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 1-2, 4-8, 12-22, 24 and 28-33 are pending.
Applicant's election with traverse of Group I, drawn to a binding molecule, that read on, filed August 19, 2026, is acknowledged.
The traversal is on the grounds that there is no undue search burden to search all of the groups of inventions. Applicant further elects, with traverse, a single, specific binding molecule or a nucleic acid sequence encoding the binding molecule wherein the binding molecule comprises a region derived from a CH1 region and a region derived from a CL region which both comprise two antigen binding loops, wherein the region derived from the CH1 region of a human IgGI CHI region of SEQ ID NO: 1 includes an antigen binding loop at the CD loop region of the CH1 region that replaces the amino acid residue S165 of the CD loop of the human IgG1 CH1 region, and/or the region derived from the CL region of a human CL kappa region of SEQ ID NO: 2 includes an antigen binding loop at the DE loop region of the CL region that replaces the amino acid residue K169 of the DE loop of the human IgGI CL region, and wherein the first and second antigen are two different antigens.
Claims 1-18 and 20 read on the elected invention. Applicant submits that there is no undue search burden to search all of the species identified in claims 10 and 11.
Upon reconsideration in light of the claim amendment, the species restriction is hereby withdrawn.
Therefore, the requirement of Group I-IV is still deemed proper and is therefore made FINAL.
Claims 19-22, 24 and 28-33 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-2, 4-8 and 12-18, drawn to a binding molecule and a nucleic acid sequence encoding said binding molecule, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/176,736 filed April 19, 2021, and claims benefit of 63/176,725, filed April 19, 2024, and claims benefit of 63/176,731, filed April 19, 2021 and claims benefit of 63/176,720, filed April 19, 2021, and claims benefit of 63/176,718, filed April 19, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on May 26, 2026, May 14, 2025 and April 4, 2024 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on Oct 18, 2023 are acceptable.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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 1-2, 4-8 and 12-18 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 applicant regards as the invention.
Regarding claims 1 and 2, the recitation of “replaces amino acid residues TSG of the CD loop of the human IgG1 CH1 region” is indefinite and ambiguous because the claim fails to provide any frame of reference that would allow one of skill in the art to unambiguously identify the TSG position being referred to in the human IgG1 CH1 region.
Regarding claims 1 and 2, the recitation of “S165” is indefinite and ambiguous because the claim fails to provide any frame of reference that would allow one of skill in the art to unambiguously identify the position being referred to in the CD loop of the human IgG1 CH1 region. Even assuming the human IgG1 CH1 domain is SEQ ID NO: 1, SEQ ID NO: 1 has just 103 amino acid residues. The position “S165” exceeds the number of residues in SEQ ID NO: 1.
Regarding claims 1 and 2, the recitation of “the amino acid residues SKD of the DE loop of the human CL kappa region” is s indefinite and ambiguous because the claim fails to provide any frame of reference that would allow one of skill in the art to unambiguously identify the SKD position being referred to in the DE loop of the human CL kappa region.
Regarding claims 1 and 2, the recitation of “K169” is indefinite and ambiguous because the claim fails to provide any frame of reference that would allow one of skill in the art to unambiguously identify the position being referred to in the DE loop of the human CL kappa region. Even assuming the human CL kappa region is SEQ ID NO: 2, the amino acid sequence of SEQ ID NO: 2 comprises just 107 amino acid residues. Amending the claim to recite wherein the K169 is according to EU numbering.
Claims 3-8, 12-18 are included in the rejection because they are dependent on rejected claim and do not correct the deficiency of the claim from which they depend.
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 1-2, 4-8 and 12-18 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).
These guidelines state that rejection of a claim for lack of written description, where the claim recites the language of an original claim should be rare. Nevertheless, these guidelines further state, “the issue of a lack of written description may arise even for an original claim when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the applicant has possession of the claimed invention” (Id. at 1105). The “Guidelines” continue:
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.
Furthermore, the Federal Circuit has commented that each case involving the issue of written description, “must be decided on its own facts. Thus, the precedential value of cases in this area is extremely limited.” Vas-Cath, 935 F.2d at 1562 (quoting In re Driscoll, 562 F.2d 1245, 1250 (C.C.P.A. 1977)). See Noelle v. Lederman, 69 USPQ2d 1508 (CAFC 2004).
Finally, with further regard to the proposition that, as original claims, the claims themselves provide in haec verba support themselves provide in haec verba support sufficient to satisfy the written description requirement, the Federal Circuit has explained that in ipsis verbis support for the claims in the specification does not per se establish compliance with the written description requirement:
Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). See also: University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 1892 (CA FC 2004).
Thus, an original claim may provide written description for itself, but it must still be an adequate written description, which establishes that the inventor was in possession of the invention.
