75) (of record) at Introduction. Thus, Applicant submits that one of ordinary skill in the art would not have had a motivation to select BCMA because the cited references do not provide a reasonable expectation that using BCMA as the anti-B cell marker, to which the binding arm of Dillon's bispecific antibody binds, would be effective for focusing cellular defense mechanisms to B-cells when the secreted BCMA isoform may interfere with binding of the bispecific antibody to B-cells.
Kindsvogel is cited for allegedly disclosing VH and VL domains that bind to the extracellular domain of human BCMA. See Office Action at p. 44. Kindsvogel discloses antibodies that bind to TACI or to BCMA, and further discloses a "dual reactive antibody" that recognizes both BCMA and TAC. See Kindsvogel at 15:27-16:7, 23:28-29. Kindsvogel's dual reactive antibody is an antibody raised against a cysteine-rich region of either BCMA or TACI. See id. at 15:27-16:7 ("One of skill in the art can produce various anti-BCMA-TACI, 'dual reactive,' antibodies with the information provided herein. 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. . . . However, to be considered as an 'anti-BCMA-TACI antibody,' an antibody produced from such polypeptides must be able to bind both BCMA and TACI." (emphases added)). While Kindsvogel tested various combinations of antibodies specific to BCMA or TACI, and dual reactive BCMA-TACI antibodies in in vivo and in vitro models, the results indicate that an antibody that binds to BCMA (i.e., either a BCMA-specific antibody, or a dual reactive antibody) did not effectively target BCMA.
In Example 1, Kindsvogel tested antibody treatment of xenogeneic lymphoma and multiple myeloma models.
Groups of six mice were treated with the following antibodies: dual reactive BCMA-TACI monoclonal antibody, 255.7, TACI murine monoclonal antibody 248.24, a combination of dual reactive BCMA-TACI monoclonal antibody 255.7 and TACI murine monoclonal antibody 248.24 (1 mg/kg each), RITUXAN (a chimeric mouse/human anti-CD20 antibody), and a negative control murine monoclonal antibody (238.12).
Kindsvogel at Example 1. One can reasonably understand that the TACI monoclonal antibody (labeled "248.24") and the dual reactive BCMA-TACI monoclonal antibody (labeled "255.7") bind differently to TACI, because of the different binding specificities.
With reference to Figure 1, Kindsvogel states:
[T]he combination of BCMA and TACI monoclonal antibodies was much more effective in prolonging survival than any other monoclonal antibody treatment. All mice treated with both antibodies survived beyond 46 days, while other monoclonal antibody treatments resulted in 67% to 0% survival at 46 days. The data suggest that targeting both TACI and BCMA simultaneously is superior than therapy with either anti-BCMA or anti-TACI alone. Id. Figure 1 is shown below:
In response to the argument that Dillon does not identify any "anti-B cell marker," let alone BCMA, for use in a bispecific context, 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 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.
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, this deficiency is made up by the teachings of Koenig, who 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. The humanized OKT3 antibody comprises a VH domain having the amino acid sequence 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 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.
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’ 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 the extracellular domain of human BCMA of Dillon 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 the extracellular domain of human BCMA and human CD3ε with a reasonable expectation success, e.g., treating various autoimmune diseases as taught by Dillon and Koenig. An ordinary artisan would have considered it obvious to use Koenig’s humanized OKT3 antibody comprising VH and VL pairs that binds to CD3 epsilon subunit within the human CD3 complex in the process of making full-size bispecific IgG antibody that binds to ECD of human BCMA and human CD3ε described in Dillons by simple substitution of a known CD3 binding domain for another, e.g., human CD3 epsilon binding domain from humanized OKT3 to arrive at the claimed invention with the expectation of that the bispecific antibody (EDC of hBCMA x hCD3ε) can recruit CD3ε expressing T cells to cell expressing BCMA for treating autoimmune disease.
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).
In response to the argument that one of ordinary skill in the art would reasonably conclude that the soluble receptor includes the extracellular domain of BCMA, and therefore would also bind to a binding domain that binds to the extracellular domain of human BCMA since Maia et al. (PLOS ONE 6(6): e20787) (of record) teaches BCMA isoform inhibits BAFF signaling at p. 8, right col and Bossen et al. (Semin Immunol 2006 Oct;18(5):263-75) teaches BCMA lacks a signal peptide, Maia et al. teaches B-ALL patients express BAFF-R, whereas BCMA was seen in some patients, see p. 2, right, Figure 1C, in particular.
