DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 1-13 and 15-17 are pending and are examined on the merits.
Specification
The use of the terms “BiTE” (throughout the specification), “IRDye” (Pg. 9, 53), “Nanodrop” (Pg. 53), “GraphPad Prism” (Pg. 52), “Nano-glo” (Pg. 51), “HaloTag” (pg. 51), “FlowJo” (pg. 50; incorrectly spelled “FlowJow”), “FLAG” (Pg. 15, 47-48), “FACSCanto” (Pg. 39), and “Biacore” (Pg. 38-39), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
The term “IgG” is used as a starting point for the structure of the claimed bispecific antibodies. Because the minimum structure comprising an IgG is not specified in the claims, an “IgG” is interpreted to comprise the structure specified on Pg. 16 lines 9-23, which is consistent with the use of the term in the art.
Specifically, “IgG” is interpreted to refer to a heterotetrameric immunoglobulin molecule consisting essentially of two Fab domains joined by a dimerized Fc domain – which is composed of two light chains and two heavy chains wherein each heavy chain, from N-to-C terminus, has a heavy chain variable domain (VH) followed by three heavy chain constant domains (CH1, CH2, CH3) and each light chain, from N-to-C terminus, has a light chain variable domain (VL) followed by a light chain constant domain (CL).
Similarly, the term “bispecfic-T-cell-engager” or “BiTE” is not structurally defined in the claims, and thus where these terms appear they are interpreted to refer to a molecule according to the definition of a “bispecific-T-cell-engager” provided on Pg 12, lines 8-12 of the instant specification: “an artificial monoclonal antibody which is a fusion protein consisting of two single-chain variable fragments (scFvs) of different antibodies, or amino acid sequences from four different genes, on a single peptide chain of about 50 kilodaltons” wherein one scFv binds a T cell via CD3 and the other binds a tumor cell.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-13 and 15-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 7 contain the trademark/trade name “BiTE®”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name.
In the present case, the trademark/trade name “BiTE®” is used to identify/describe an antibody format consisting of a single peptide chain comprising two single-chain variable fragments (scFvs) wherein one scFv binds the CD3 antigen on T cells and the other scFv binds a tumor antigen (see definition at Pg. 12 lines 8-12 of the instant specification). Accordingly, the identification/description is indefinite. Claims 2-6, 8-13, and 15-17, which incorporate all of the limitations of Claim 1, are rejected for the same reasons.
Claim 1 is further rejected for the limitation “(iii) an IgG wherein both Fab arms are replaced by scFvs with different specificities”. It is unclear if the claimed scFvs have different specificities from one another or from the Fab arms that they replaced. Along the same lines, it is unclear if the specificities are meant to be “different” from the oxMIF and CD3 targets from the preamble of the claim – and if so, it is unclear how such an antibody would fulfill the structural requirements of the claim. For the purposes of examination, the structure of option (iii) is interpreted to be directed to an IgG wherein the first and second Fab arm is replaced by an scFv specifically recognizing oxMIF and an scFv specifically recognizing CD3, respectively.
Claim 1 is further rejected for reciting a binding site comprising “a variable CDR comprising sequences...”. The binding domain of an antibody is generally understood to comprise two discrete variable regions – a heavy chain variable domain (VH) and a light chain variable domain (VL) – each comprising a set of three discrete complementarity determining regions (abbreviated CDR1-H, CDR2-H, CDR3-H, CDR1-L, CDR2-L, and CDR3-L in the instant specification; e.g. Pg. 6). It is therefore unclear what is meant by a “variable CDR” (e.g. is this term intended to encompass the VH, the VL, or any one of the constituent CDRs?), and it is further unclear which of the recited sequences corresponds to which particular CDR (CDR1, CDR2, or CDR3) and on which variable chain (VH or VL). Claims 2-6, 8-13, and 15-17, which incorporate all of the limitations of Claim 1, are rejected for the same reasons.