In this case, claim 1 encompasses any binding molecule comprising a region derived from a CH 1 region of an antibody heavy chain and/or a region derived from a CL region of an antibody light chain,
wherein the region derived from the CH1 region and/or the region derived from the CL region comprises one or more antigen binding loop(s), wherein:
A) the one or more antigen binding loop(s) in the region derived from the CH1 region are at CD and/or DE loop regions of the CH1 region; wherein the region derived from the CH1 region is a region derived from a human IgG1 CH1 region comprising an amino acid sequence of SEQ ID NO:1, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:1,
a) the antigen binding loop at the CD loop region of the CH1 region replaces any amino acid residues TSG of the CD loop of the human IgG1 CH1 region; and/or
b) the antigen binding loop at the DE loop region of the CH1 region replaces amino acid residues QSS of the DE loop of the human IgG1 CH1 region; and/or
c) the antigen binding loop at the CD loop region of the CH1 region replaces amino acid S165 of the CD loop of the human IgG1 CH1 region; and/or
B) the one or more antigen binding loop(s) in the region derived from the CL region are at CD and/or DE loop regions of the CL region; wherein the region derived from the CL region is a region derived from a human CL kappa region comprising an amino acid sequence of SEQ ID NO:2, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:2,
a) the antigen binding loop at the CD loop region of the CL region replaces amino acid residues SGNS of the CD loop of the human CL kappa region; and/or
b) the antigen binding loop at the DE loop region of the CL region replaces the amino acid residues SKD of the DE loop of the human CL kappa region; and/or
c) the antigen binding loop at the DE loop region of the CL regions replaces the amino acid K169 of the DE loop of the human CL kappa region.
Claim 2 encompasses any binding molecule comprising:
a first polypeptide comprising a heavy chain variable region (VH) and a region derived from a CH1 region of an antibody heavy chain; and
(ii) a second polypeptide comprising a light chain variable region (VL) and a region derived from a CL region of an antibody light chain, wherein the region derived from the CH1 region and/or the region derived from the CL region comprises one or more antigen binding loop(s), wherein:
A) the one or more antigen binding loop(s) in the region derived from the CH1 region are at CD and/or DE loop regions of the CH1 region; wherein the region derived from the CH1 region is a region derived from a human IgG1 CH1 region comprising an amino acid sequence of SEQ ID NO:1, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:1,
a) the antigen binding loop at the CD loop region of the CH1 region replaces amino acid residues TSG of the CD loop of the human IgG1 CH1 region; and/or
b) the antigen binding loop at the DE loop region of the CH1 region replaces amino acid residues QSS of the DE loop of the human IgG1 CH1 region; and/or
c) the antigen binding loop at the CD loop region of the CH1 region replaces amino acid S165 of the CD loop of the human IgG1 CH1 region; and/or
B) the one or more antigen binding loop(s) in the region derived from the CL region are at CD and/or DE loop regions of the CL region; wherein the region derived from the CL region is a region derived from a human CL kappa region comprising an amino acid sequence of SEQ ID NO:2, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:2,
a) the antigen binding loop at the CD loop region of the CL region replaces amino acid residues SGNS of the CD loop of the human CL kappa region; and/or
b) the antigen binding loop at the DE loop region of the CL region replaces the amino acid residues SKD of the DE loop of the human CL kappa region; and/or
c) the antigen binding loop at the DE loop region of the CL regions replaces the amino acid K169 of the DE loop of the human CL kappa region.
Claim 4 encompasses the binding molecule of claim 1, wherein:
the region derived from the CH1 region comprises one or two antigen binding loop(s); and/or
(ii) the region derived from the CL region comprises one or two antigen binding loop(s).
Claim 5 encompasses the binding molecule of claim 1, wherein:(i) the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region; and/or (ii) the region derived from the CH1 region comprises one antigen binding loop at the DE loop region of the CH1 region.
Claim 6 encompasses the binding molecule of claim 1, wherein the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region and one antigen binding loop at the DE loop region of the CH1 region.
Claim 7 encompasses the binding molecule of claim 1, wherein the region derived from the CL region comprises:(i) one antigen binding loop at the CD loop region of the CL region;(ii) one antigen binding loop at the DE loop region of the CL region; or (iii) one antigen binding loop at the CD loop region of the CL region and one antigen binding loop at the DE loop region of the CL region.
Claim 8 encompasses the binding molecule of claim 2, wherein:
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the DE loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region and one antigen binding loop at the DE loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the DE loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region and one antigen binding loop at the DE loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region and one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region and one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the DE loop region of the CL region; or
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region and one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region and one antigen binding loop at the DE loop region of the CL region.
Claim 12 encompasses the binding molecule of claim 1, wherein each of the one or more antigen binding loop(s) comprises any 7 to 15 amino acid residues.
Claim 13 encompasses the binding molecule of claim 2, wherein the VH region and the VL region bind to a first antigen; and the region derived from the CH1 region and/or the region derived from the CL region bind to a second antigen.
Claim 14 encompasses the binding molecule of claim 13, wherein:(i) the first antigen and the second antigen are the same antigen; or (ii) the first antigen and the second antigen are two different antigens (elected species).
Claim 15 encompasses any nucleic acid encoding the binding molecule of claim 1.
Claim 16 encompasses a vector comprising the nucleic acid of claim 15.
Claim 17 encompasses a method of making a binding molecule, comprising expressing a polynucleotide encoding the binding molecule of claim 1 in a host cell.