Maia et al. does not teach antibody that binds to the extracellular domain of human BCMA. Maia et al. teaches blockade of signals using a BCMA-Fc decoy markedly inhibit or abrogate the effects of BAFF signals in B-ALL cell survival (see p. 7, left col) would have led one of ordinary skill in the art to use antibody that binds to the extracellular domain of BCMA to inhibit or abrogate the effects of BAFF signals in B-ALL cell survival, inhibited basal leukemia cell proliferation, see p. 7, right col.
Bossen et al. (Semin Immunol 2006 Oct;18(5):263-75) teaches that omission of exon 2 in human BCMA generates a predicted soluble receptor, but in the absence of a signal peptide, this protein is not expected to be secreted, see p. 267, left col. (Fig. 2A).
Like Maia, Bossen does not teach any antibody, much less full-size bispecific antibody comprising at least two binding domain, wherein the first binding domain comprises a first antigen-binding heavy chain variable domain (VH)/light chain variable domain (VL) pair that binds to the extracellular domain of human B cell maturation antigen (BCMA) and a second binding domain comprises a second antigen-binding VH/VL pair that binds to human CD3 epsilon.
In response to the argument that one of ordinary skill in the art would not have had a motivation to select BCMA as the anti-B cell marker, to which the binding arm of Dillon's bispecific antibody binds, one of ordinary skill in the art would have had a motivation to select the extracellular domain of human BCMA as the anti-B cell marker because Chevrier teaches that there is widespread belief in the scientific community that antagonists of Neutrokine-alpha have therapeutic potential in the treatment of autoimmune diseases, including but not limited to Systemic lupus erythematosus (SLE or "lupus"), see para. [0005] to [0006] and the anti-Neutrokine-alpha antibody, e.g., anti-BCMA antibody works by reducing B cell numbers and/or B cell activity, see para. [0029] to [0030]. Chevrier teaches receptor-specific BCMA antibodies which both prevent ligand binding and receptor activation as well as BCMA antibodies that recognize the receptor-ligand complex, and, preferably, do not specifically recognize the unbound receptor or the unbound ligand may be used in the methods of the invention, see para. [0265].
The arguments with respect to Kindsvogel is moot as the rejection based on Kindsvogel’s reference has been withdrawn.
For these reasons, the rejection is maintained.
Claims 18, 23, 34, 44, 46, 47, 48 and 49 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kufer et al (newly cited, US20070123479, published May 31, 2007; PTO 892) in view of Kalled et al (newly cited, WO2010104949 publication, published September 16, 2010; PTO 892) or Ryan et al (newly cited, Mol Cancer Ther 6(11): 3009-3018, 2007; PTO 1449).
Claim interpretation:
The specification discloses:
[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 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.
Thus, the bispecific full-size antibody is a bispecific single chain BiTE antibody format.
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 44 encompasses the bispecific binding agent of claim 18, wherein the full-size antibody is a bivalent 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 claims 18, 48, 49, Kuffer et al teaches bispecific single chain antibody construct arranged, from N-terminus to C-terminus, in the order, comprising at least two binding domains, wherein a first binding domain comprises a first antigen-binding heavy chain variable domain (VH) and a first light chain variable domain (VL) pair that binds to the extracellular domain of human CD19 and human CD3 epsilon, such as V.sub.H(CD19)-V.sub.L(CD19)-V.sub.H(CD3)-V.sub.L(CD3), which is full-size as defined in the specification, see entire document, para. [0001], [0006], [0027], claims in particular.
Regarding claim 34, Kuffer et al teaches a pharmaceutical composition comprising the bispecific antibody and a pharmaceutically acceptable carrier, e.g., phosphate buffer saline solutions, water, etc., see para. [0013], in particular.
Claim 44 is included as Kuffer’s bispecific single chain antibody has just two binding domains VH-VL, aka bivalent, see para. [0009], [0042], in particular.
The reference antibody is useful for treating autoimmune disease such as rheumatoid arthritis, see reference claim 24, or B-cell malignancy, see reference claims 21, 23.