For the purposes of examination, the claims are interpreted to be directed to an anti-oxMIF binding domain comprising a VH and VL comprising a CDR1-H, CDR2-H, CDR3-H, CDR1-L, CDR2-L, and CDR3-L comprising, in order, each of the recited sequence identifiers, respectively (e.g. an anti-oxMIF binding domain comprising a CDR1-H comprising SEQ ID NO: 7, a CDR2-H comprising SEQ ID NO: 8, a CDR3-H comprising SEQ ID NO: 9, a CDR1-L comprising SEQ ID NO: 10, a CDR2-L comprising SEQ ID NO: 11, and a CDR3-L comprising SEQ ID NO: 12).
Similarly, Claim 3 is rejected for reciting “a variable region” comprising six different CDR sequences. As stated above, the binding domain of an antibody is generally understood to comprise two discrete variable regions – a heavy chain variable domain (VH) and a light chain variable domain (VL) – each comprising a set of three discrete complementarity determining regions (abbreviated CDR1-H, CDR2-H, CDR3-H, CDR1-L, CDR2-L, and CDR3-L in the instant specification; e.g. Pg. 6). It is therefore unclear what is meant by an antibody comprising a variable region comprising six CDR sequences, and it is further unclear which sequence corresponds to which particular CDR (CDR1, CDR2, or CDR3) and on which variable chain (VH or VL).
For the purposes of examination, Claim 3 is interpreted to be directed to an anti-CD3 binding domain comprising a VH and VL comprising a CDR1-H, CDR2-H, CDR3-H, CDR1-L, CDR2-L, and CDR3-L comprising, in order, each of the recited sequence identifiers, respectively (e.g. an anti-CD3 binding domain comprising a CDR1-H comprising SEQ ID NO: 167, a CDR2-H comprising SEQ ID NO: 168, a CDR3-H comprising SEQ ID NO: 169, a CDR1-L comprising SEQ ID NO: 178, a CDR2-L comprising SEQ ID NO: 179, and a CDR3-L comprising SEQ ID NO: 180).
Claims 4-5 are rejected for reciting SEQ ID NOs: 167, 168, 169, 178, 179, and 180, each of which lacks antecedent basis. Claim 4-5 depend from Claim 1, however, SEQ ID NOs: 167, 168, 169, 178, 179, and 180 correspond to CDR sequences comprised with an anti-CD3 binding domain as defined in Claim 3 but absent from Claim 1.
Claims 6-8 are rejected because “the VL and VH chains” as recited in each of the claims lacks antecedent basis. Claim 1, from which Claims 6-8 depend, does not establish scFvs or bispecific T cell-engagers comprising a VH or a VL, but rather recites binding domains comprising “a variable CDR”.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-13 and 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Scope of the claimed genus
The claims, as best understood in view of the 112(b) issues identified above, are drawn to bispecific antibodies comprising an anti-CD3 binding domain and at least one binding domain specific for oxMIF wherein oxMIF binding domain comprises 3 heavy chain and 3 light chain CDRs each with “at least 70% identity” to the recited SEQ ID NOs.
Claim 3 further specifies the CDR sequences for the anti-CD3 binding domain, but allows for each to comprise “0, 1, or 2 point mutations”. Similarly, Claim 2 narrows the scope of the anti-oxMIF CDR sequences to those comprising “0, 1, or 2 point mutations” and Claim 4 specifies a particular set of CDR sequences for both the oxMIF binding domain and the CD3 binding domain, each comprising “0 or 1” point mutations. While Claim 5 specifies complete CDR sequences without modifications, the claim only requires “one or more” of the sequences, allowing for variation in any of the other CDRs. Each of the remaining dependent claims fail to further define the CDR sequences.
Accordingly, the breadth of the claims is very large. For example, a CDR with “70%” sequence identity to SEQ ID NO: 78 allows for CDRs comprising up to 5 amino acid differences – encompassing substitutions, insertions, and deletions, and wherein said differences can be any amino acid in any position. While slightly narrower in scope, the point mutations of Claims 2-4 still account for a near-limitless number of potential species of oxMIF and CD3 binding domains, wherein each and every position in each and every CDR may be substituted with any amino acid – with Claims 2-3 further allowing for combinations of said substitutions.
State of the relevant art
Anti-oxMIF binding domains were known in the art, including those comprising the instantly claimed CDRs (see, for example, WO 2009086920 A1; IDS). Likewise, anti-CD3 binding domains are well known, as are their utility in binding and redirecting T cells in cancer immunotherapies (see, for example, US 9,856,327 B2; PTO-892). The antibody arts, however, are unpredictable, and knowledge of these known antigen binding domains does not allow one of ordinary skill in the art to recognize or envisage an entire genus of antibodies capable of binding the same target antigen.