Claim 18 encompasses a pharmaceutical composition comprising (a) the binding molecule of claim 1, and (b) a pharmaceutically acceptable excipient.
The specification discloses Fab constant region library (CRL) used in panning pool 3 (P3) was constructed by using diversified 7 and 9 amino acid binding loops to replace three amino acids (SKD.sub.168-170, EU numbering) within CL kappa DE loop; the Fab CRL used in panning pool 4 (P4) was constructed by using diversified 7 and 9 amino acid binding loops to replace three amino acids (TSG.sub.164-166, EU numbering) within CH1 CD loop; the Fab CRL used in panning pool 5 (P5) was constructed by using 9 amino acid binding loops to replace three amino acids (SKD.sub.168-170, EU numbering) within CL kappa DE loop and three amino acids (TSG.sub.164-166, EU numbering) within CH1 CD loop. The concentrations of anti-polyhistidine monoclonal antibody used in round 1, 3, 4, 5, and 6 of panning were 100 nM, 50 nM, 10 nM, 10 nM, and 10 nM, respectively. Round 2 panning was against XO1B1 to remove any CRL Fabs that do not maintain CDR-mediated target binding.
[0578] After each round of panning (except round 2), an aliquot of the output phage from each round of the three pools was analyzed by polyclonal phage ELISA for anti-polyhistidine monoclonal antibody binding and XO1B1 binding. As shown in FIG. 2A, the pools were gradually enriched with Fab constant region binders binding to anti-polyhistidine monoclonal antibody. As shown in FIG. 2B, the binding of the enriched pools against XO1B1 is comparable to that of the parent Fab. Furthermore, as demonstrated by the sequencing result shown in FIG. 2C, the originally diversified binding loops of the Fab CRL were enriched for histidine, confirming that Fab constant region binders to a target of interest can be selected from Fab CRLs.
Example 3—Selecting Fab Constant Region Binders to mEphA2-Fc De Novo Fab CRLs Panning Against mEphA2-Fc
[0579] The overall process of selecting Fab constant region binders to recombinant murine EphA2-human IgG1 Fc chimera (herein referred to as mEphA2-Fc) from Fab CRLs is shown in FIG. 3. G1, G2, and G5 single and double loop Fab CRLs went through multiple rounds of panning against mEphA2-Fc under specific panning conditions. After each round of panning, the pools were analyzed by polyclonal phage ELISA for binding to mEphA2-Fc, XO1B1, and a negative control Fc fusion protein. Any pools showing enrichment for EphA2 binding were further analyzed by monoclonal phage ELISA to identify clonal mEphA2-Fc binders, which were subsequently sequenced. Next generation sequencing (NGS) was also applied to selected panning pools to identify additional potential Fab constant region binders to mEphA2-Fc. Finally, hits identified by both methods (phage ELISA and NGS) were further characterized following purification from mammalian expression.
[0580] In total seventeen panning conditions, referred to as panning pools P1-P17, were explored to identify conditions that were most productive in yielding hits against the mEphA2-Fc antigen. For general panning methods, refer to Antibody Phage Display, Methods and Protocols by Robert Aitken (ISBN 978-1-60327-302-2). In all cases, selections were carried out by binding the CRL to non-specifically biotinylated mEphA2-Fc antigen captured on neutravidin beads in the presence of a block mixture. A human IgG1 Fc competitor was used in all rounds of panning for all pools to prevent enrichment of binders to the Fc region of the mEphA2-Fc antigen. After extensive washing, the bound phage were used to infect MC1061F′ E. coli bacteria cells and amplified for subsequent panning rounds or characterization by phage ELISA. The panning conditions that were varied included (1) which library was used in the panning, (2) the amount of antigen used in each panning round, (3) the length of antigen binding time, and (4) the method for maintaining CDR-mediated binding to XO1B1. The specific panning condition of each pool during panning rounds one to six is listed in Table 2 below.
[0581] Each of the seventeen pools went through six to eight rounds of panning against mEphA2-Fc. After six to eight rounds of panning, an aliquot of the output phage from each round of the seventeen pools was analyzed by polyclonal phage ELISA for mEphA2-Fc binding relative to the anti-XO1B1 parent Fab.
[0582] According to the result of polyclonal phage ELISA for mEphA2-Fc binding, twelve out of the seventeen pools showed no enrichment for mEphA2-Fc binding; four pools (P5-R8, P9-R8, P15-R8, P17-R8) showed weak enrichment (3.4-34-fold binding signal of phage library pool relative to the anti-XO1B1 parent Fab) for mEphA2-Fc binding; one pool (P8-R6) showed robust enrichment (8335-fold binding signal of phage library pool relative to the anti-XO1B1 parent Fab) for mEphA2-Fc binding. A summary of the results of polyclonal phage ELISA for mEphA2-Fc binding of the five enriched pools (P5, P8, P9, P15, P17) after four to eight rounds of panning is shown in FIG. 4A, which highlights that the G5 libraries with the longer 15 amino acid loops were the most productively enriched in the mEphA2-Fc panning.