Kuffer does not teach the first binding domain comprises a VH and VL that binds to the extracellular domain of human B cell maturation antigen (BCMA) as per claim 18 wherein the first binding domain is obtained from a mouse antibody as per claim 23 and 47, wherein the mouse antibody is obtained by immunization of mice with an antigen comprising an extracellular of human BCMA as per claim 46.
However, Kalled teaches anti-human BCMA monoclonal antibody that binds to human B cell maturation antigen (BCMA, also known as TNFRSF17 or CD269), see entire document, para. [005], [0008], in particular. Kalled teaches that the antibodies and antibody fragment thereof bind to the extracellular domain of BCMA, see para. [038]. Kalled teaches the Certain anti-BCMA mAbs, including clone C4E2.2 (hamster IgG) generated at Legacy Biogen (6); clone VICKY-1 (rat IgGI) (Alexis Biochemicals, Lausen, Switzerland, also sold as 6D10 by Santa Cruz Biotechnology, Santa Cruz, CA); and clone 335004 (rat lgG2a) (R&D Systems, Inc., Minneapolis, MN), see para. [016].
Regarding claim 23, Kalled teaches that the antibodies A7D12.2, C11D5.3, C12A3.2, and C13F12.1. Each of these is a murine monoclonal antibody, see para. [018]. Kalled teaches that the heavy chain variable domain comprises SEQ ID NO:1 and the light chain variable domain comprises SEQ ID NO:2 or the heavy chain variable domain comprises SEQ ID NO:3 and the light chain variable domain comprises SEQ ID NO:12 or the heavy chain variable domain comprises SEQ ID NO:5 and the light chain variable domain comprises SEQ ID NO:6 or the heavy chain variable domain comprises SEQ ID NO:7 and the light chain variable domain comprises SEQ ID NO:8, see reference claims 17-20.
Regarding claims 46, 47, Kalled teaches that the anti-BCMA monoclonal antibodies (mAbs) were generated by immunizing female RBF mice with BCMA-Fc/KLH conjugate protein i.p. in CFA, followed by additional immunizations at regular intervals with IFA, except that the last boost used RIBI instead of IFA, prior to splenocyte fusion to the FL653 myeloma cell line after the method of Harlow and Lane (1998), Using Antibodies: A Laboratory Manual: Portable Protocol No. I, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Briefly, splenocytes isolated from a mouse 3 days after the final boost were washed twice and mixed in a 7:1 ratio with twice-washed log phase FL653 myeloma cells. The cell mixture was split four ways, pelleted, and incubated in 370C PEG for 1 min during which time cells were gently resuspended, followed by careful addition of 10 ml ice-cold DMEM. Cells were mixed, pelleted, and resuspended in AAT hybridoma growth selection media. Cell supernatants were screened for BCMA-specific reactivity by ELISA and flow cytometry. Clones that scored positive for BCMA and negative for Fc-specificity in an ELISA format, positive on BCMA-transfected cells, and negative on mock-transfected cells were expanded and subcloned. Four BCMA-specific clones were selected for further evaluation: C11 D5.3 (IgGI), C12A3.2 (IgGI), C13F12.1 (IgGI) and A7D12.2 (lgG2b), see para. [058], Example 1. The anti-BCMA mAbs bind to B cells of SLE-afflicted individuals, see Example 6. The chimeric anti-human BCMA mAbs are able to deplete human plasma cells (PC), HSC/NSG mice received various amounts of chimeric anti-human BCMA clones chAC11 D5.3, chC12A3.2, chC13F12.1 , and chA7D12.2 (Example 7), see para. [084], [088].
Likewise, Ryan teaches antagonist SG1 antibody that binds to human BCMA extracellular domain (ECD, amino acids 5-545), see entire document, p. 3011, left col, in particular. Ryan teaches that the VL domain was fused to the human kappa constant domain and the SC1 VH domain was fused to the human IgG1 constant domains. The triple Fc mutation S293D, A330L, I332E was introduced into the SG1 IgG1 construct, see p. 3011, right col. Ryan teaches that the BCMA antibody can specifically block APRIL signaling and APRIL-dependent NF-κB signaling in tumor cells, see p. 3013, Fig. 3-4, in particular. Ryan teaches that BCMA as a potential therapeutic target for oncology by creating ligand-blocking BCMA antibodies and pure antagonist antibody such as SG1 could be used to modulate BCMA signaling for oncology as well as immunologic application, see p. 3016, right col.