As was well-known in the antibody art at the time of filing, the formation of an intact antigen-binding site in an antibody typically requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope (reviewed in Sela-Culang et al. Frontiers in immunology 4 (2013): 302.; PTO-892).
Further the skilled artisan has long recognized that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function, as evidenced by Rudikoff 1982 (PNAS 79.6 (1982): 1979-1983.; PTO-892). Rudikoff teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Although more recent advances in computational modelling of CDRs have led to improvements in rational mutagenesis of antibodies, the overall effects of any given mutation on antibody function remain unpredictable.
For example, Chiu et al. 2019 (Antibodies, 8(4), 55.; PTO-892) teaches that although modeling has proven accurate for framework region sequences, CDR modeling requires further development and improvement (Pg. 6, ¶2). In particular, prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (Pg. 6, ¶2). Chiu further states “despite the obvious development in algorithms and computer power, the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate” (Pg. 11, ¶ 2). Accordingly, the skilled artisan would have recognized that it was highly unpredictable that any of the instantly claimed CDRs could be modified without altering or abolishing CD3 or oxMIF binding.
Description of representative species in the specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The disclosure provides CDR sequences for just six different anti-oxMIF and 8 different anti-CD3 binding domains (Tables 1-4). No additional variants of any of these antibodies is disclosed. Because the number of species in the disclosure represents only a tiny fraction of the scope of antibodies encompassed by the instant claims, one of ordinary skill in the art would not reasonably consider such a disclosure adequately representative of the claimed genus.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed oxMIF and CD3 binding activity.
However, the disclosure provides no guidance on which residues in which CDRs can be changed while preserving binding function, neither is there a disclosure of any structure-function relationship between the particular CDR sequences and their particular contribution to the anti-oxMIF or anti-CD3 binding affinity. While additional variants of the claimed CD3 antigen binding domains are known to the art (see below 103 rejection for an example), as discussed above, the state of the antibody arts does not generally equip the skilled artisan with the means to predict how any given point mutation impacts antigen binding specificity of an antibody. Accordingly, Applicant has not reasonably conveyed to one of ordinary skill in the art that they were in possession of antigen binding domains specific for oxMIF or CD3 commensurate in scope with the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-6, 8-9, 11-13, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Bernett et al. 2018 (US 9,856,327 B2; PTO-892), herein “Bernett”, and in view of Schinagl et al. 2016 (Oncotarget, 7(45), 73486; IDS filed 07/12/2022), herein “Schinagl”, as evidenced by PDB entry: 6FOE (rcsb.org/fasta/entry/6FOE/display; released 2018-02-28; PTO-892).
Bernett teaches a variety of bispecific antibody formats targeting the both T cell antigen CD3 and a target tumor antigen (TTA) (§ Brief Summary of the Invention; Fig. 1), among which are the “mAb-scFv” format comprising a tumor-targeted mAb fused to a single anti-CD3 scFv at the C-terminus of of one of the Fc regions, and a “Dual scFv” which comprises a pair of Fc domains wherein the Fab domains are replaced by scFvs, wherein one scFv is specific for a tumor antigen and the second binds CD3 (Fig 1A, 1B; reproduced below). The mAb-scFv and Dual scFv formats fulfill the structural requirements of the bispecific molecule according to options (i) and (iii) of Claim 1, respectively.