[0583] To assess the binding properties of individual clones within the enriched phage pools, a total of 378 clones from the five enriched pools (P5, P8, P9, P15, P17) were further analyzed by monoclonal phage ELISA binding to mEphA2-Fc (FIG. 4B) and XO1B1 (FIG. 4C). Single clones were selected for Sanger sequencing analysis if the mEphA2-Fc binding signal over that of the negative control was no less than 60 and the XO1B1 binding signal relative to that of the parent Fab was no less than 50%. This selection criteria resulted in sixteen clones being chosen from P8, which is derived from the G5 CH1-CD loop library. P5 (G2 CH1-DE loop library) clones lost all CDR-mediated binding to XO1B1, indicating potential misfolding or truncation of clones in this panning pool. P9 (G5 double loop library) clones also had a large reduction in XO1B1 binding and only modest increases in EphA2 binding, so no clones were chosen for further sequence analysis from this pool. While clones from P15 and P17 (G5 CL kappa-DE loop library) maintained XO1B1 binding similar to the parent anti-XO1B1 Fab, the mEphA2-Fc binding signals did not meet the selection criteria, and no clones were chosen for further sequence analysis. The sixteen selected clones from P8 after six rounds of panning are shown in FIG. 4D, with a majority of clones having a similar mEphA2-Fc and XO1B1 binding profile. The sixteen selected clones were sequenced, and all of the sixteen selected clones had the same anti-mEphA2-Fc binding sequence in the CH1 CD loop, which is shown in FIG. 4E. Interestingly, the selected loop was 13 amino acids in length, representing a truncation variant derived from the designed 15 amino acid loop library.
[0584] To confirm the binding properties of the identified clone, this single Fab constant region binder to mEphA2-Fc (identified as EPAXB1) was purified as a His-tagged fusion from mammalian expression in HEK Expi293 cells. After a single-step purification by Immobilized Metal Affinity Chromatography (IMAC), a yield of 269 mg protein per liter expression volume was achieved. The protein was characterized by analytical size exclusion-high performance liquid chromatography (SE-HPLC), reducing (R) and non-reducing (NR) sodium dodecyl sulfate-polyacrylamide gel electrophoresis SDS-PAGE, and intact mass spectrometry (MS). A single peak (aside from a histidine buffer peak) was observed by SE-HPLC and high purity was observed by SDS-PAGE. The observed molecular weight (49,119 Da) of the intact purified protein was near the predicted molecular weight of 49,110 Da. The purified protein analysis is shown in FIG. 4F.
[0585] To confirm bispecificity of the purified Fab, the binding kinetics and affinity of EPAXB1 against both mEphA2-Fc and XO1B1 were analyzed using surface plasmon resonance (SPR). The binding kinetics and affinity of the anti-XO1B1 parent Fab against both mEphA2-Fc and XO1B1 were also analyzed as a reference. As shown in FIG. 4G, the parent Fab does not bind to mEphA2-Fc, while EPAXB1 binds with 2.18 nM affinity, confirming that the CRL loop identified during the panning confers novel binding in the Fab constant region. In the meantime, EPAXB1 can bind XO1B1 with a comparable affinity (KD=0.36 nM) as that of the parent Fab (KD=0.35 nM), indicating that the CDR-mediated binding is not perturbed by the addition of the CRL loop.
Regarding one or more antigen binding loops in the region derived from the CH1 region and comprises an amino acid sequence of SEQ ID NO: 1, the phrase “an amino acid sequence” encompasses the full-length as well as any fragment thereof. The term “derived” encompasses any substitution, deletion, addition and a combination thereof. The specification discloses unmodified human IgG1 CH1 domain comprises the amino acid sequence of SEQ ID NO: 1. However, the specification does not teach antigen binding fragment comprises any fragment of human IgG1 CH1 and binds to any and all antigen.
Likewise, the specification does not teach binding fragment comprises any antigen fragment of human CL kappa region and binds to any and all antigen.
Regarding an amino acid sequence at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 1 or SEQ ID NO: 2, the specification does not teach where and what within the full-length sequence of SEQ ID NO: 1 or SEQ ID NO: 2 to be substituted, deleted, added or a combination thereof still maintains binding to second antigen.
Regarding replaces amino acid residues TSG of the CD loop and/or QSS of DE loop and/or S165 of CD loop of human IgG1 CH1 region, the specification does not disclose what changes being made in the CD loop and/or DE loop, such as TSG in the CD loop and/or QSS in the DE loop and/or S165 in the CD loop in the human IgG1 constant domain regions, and whether the said positions TSG being referred to are located within the amino acid sequence of SEQ ID NO: 1 (unmodified human IgG1 CH1). One cannot predict, a prior, which modifications will convey the desired functional binding activity.
Regarding replaces amino acid residues SGNS of the CD loop and/or SKD of DE loop and/or K169 of human CL kappa region, the specification does not disclose what changes in in the CD loop and/or DE loop and/or K169, such as SGNS in the CD loop, SKD in the DE loop and/or K169 of human CL kappa region that bind to any and all second antigen and whether the said positions are located within the amino acid sequence of SEQ ID NO: 2, which is an unmodified human CL kappa domain.
The specification does not describe the structure-identifying information e.g., amino acid sequences of the VH, VL CH1 and CL domains about the claimed binding molecules, nor describe a representative number of species falling with the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed binding molecule themselves. The specification does not describe a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed binding molecule.