In view of the combined teachings of Kuffer and Kalled or Ryan, 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 antibody using Kuffer’s method by substituting the first binding domain comprises a VH and a VL that binds to CD19 in the bispecific scFv antibody of Kuffer for any one of the VH and VL that binds to the extracellular domain of human BCMA as taught by Kalled or Ryan to arrive at the claimed invention with a reasonable expectation of success, e.g., full-size bispecific single chain antibody V.sub.H(BCMA)-V.sub.L(BCMA)-V.sub.H(CD3)-V.sub.L(CD3) without or with the Fc domain having triple mutations S239D, A330L and L332E substitution for depleting BCMA expressing B cells.
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 single chain antibody that binds to the extracellular domain of human BCMA and human CD3ε because Kuffer teaches that bispecific single chain full-size antibody format that binds to antigen on B cells and CD3 epsilon on T cell is useful for treating B cell-related disorder and Kalled teaches that antibody to the extracellular domain of BCMA that expressed on plasma cells is useful for treating B-cell related disorder, e.g., B-cell related disorder is plasmacytoma, autoimmune disease, such as systemic lupus erythematosus.
One of ordinary skill in the art would have had a reasonable expectation of success at the time the invention was made to make bispecific single chain full size antibody because Kufer teaches that the bispecific single chain construct(s) are also well known in the art and illustrated in the appended examples, see para. [0026].
One of ordinary skill in the art would not have had a motivation to select antibody that binds to the extracellular domain of BCMA because Kalled teaches that such antibody and antibody fragment thereof bind to the extracellular domain of BCMA is useful for treating SLE-afflicted individuals (see Example 6) and able to deplete human plasma cells (PC), see para. [084], [088] and Kuffer’s teachings pertaining to constructs having the bispecific single chain BITE formats VH(BCMA)-VL(BCMA)-VH(CD3)-VL(CD3) and VH(CD3)-VL(CD3)-VH(BCMA)-VL(BCMA) demonstrate advantageous properties in addition to high cytotoxic activity which make these constructs well-suited to inclusion in pharmaceutical compositions, see para. [0026].
One of ordinary skill in the art would not have had a motivation to so because Ryan teaches that pure antagonist antibody such as SG1 could be used to modulate BCMA signaling for oncology as well as immunologic application (see p. 3016, right col) and triple mutations S239D, A330L and L332E in the Fc of IgG1 enhanced binding affinity of IgG1 for FcγRIIIA and increase the in vitro potency of mAbs in ADCC assay, see p. 3015, right.
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. Interdigital 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.
Claims 18, 43, 44 and 45 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kufer et al (newly cited, US20070123479, published May 31, 2007; PTO 892) in view of Kalled et al (newly cited, WO2010104949 publication, published September 16, 2010; PTO 892) or Ryan et al (newly cited, Mol Cancer Ther 6(11): 3009-3018, 2007; PTO 1449) as applied to claims 18, 23, 34, 44, 46, 47, 48 and 49 mentioned above and further in view of Igawa et al (newly cited, US20090263392, published Oct 22, 2009; PTO 892), or Zhu et al (newly cited, US20020103345, published August 1, 2002; PTO 892).
Claim interpretation:
The specification discloses:
[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 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.
Thus, the bispecific full-size antibody is a bispecific IgG antibody format.
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 43 encompasses the bispecific binding agent of claim 18, wherein the full-size antibody is an IgG antibody.
Claim 44 encompasses the bispecific binding agent of claim 18, wherein the full-size antibody is bivalent.
Claim 45 encompasses the bispecific binding agent of claim 18, wherein the full-size antibody is a bivalent, IgG antibody.
The combine teachings of Kufer, Kalled and Ryan have been discussed supra.
The references do not teach the full-size bispecific binding agent is an IgG antibody as per claim 43 wherein the full-size antibody is a bivalent, IgG antibody as per claim 45.
However, Igawa teaches bispecific antibody may also be an antibody-like molecule (for example, scFv-Fc) produced by fusing an scFv (or sc(Fv)2), in which a heavy chain variable region and a light chain variable region are linked, to an Fc region. The multispecific antibody consisting of scFv-Fc has an (scFv)2-Fc type structure with VH1-linker-VL1-Fc as the first polypeptide and VH2-linker-VL2-Fc as the second polypeptide. Alternatively, the bispecific antibody may be an antibody-like molecule in which a single domain antibody is linked with an Fc region, see para. [0177]. Igawa further teaches that the heavy chain variable region is linked to the heavy chain constant regions of human IgG1, human IgG2, or human IgG4, see para. [0252]. Igawa further teaches that the heavy chain constant region (Fc) each has amino acid substitution in its CH3 referring to as the knobs-into-holes technique to promote pairing of two heavy chains (aka full-size IgG like antibody), see para. [0200].