PNG
media_image1.png
256
196
media_image1.png
Greyscale
PNG
media_image2.png
263
373
media_image2.png
Greyscale
Regarding instant Claim 3, Bernett teaches the anti-CD3 binding domain comprises 3 heavy chain and 3 light chain CDRs wherein CDR1-H, CDR2-H, CDR1-L, and CDR2-L are identical to instant SEQ ID NOs: 170, 171, 181, and 182, respectively, and wherein each the CDR3-H and CDR3-L comprise a single point mutation relative to instant SEQ ID NOs 172 and 183, respectively (see alignment below):
B-VH = Bernett SEQ ID NO: ; CDR-H = Instant SEQ ID NOs: 170-172
B-VH 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYAT 60
|||||||||| |||||||||||
CDR-H -------------------------GFTFSTYAMN--------------RIRSKYNNYAT
B-VH 61 YYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGDSYVSWFAYWGQGTL 120
|||||||| |||||||:||||||||
CDR-H YYADSVKG------------------------------VRHGNFGNSYVSWFAY------
B-VH 121 VTVSS 125
CDR-H -----
B-VL = Bernett SEQ ID NO: ; CDR-L = Instant SEQ ID NOs: 181-183
B-VL 1 QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGV 60
|||||||||||||| |||||||
CDR-L ----------------------GSSTGAVTTSNYAN---------------GTNKRAP--
B-VL 61 PARFSGSLLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTVL 109
|||||| ||
CDR-L ------------------------------ALWYSNLWV
Regarding instant Claims 6 and 8, Bernett teaches scFvs comprise a variable heavy chain, an scFv and a variable light domain joined by a peptide linker (Col. 24, lines 45-46).
Regarding instant Claim 11, Bernett teaches that the light chain constant domain (Bernett SEQ ID NO: 473) is identical to residues 108-214 of instant SEQ ID NO: 140.
Bernett further teaches that described are generalized useful immunoglobulin formats for co-engagement of CD3 and a tumor antigen – and as such, any anti-CD3 binding domains and/or tumor antigen binding domains may be substituted for those employed therein (Col. 35, lines 1-40).
Bernett teaches that the the disclosed anti-CD3/anti-TTA bispecific formats successfully activated T cells and induced cytotoxicity in the presence of cells expressing the targeted tumor antigen (e.g. Fig. 38).
Bernett does not teach that the tumor antigen is oxMIF, that the antigen binding domains targeting oxMIF comprise the instantly recited sequences, nor that the cancer to be treated is colorectal, pancreatic, ovarian, or lung. These deficiencies are cured by Schinagl.
Schinagl teaches that the oxidized form of macrophage migration inhibitory factor (oxMIF) is specifically expressed in tumor tissue from patients with colorectal, pancreatic, ovarian, and lung cancers (Abstract).
Schinagl teaches an antibody specific for oxMIF, but not reduced MIF (redMIF), termed BaxB01 (Pg. 73487, ¶2). BaxB01 comprises the same variable heavy chain (VH; instant SEQ ID NO: 158) and variable light chain sequences (VL; instant SEQ ID NO: 134; instant SEQ ID NO: 140 residues 1-107) the instantly claimed anti-oxMIF binding domain – as evidenced by PDB entry: 6FOE. See alignment below, CDRs corresponding to instant SEQ ID NOs: 7-12 are highlighted:
anti-oxMIF Heavy Chain; Instant SEQ ID NO (SEQ158) and BaxB01 heavy chain (6FOE_1)
SEQ158 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYSMNWVRQAPGKGLEWVSSIGSSGGTTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
6FOE_1 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYSMNWVRQAPGKGLEWVSSIGSSGGTTYY 60
SEQ158 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGSQWLYGMDVWGQGTTVTVSS 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
6FOE_1 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGSQWLYGMDVWGQGTTVTVSS 118
anti-oxMIF Light Chain; Instant SEQ ID NO (SEQ134) and BaxB01 light chain (6FOE_2)
SEQ134 1 DIQMTQSPSSLSASVGDRVTITCRSSQRIMTYLNWYQQKPGKAPKLLIFVASHSQSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
6FOE_2 1 DIQMTQSPSSLSASVGDRVTITCRSSQRIMTYLNWYQQKPGKAPKLLIFVASHSQSGVPS 60
SEQ134 61 RFRGSGSETDFTLTISGLQPEDSATYYCQQSFWTPLTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
6FOE_2 61 RFRGSGSETDFTLTISGLQPEDSATYYCQQSFWTPLTFGGGTKVEIK 107
Schinagl teaches that, in contrast to antibodies that cannot discriminate between oxMIF and redMIF, antibodies specific for oxMIF are able to reduce cell growth and viability of prostate cancer cells (Pg. 73490, Col. 2, ¶2).