While it may well be possible to make and screen library for additional peptides that would bind histidine, mouse EphA2, adequate written description requires applicant to describe products sufficiently to show that applicant was in possession of the claimed binding molecule, not simply to have a plan for identifying them. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004).
Regarding pharmaceutical composition (claim 18), since the structure of the of the claimed binding molecule that correlated with binding specificity of the binding molecules are not adequately described, the pharmaceutical composition comprising said binding molecule is not adequately described.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., 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).
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).
Barrios et al (J Molecular Recognition 17: 332-338, 2004; PTO 892) teach the amino acid residues in the CDRs and the length of the antibody heavy chain complementarity determining region (CDR3) are critical for antigen specific binding site (see abstract, in particular). The length of the amino acid sequence that links the CDRs of immunoglobulin light and heavy chains is important in maintaining their required conformation for binding and in vivo activity.
Wu et al (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.
Poosarla et al (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.)
Thus, the specification does not disclose a representative number of species of binding molecule having any replacement in the CD loop and/or DE loop of the human IgG1 CH1 and/or human CL kappa region in the claimed binding molecule, nor sufficient structure/function relationship correlative to the recited binding to different antigens. Since the binding molecule is not adequately described, neither is the claimed pharmaceutical composition (claim 18) or the nucleic acid encoding said binding molecule (claim 15), vector comprising said nucleic acid (claim 16) and method of making said binding molecule (claim 17) for treating any and all possible diseases that the uses the claimed binding molecule.
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. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Given the lack of particularity with which the binding molecules are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize or distinguish at least most of the members of the claimed genera, to which the claims are directed; and therefore the specification would not reasonably convey to the skilled artisan that Applicant had possession of the claimed invention at the time the application was filed.
Therefore, only (1) a bispecific binding molecule comprising:
a first polypeptide comprising a heavy chain variable region (VH) and a CH1 region of an antibody heavy chain; and
a second polypeptide comprising a light chain variable region (VL) and a CL region of an antibody light chain, wherein the CH1 region and the CL region comprises one or more antigen binding loop(s), wherein:
the antigen binding loop at the CD loop region of the CH1 region replaces any amino acid residues T164, S165 and G166 of the CD loop of the human IgG1 CH1 region with SEQ ID NO: 43 or 44, according to the EU numbering system; and/or
the antigen binding loop at the DE loop region of the CL region replaces the amino acid residues S168, K169 and D170 of the DE loop of the human CL kappa region with SEQ ID NO: 45 or SEQ NO: 46, wherein the binding molecule is a Fab that binds to XO1B1 and EphA2 as shown in Table 4,
(2) a binding molecule comprising:
a first polypeptide comprising a heavy chain variable region (VH) and a CH1 region of an antibody heavy chain; and
a second polypeptide comprising a light chain variable region (VL) and a CL region of an antibody light chain, wherein the CH1 region and/or the CL region comprises one or more antigen binding loop(s),
wherein the antigen binding loop consisting of the amino acid sequence selected from the group consisting of SEQ ID NO: 1-5, 7-10, 12, 14, 15, 16 to 42 replaces:
a) amino acid residues T164, S165 and G166 of the CD loop of the human IgG1 CH1 region; and/or
b) amino acid residues Q175, S176 and S177 of the DE loop of the human IgG1 CH1 region; and/or
c) amino acid S165 of the CD loop of the human IgG1 CH1 region; and/or
d) amino acid residues S156, G157, N158 and S159 of the CD loop of the human CL kappa region; and/or
e) amino acid residues S168, K168 and D170 of the DE loop of the human CL kappa region; and/or
c) amino acid K169 of the DE loop of the human CL kappa region, numbering according to the EU numbering system, and wherein the binding molecule binds to IL23R and EphA2 or Her2 and EphA, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph.