Claim 44 is included as the bispecific antibody (scFv)2-Fc of Igawa is bivalent (aka two antigen binding domains or scFv2).
Likewise, Zhu teaches bispecific immunoglobulin-like antigen binding protein. These bispecific antigen-binding proteins are optimized in their avidity for antigen(s) but maintain their ability to function as a natural antibody, including the ability to activate complement mediated cytotoxicity and antibody dependent cellular toxicity. Bispecific antibodies (BsAbs) are antibodies which have two different antigen-binding specificities or sites, see para. [0003]. The antigen-binding sites can be specific for any antigen and can be obtained by any means. For example, a scFv can be obtained from a monoclonal antibody, or from a library of random combinations of and VL and VH domains, see para. [0016].
Zhu teaches that bispecific antibody having the following structures:
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FIG 1 is a schematic diagram of Bs(scFv)4-IgG and Bs(scFv)2-Fab molecules. In Bs(scFv)4-IgG, the V.sub.H and V.sub.L domains of a human IgGI molecule are replaced by two scFv antibodies of different specificity. Co-expression of the scFv-light and scFv-heavy chain fusion polypeptides in mammalian cells results in the formation of a bivalent, IgG-like bispecific molecule. In Bs(scFv)2-Fab, a stop codon is introduced at the C-terminal end of the heavy chain C.sub.H1 domain, which results in the expression of a bivalent, Fab-like bispecific molecule (also see FIG. 2A). Antigen-binding proteins of the invention can have a binding site for any cell surface antigen of an immune system effector cell. Such cell surface antigens include, for example, CD3. In general, antigen binding sites are provided by scFvs which are derived from antibodies to the aforementioned antigens and which are well known in the art, see para. [0064].
The antigen-binding proteins of the invention which are bivalent and bispecific have a combination of desirable features. First, they are homogeneous. By design, mispairing of antibody heavy and light chains is greatly reduced or eliminated, see para. [0022].
A second advantage of bispecific proteins of the invention is that in tetrameric form, they are bivalent for each binding specificity. A feature of a natural antibody which is missing from a dimeric BsAb is that the natural antibody is bivalent for the antibody binding site that it comprises. A dimeric BsAb is monovalent for each of the two binding sites that it comprises. This is significant for antibody function because bivalency allows for cooperativity of binding and a significant increase in binding avidity over a molecule comprising a single antigen-binding site, see para. [0023].
A third advantage of proteins of the invention is that heavy chain constant domains which constitute the Fc region (e.g., C.sub.H2 and C.sub.H3 for an IgG molecule) of a natural antibody and which provide other antibody functions can be present. Furthermore, the multiple binding domains, along with the C.sub.L and C.sub.H1 domains, are separated from the Fc region such that functions provided by the Fc region are not impaired, see para. [0024].
In view of the combined teachings of Kufer and Kalled in view of Igawa or Zhu, 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 Igawa’s methods by fusing one scFv that binds to ECD of human BCMA to one of the two heavy chain Fc constant region and the scFv that binds to human CD3ε to the other heavy chain Fc constant region to form a bivalent IgG like (scFv)2-Fc with a reasonable expectation success, e.g., homogenous full-size IgG like antibody that binds to the extracellular domain of human BCMA and human CD3 epsilon for treating B-cell related disorder.
In the alternative, 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 Zhu’s method to create a full size bispecific IgG antibody, e.g., Bs(scFv)4-IgG or Bs(scFv)2-Fab having one arm that binds to ECD of human BCMA and the arm that binds to human CD3ε to arrive at the claimed invention with a reasonable expectation of success, e.g., without mispairing of the heavy and light chains.
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 Zhu teaches that that by design, the mispairing of antibody heavy and light chains is greatly reduced or eliminated, see para. [0022]) and Igawa teaches that the scFv domains may simply fused to the heavy chain constant region (Fc) of any isotype to form bispecific (scFv)2-Fc.
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. Interdigital 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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