Schinagl teaches that although anti-oxMIF antibodies do not directly induce complement-dependent or antibody-dependent cellular cytotoxicity, combination of anti-oxMIF antibodies with chemotherapeutics sensitize cancer cells these cytotoxic drugs and improve anti-tumor efficacy of cytotoxic agents alone (Pg. 73492, ¶2; Fig. 3).
It would have been obvious to one of ordinary skill in the art to substitute the tumor-specific binding domains of the anti-CD3 bispecific antibodies of Bernett with the anti-oxMIF binding domain taught by Schinagl, to arrive at an anti-CD3/oxMIF bispecific T cell engager meeting all of the limitations of the formats of instant Claim 1 (i) and (iii) (claimed separately in instant Claims 6 and 8, respectively). Additionally, as each of the anti-oxMIF CDRs taught by Schinagl are identical to the CDRs of instant SEQ ID NOs: 7-12, any molecule comprising said binding domain meets the limitations of instant Claims 4-5 (i.e. comprising one or more of the recited sequences). Similarly, any molecule comprising the anti-oxMIF Fab of the prior art would comprise SEQ ID NO: 140, as required by instant Claim 11, which is identical to the complete light chain sequence of anti-oxMIF antibody BaxB01.
Regarding Claims 12-17, it further would have been obvious that the bispecific an anti-CD3/oxMIF antibodies according to the combined teachings of Bernett and Schinagl could be expressed from a nucleic acid vector in a host cell, formulated in a pharmaceutical composition, and administered in a therapeutically effective amount to a patient in need in order to treat cancer associated with oxMIF expression, such as colorectal cancer.
The skilled artisan would have been motivated to make and use anti-CD3/oxMIF bispecific antibodies according to the combined teachings of Bennet and Schniagl because Schinagl teaches that oxMIF is an attractive cancer target expressed on, for example, colorectal cancer, but antibodies specific to oxMIF lacked direct cytotoxic activity – a problem which can be solved by incorporating these oxMIF binding domains into anti-CD3 bispecific T cell engager formats such as that taught by Bernett.
There would have been a reasonable expectation of success because Bernett teaches that the anti-CD3/anti-TAA formats taught therein redirect T cell cytotoxicity to cells expressing the targeted tumor antigen, and Schinagl teaches that oxMIF is a disease-specific form of macrophage migration inhibitory factor that is highly expressed on a variety of cancers including colorectal, pancreatic, ovarian, and lung cancers.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Bernett et al. 2018 (US 9,856,327 B2; PTO-892), herein “Bernett”, and Schinagl et al. 2016 (Oncotarget, 7(45), 73486; IDS filed 07/12/2022), herein “Schinagl”, as evidenced by PDB entry: 6FOE (rcsb.org/fasta/entry/6FOE/display; released 2018-02-28; PTO-892), as applied to Claim 1 above, and further in view of Watkins et al. 2020 (WO 2020/237173 A1; Effectively filed 05/23/2019; PTO-892), herein “Watkins”.
The teachings of Bernett and Schinagl are summarized above.
Regarding Claim 10, Bernett and Schinagl do not teach an anti-CD3 binding domain comprising a heavy chain variable region (VH) and light chain variable region (VL) having at least 80% identity to instant SEQ ID NOs: 135 and 136, respectively. This deficiency is cured by Watkins.
Watkins teaches bispecific T cell engagers comprising an antigen binding domain specific for a tumor antigen and an anti-CD3 binding domain wherein the anti-CD3 binding domain comprises a VH and VL identical to instant SEQ ID NOs: 135 and 136, respectively (Watkins SEQ ID NOs: 68-69; Watkins claim 5; see alignment below).
VH; instant SEQ ID NO: 135 (SEQ135)/Watkins SEQ ID NO: 68 (Wat68)
SEQ135 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWMGYINPSRGYTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Wat68 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWMGYINPSRGYTNY 60
SEQ135 61 NQKFKDRVTLTTDKSSSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTLVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Wat68 61 NQKFKDRVTLTTDKSSSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTLVTVSS 119
VL; instant SEQ ID NO: 136 (SEQ136)/Watkins SEQ ID NO: 69 (Wat69)
SEQ136 1 DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQKPGKAPKRLIYDTSKLASGVPSR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Wat69 1 DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQKPGKAPKRLIYDTSKLASGVPSR 60
SEQ136 61 FSGSGSGTDFTLTISSLQPEDFATYYCQQWSSNPFTFGQGTKLEIK 106
||||||||||||||||||||||||||||||||||||||||||||||
Wat69 61 FSGSGSGTDFTLTISSLQPEDFATYYCQQWSSNPFTFGQGTKLEIK 106
Watkins further teaches that bispecific antibodies comprising said anti-CD3 binding domain redirects T cell toxicity towards cells expressing the targeted tumor antigen (Example 5).