Claims 1-2, 4-8 and 12-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) a bispecific binding molecule comprising:
a first polypeptide comprising a heavy chain variable region (VH) and a CH1 region of an antibody heavy chain; and
a second polypeptide comprising a light chain variable region (VL) and a CL region of an antibody light chain, wherein the CH1 region and the CL region comprises one or more antigen binding loop(s), wherein:
the CD loop region of the CH1 region comprises amino acid residues T164, S165 and G166 of the human IgG1 CH1 region is replaced with the EphA2 specific antigen binding loop comprises SEQ ID NO: 43 or SEQ ID NO: 44, according to the EU numbering system; and
the DE loop region of the CL region comprises the amino acid residues S168, K169 and D170 of the human CL kappa region is replaced with the EphA specific antigen binding loop comprises SEQ ID NO: 45 or SEQ NO: 46, wherein the bispecific binding molecule is a Fab that binds to XO1B1 and EphA2 as shown in Table 4,
(2) binding molecule comprising:
a first polypeptide comprising a heavy chain variable region (VH) and a CH1 region of an antibody heavy chain; and
a second polypeptide comprising a light chain variable region (VL) and a CL region of an antibody light chain, wherein the CH1 region and/or the CL region comprises one or more antigen binding loop(s),
wherein the antigen binding loop consisting of the amino acid sequence selected from the group consisting of SEQ ID NO: 1-5, 7-10, 12, 14, 15, 16 to 42 replaces:
a) amino acid residues T164, S165 and G166 of the CD loop of the human IgG1 CH1 region; and/or
b) amino acid residues Q175, S176 and S177 of the DE loop of the human IgG1 CH1 region; and/or
c) amino acid S165 of the CD loop of the human IgG1 CH1 region; and/or
d) amino acid residues S156, G157, N158 and S159 of the CD loop of the human CL kappa region; and/or
e) amino acid residues S168, K168 and D170 of the DE loop of the human CL kappa region; and/or
c) amino acid K169 of the DE loop of the human CL kappa region, numbering according to the EU numbering system, and wherein the bispecific binding molecule binds to IL23R and EphA2 or Her2 and EphA, does not reasonably provide enablement for any binding molecule set forth in claims 1-2, 4-8 and 12-14 as a pharmaceutical composition set forth in claim 18, nucleic acid encoding such and method of making such binding molecule set forth in claims 15-17. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses any binding molecule comprising a region derived from a CH 1 region of an antibody heavy chain and/or a region derived from a CL region of an antibody light chain,
wherein the region derived from the CH1 region and/or the region derived from the CL region comprises one or more antigen binding loop(s), wherein:
A) the one or more antigen binding loop(s) in the region derived from the CH1 region are at CD and/or DE loop regions of the CH1 region; wherein the region derived from the CH1 region is a region derived from a human IgG1 CH1 region comprising an amino acid sequence of SEQ ID NO:1, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:1,
a) the antigen binding loop at the CD loop region of the CH1 region replaces any amino acid residues TSG of the CD loop of the human IgG1 CH1 region; and/or
b) the antigen binding loop at the DE loop region of the CH1 region replaces amino acid residues QSS of the DE loop of the human IgG1 CH1 region; and/or
c) the antigen binding loop at the CD loop region of the CH1 region replaces amino acid S165 of the CD loop of the human IgG1 CH1 region; and/or
B) the one or more antigen binding loop(s) in the region derived from the CL region are at CD and/or DE loop regions of the CL region; wherein the region derived from the CL region is a region derived from a human CL kappa region comprising an amino acid sequence of SEQ ID NO:2, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:2,
a) the antigen binding loop at the CD loop region of the CL region replaces amino acid residues SGNS of the CD loop of the human CL kappa region; and/or
b) the antigen binding loop at the DE loop region of the CL region replaces the amino acid residues SKD of the DE loop of the human CL kappa region; and/or
c) the antigen binding loop at the DE loop region of the CL regions replaces the amino acid K169 of the DE loop of the human CL kappa region.
Claim 2 encompasses any binding molecule comprising:
a first polypeptide comprising a heavy chain variable region (VH) and a region derived from a CH1 region of an antibody heavy chain; and
(ii) a second polypeptide comprising a light chain variable region (VL) and a region derived from a CL region of an antibody light chain, wherein the region derived from the CH1 region and/or the region derived from the CL region comprises one or more antigen binding loop(s), wherein:
A) the one or more antigen binding loop(s) in the region derived from the CH1 region are at CD and/or DE loop regions of the CH1 region; wherein the region derived from the CH1 region is a region derived from a human IgG1 CH1 region comprising an amino acid sequence of SEQ ID NO:1, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:1,
a) the antigen binding loop at the CD loop region of the CH1 region replaces amino acid residues TSG of the CD loop of the human IgG1 CH1 region; and/or
b) the antigen binding loop at the DE loop region of the CH1 region replaces amino acid residues QSS of the DE loop of the human IgG1 CH1 region; and/or
c) the antigen binding loop at the CD loop region of the CH1 region replaces amino acid S165 of the CD loop of the human IgG1 CH1 region; and/or
B) the one or more antigen binding loop(s) in the region derived from the CL region are at CD and/or DE loop regions of the CL region; wherein the region derived from the CL region is a region derived from a human CL kappa region comprising an amino acid sequence of SEQ ID NO:2, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:2,
a) the antigen binding loop at the CD loop region of the CL region replaces amino acid residues SGNS of the CD loop of the human CL kappa region; and/or
b) the antigen binding loop at the DE loop region of the CL region replaces the amino acid residues SKD of the DE loop of the human CL kappa region; and/or
c) the antigen binding loop at the DE loop region of the CL regions replaces the amino acid K169 of the DE loop of the human CL kappa region.
Claim 4 encompasses the binding molecule of claim 1, wherein: (i) the region derived from the CH1 region comprises one or two antigen binding loop(s); and/or (ii) the region derived from the CL region comprises one or two antigen binding loop(s).
Claim 5 encompasses the binding molecule of claim 1, wherein: (i) the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region; and/or (ii) the region derived from the CH1 region comprises one antigen binding loop at the DE loop region of the CH1 region.
Claim 6 encompasses the binding molecule of claim 1, wherein the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region and one antigen binding loop at the DE loop region of the CH1 region.