It would have been obvious to one of ordinary skill in the art to substitute the anti-CD3 binding domain of the bispecific anti-CD3/oxMIF antibodies according to the combined teachings of Bernett and Schinagl with the anti-CD3 binding domain taught by Watkins. The skilled artisan would have appreciated that doing so constitutes a simple substitution of one known CD3 binding domain for another, wherein either binding domain is suitable for the same purpose. There would have been a reasonable expectation of success because Watkins teaches the anti-CD3 binding domains disclosed therein can be incorporated into bispecific antibodies used to redirect T cell toxicity towards a tumor antigen.
Claims 1-2, 4-5, 7, 9, 11-13, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Kontermann et al. 2021 (WO 2021/058807 A1; Effectively filed 09/25/2019; PTO-892), herein “Kontermann”, and in view of Schinagl et al. 2016 (Oncotarget, 7(45), 73486; IDS filed 07/12/2022), herein “Schinagl”, as evidenced by PDB entry: 6FOE (rcsb.org/fasta/entry/6FOE/display; released 2018-02-28; PTO-892).
Regarding instant Claims 1 and 7, Kontermann teaches a bispecific, trivalent antibody-like molecule termed “scDb/Fab-FC” comprising a pair of Fc domains wherein one Fc domain has a tumor-targeted Fab arm and the other has a single-chain arm comprising two Fv fragments (i.e. a “BiTE”) wherein one variable domain specifically recognizes CD3 (“huU3” binder) and the other variable domain specifically recognizes the same tumor antigen as the Fab arm, and wherein peptide linkers join the VL and VH chains (Fig. 6A; reproduced below).
PNG
media_image3.png
228
483
media_image3.png
Greyscale
Kontermann teaches that bispecific antibodies are designed to bind simultaneously to a trigger molecule on an immune effector cell, like CD3, and a surface antigen on a target tumor cell thus bringing the effector and target cells into close proximity and triggering the cytotoxic immune response of the effector cell (Pg. 2, lines 6-9).
Kontermann teaches that monovalent binding to CD3 “has been identified as a prerequisite to avoid a systemic activation of T-cells and to restrict receptor cross-linking and T-cell activation to target cell-bound molecules” (Pg. 2, lines 19-21).
Kontermann teaches that trivalent binding molecules comprising two binding sites for the tumor antigen exhibit strongly increased target cell binding and increased cytotoxic potential compared to bivalent bispecific molecules (Pg. 39, lines 3-6).
Regarding instant Claims 12-13 and 15-17, Kontermann teaches pharmaceutical compositions comprising the disclosed bispecific antibodies, methods of treatment comprising administering said antibodies, nucleic acids expressing said antibodies, and host cells comprising said nucleic acids (Pg. 44).
Kontermann does not teach that the tumor antigen is oxMIF nor that the antigen binding domains targeting oxMIF comprise the instantly recited sequences. This deficiency is cured by Schinagl.
Schinagl teaches that the oxidized form of macrophage migration inhibitory factor (oxMIF) is specifically expressed in tumor tissue from patients with colorectal, pancreatic, ovarian, and lung cancers (Abstract).
Schinagl teaches an antibody specific for oxMIF, but not reduced MIF (redMIF), termed BaxB01 (Pg. 73487, ¶2). BaxB01 comprises the same variable heavy chain (VH; instant SEQ ID NO: 158) and variable light chain sequences (VL + CL; instant SEQ ID NO: 134 and 140) the instantly claimed anti-oxMIF binding domain – as evidenced by PDB entry: 6FOE (). See alignment below, CDRs corresponding to instant SEQ ID NOs: 7-12 are highlighted; light chain constant region is separately aligned (relevant to instant Claim 11):
anti-oxMIF variable Heavy Chain; Instant SEQ ID NO 158 (SEQ158) and BaxB01 heavy chain (6FOE_1)
SEQ158 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYSMNWVRQAPGKGLEWVSSIGSSGGTTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
6FOE_1 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYSMNWVRQAPGKGLEWVSSIGSSGGTTYY 60
SEQ158 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGSQWLYGMDVWGQGTTVTVSS 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
6FOE_1 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGSQWLYGMDVWGQGTTVTVSS 118
anti-oxMIF variable Light Chain; Instant SEQ ID NO 134/140 (SEQ134) and BaxB01 light chain (6FOE_2)
SEQ134 1 DIQMTQSPSSLSASVGDRVTITCRSSQRIMTYLNWYQQKPGKAPKLLIFVASHSQSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
6FOE_2 1 DIQMTQSPSSLSASVGDRVTITCRSSQRIMTYLNWYQQKPGKAPKLLIFVASHSQSGVPS 60
SEQ134 61 RFRGSGSETDFTLTISGLQPEDSATYYCQQSFWTPLTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
6FOE_2 61 RFRGSGSETDFTLTISGLQPEDSATYYCQQSFWTPLTFGGGTKVEIK 107
anti-oxMIF variable Light Chain; Instant SEQ ID NO 134/140 (SEQ134) and BaxB01 light chain (6FOE_2)
Schinagl teaches that, in contrast to antibodies that cannot discriminate between oxMIF and redMIF, antibodies specific for oxMIF are able to reduce cell growth and viability of prostate cancer cells (Pg. 73490, Col. 2, ¶2).
Schinagl teaches that although anti-oxMIF antibodies do not directly induce complement-dependent or antibody-dependent cellular cytotoxicity, combination of anti-oxMIF antibodies with chemotherapeutics sensitize cancer cells these cytotoxic drugs and improve anti-tumor efficacy of cytotoxic agents alone (Pg. 73492, ¶2; Fig. 3).
It would have been obvious to one of ordinary skill in the art to substitute the tumor-specific binding domains of the anti-CD3 bispecific trivalent antibody of Kontermann with the anti-oxMIF binding domain taught by Schinagl, to arrive at an anti-CD3/oxMIF bispecific T cell engager useful for treating a variety of cancers such as colorectal cancer. Additionally, as each of the anti-oxMIF CDRs taught by Schinagl are identical to the CDRs of instant SEQ ID NOs: 7-12, any molecule comprising said binding domain meets the limitations of instant Claims 4-5 (i.e. comprising one or more of the recited sequences). Similarly, any molecule comprising the anti-oxMIF Fab of the prior art would comprise SEQ ID NO: 140, as required by instant Claim 11, which is identical to the complete light chain sequence of anti-oxMIF antibody BaxB01.
Regarding Claims 12-17, it further would have been obvious that the bispecific an anti-CD3/oxMIF antibodies according to the combined teachings of Bernett and Schinagl could be expressed from a nucleic acid vector in a host cell, formulated in a pharmaceutical composition, and administered in a therapeutically effective amount to a patient in need in order to treat cancer associated with oxMIF expression, such as colorectal cancer.
The skilled artisan would have been motivated to do so because Schinagl teaches that oxMIF is an attractive cancer target, but antibodies specific to oxMIF lacked direct cytotoxic activity – a problem which can be solved by incorporating these oxMIF binding domains into anti-CD3 bispecific T cell engager formats such as that taught by Kontermann.
There would have been a reasonable expectation of success because Kontermann teaches that the 2+1 valency (tumor:CD3) improves tumor targeting and reduces systemic T cell activation, and Schinagl teaches that oxMIF is a disease-specific form of macrophage migration inhibitory factor that is highly expressed on a variety of cancers including colorectal, pancreatic, ovarian, and lung cancers. In addition, Kontermann teaches host cells comprising nucleic acids encoding for trivalent bispecific antibodies and that the antibodies can be part of a pharmaceutical composition that is administered to a patient to treat cancer.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRYAN WILLIAM HECK whose telephone number is (703)756-4701. The examiner can normally be reached Mon-Fri 8:00am - 5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643