Claim 7 encompasses the binding molecule of claim 1, wherein the region derived from the CL region comprises:(i) one antigen binding loop at the CD loop region of the CL region; (ii) one antigen binding loop at the DE loop region of the CL region; or (iii) one antigen binding loop at the CD loop region of the CL region and one antigen binding loop at the DE loop region of the CL region.
Claim 8 encompasses the binding molecule of claim 2, wherein:
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the DE loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region and one antigen binding loop at the DE loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the DE loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region and one antigen binding loop at the DE loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region and one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region;
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region and one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the DE loop region of the CL region; or
the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region and one antigen binding loop at the DE loop region of the CH1 region; and the region derived from the CL region comprises one antigen binding loop at the CD loop region of the CL region and one antigen binding loop at the DE loop region of the CL region.
Claim 12 encompasses the binding molecule of claim 1, wherein each of the one or more antigen binding loop(s) comprises any 7 to 15 amino acid residues.
Claim 13 encompasses the binding molecule of claim 2, wherein the VH region and the VL region bind to a first antigen; and the region derived from the CH1 region and/or the region derived from the CL region bind to a second antigen.
Claim 14 encompasses the binding molecule of claim 13, wherein:(i) the first antigen and the second antigen are the same antigen; or (ii) the first antigen and the second antigen are two different antigens (elected species).
Claim 15 encompasses any nucleic acid encoding the binding molecule of claim 1.
Claim 16 encompasses a vector comprising the nucleic acid of claim 15.
Claim 17 encompasses a method of making a binding molecule, comprising expressing a polynucleotide encoding the binding molecule of claim 1 in a host cell.
Claim 18 encompasses a pharmaceutical composition comprising (a) the binding molecule of claim 1, and (b) a pharmaceutically acceptable excipient.
The specification discloses Fab constant region library (CRL) used in panning pool 3 (P3) was constructed by using diversified 7 and 9 amino acid binding loops to replace three amino acids (SKD.sub.168-170, EU numbering) within CL kappa DE loop; the Fab CRL used in panning pool 4 (P4) was constructed by using diversified 7 and 9 amino acid binding loops to replace three amino acids (TSG.sub.164-166, EU numbering) within CH1 CD loop; the Fab CRL used in panning pool 5 (P5) was constructed by using 9 amino acid binding loops to replace three amino acids (SKD.sub.168-170, EU numbering) within CL kappa DE loop and three amino acids (TSG.sub.164-166, EU numbering) within CH1 CD loop. The concentrations of anti-polyhistidine monoclonal antibody used in round 1, 3, 4, 5, and 6 of panning were 100 nM, 50 nM, 10 nM, 10 nM, and 10 nM, respectively. Round 2 panning was against XO1B1 to remove any CRL Fabs that do not maintain CDR-mediated target binding.
[0578] After each round of panning (except round 2), an aliquot of the output phage from each round of the three pools was analyzed by polyclonal phage ELISA for anti-polyhistidine monoclonal antibody binding and XO1B1 binding. As shown in FIG. 2A, the pools were gradually enriched with Fab constant region binders binding to anti-polyhistidine monoclonal antibody. As shown in FIG. 2B, the binding of the enriched pools against XO1B1 is comparable to that of the parent Fab. Furthermore, as demonstrated by the sequencing result shown in FIG. 2C, the originally diversified binding loops of the Fab CRL were enriched for histidine, confirming that Fab constant region binders to a target of interest can be selected from Fab CRLs.
Example 3—Selecting Fab Constant Region Binders to mEphA2-Fc De Novo Fab CRLs Panning Against mEphA2-Fc
[0579] The overall process of selecting Fab constant region binders to recombinant murine EphA2-human IgG1 Fc chimera (herein referred to as mEphA2-Fc) from Fab CRLs is shown in FIG. 3. G1, G2, and G5 single and double loop Fab CRLs went through multiple rounds of panning against mEphA2-Fc under specific panning conditions. After each round of panning, the pools were analyzed by polyclonal phage ELISA for binding to mEphA2-Fc, XO1B1, and a negative control Fc fusion protein. Any pools showing enrichment for EphA2 binding were further analyzed by monoclonal phage ELISA to identify clonal mEphA2-Fc binders, which were subsequently sequenced. Next generation sequencing (NGS) was also applied to selected panning pools to identify additional potential Fab constant region binders to mEphA2-Fc. Finally, hits identified by both methods (phage ELISA and NGS) were further characterized following purification from mammalian expression.
[0580] In total seventeen panning conditions, referred to as panning pools P1-P17, were explored to identify conditions that were most productive in yielding hits against the mEphA2-Fc antigen. For general panning methods, refer to Antibody Phage Display, Methods and Protocols by Robert Aitken (ISBN 978-1-60327-302-2). In all cases, selections were carried out by binding the CRL to non-specifically biotinylated mEphA2-Fc antigen captured on neutravidin beads in the presence of a block mixture. A human IgG1 Fc competitor was used in all rounds of panning for all pools to prevent enrichment of binders to the Fc region of the mEphA2-Fc antigen. After extensive washing, the bound phage were used to infect MC1061F′ E. coli bacteria cells and amplified for subsequent panning rounds or characterization by phage ELISA. The panning conditions that were varied included (1) which library was used in the panning, (2) the amount of antigen used in each panning round, (3) the length of antigen binding time, and (4) the method for maintaining CDR-mediated binding to XO1B1. The specific panning condition of each pool during panning rounds one to six is listed in Table 2 below.
[0581] Each of the seventeen pools went through six to eight rounds of panning against mEphA2-Fc. After six to eight rounds of panning, an aliquot of the output phage from each round of the seventeen pools was analyzed by polyclonal phage ELISA for mEphA2-Fc binding relative to the anti-XO1B1 parent Fab.
[0582] According to the result of polyclonal phage ELISA for mEphA2-Fc binding, twelve out of the seventeen pools showed no enrichment for mEphA2-Fc binding; four pools (P5-R8, P9-R8, P15-R8, P17-R8) showed weak enrichment (3.4-34-fold binding signal of phage library pool relative to the anti-XO1B1 parent Fab) for mEphA2-Fc binding; one pool (P8-R6) showed robust enrichment (8335-fold binding signal of phage library pool relative to the anti-XO1B1 parent Fab) for mEphA2-Fc binding. A summary of the results of polyclonal phage ELISA for mEphA2-Fc binding of the five enriched pools (P5, P8, P9, P15, P17) after four to eight rounds of panning is shown in FIG. 4A, which highlights that the G5 libraries with the longer 15 amino acid loops were the most productively enriched in the mEphA2-Fc panning.
[0583] To assess the binding properties of individual clones within the enriched phage pools, a total of 378 clones from the five enriched pools (P5, P8, P9, P15, P17) were further analyzed by monoclonal phage ELISA binding to mEphA2-Fc (FIG. 4B) and XO1B1 (FIG. 4C). Single clones were selected for Sanger sequencing analysis if the mEphA2-Fc binding signal over that of the negative control was no less than 60 and the XO1B1 binding signal relative to that of the parent Fab was no less than 50%. This selection criteria resulted in sixteen clones being chosen from P8, which is derived from the G5 CH1-CD loop library. P5 (G2 CH1-DE loop library) clones lost all CDR-mediated binding to XO1B1, indicating potential misfolding or truncation of clones in this panning pool. P9 (G5 double loop library) clones also had a large reduction in XO1B1 binding and only modest increases in EphA2 binding, so no clones were chosen for further sequence analysis from this pool. While clones from P15 and P17 (G5 CL kappa-DE loop library) maintained XO1B1 binding similar to the parent anti-XO1B1 Fab, the mEphA2-Fc binding signals did not meet the selection criteria, and no clones were chosen for further sequence analysis. The sixteen selected clones from P8 after six rounds of panning are shown in FIG. 4D, with a majority of clones having a similar mEphA2-Fc and XO1B1 binding profile. The sixteen selected clones were sequenced, and all of the sixteen selected clones had the same anti-mEphA2-Fc binding sequence in the CH1 CD loop, which is shown in FIG. 4E. Interestingly, the selected loop was 13 amino acids in length, representing a truncation variant derived from the designed 15 amino acid loop library.
[0584] To confirm the binding properties of the identified clone, this single Fab constant region binder to mEphA2-Fc (identified as EPAXB1) was purified as a His-tagged fusion from mammalian expression in HEK Expi293 cells. After a single-step purification by Immobilized Metal Affinity Chromatography (IMAC), a yield of 269 mg protein per liter expression volume was achieved. The protein was characterized by analytical size exclusion-high performance liquid chromatography (SE-HPLC), reducing (R) and non-reducing (NR) sodium dodecyl sulfate-polyacrylamide gel electrophoresis SDS-PAGE, and intact mass spectrometry (MS). A single peak (aside from a histidine buffer peak) was observed by SE-HPLC and high purity was observed by SDS-PAGE. The observed molecular weight (49,119 Da) of the intact purified protein was near the predicted molecular weight of 49,110 Da. The purified protein analysis is shown in FIG. 4F.
[0585] To confirm bispecificity of the purified Fab, the binding kinetics and affinity of EPAXB1 against both mEphA2-Fc and XO1B1 were analyzed using surface plasmon resonance (SPR). The binding kinetics and affinity of the anti-XO1B1 parent Fab against both mEphA2-Fc and XO1B1 were also analyzed as a reference. As shown in FIG. 4G, the parent Fab does not bind to mEphA2-Fc, while EPAXB1 binds with 2.18 nM affinity, confirming that the CRL loop identified during the panning confers novel binding in the Fab constant region. In the meantime, EPAXB1 can bind XO1B1 with a comparable affinity (KD=0.36 nM) as that of the parent Fab (KD=0.35 nM), indicating that the CDR-mediated binding is not perturbed by the addition of the CRL loop.
Applicants have provided insufficient evidence or nexus that would lead the skilled artisan to predict which combination of amino acids inserted into the CD loop and/or DE loop of human IgG1 CH1 domain and the CD loop and/or DE loop of human CL kappa region bind to any and all potential antigen. The specification does not enable the genus because where the results are unpredictable. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one particular species, what other species will work. See MPEP 2164.03.
Regarding one or more antigen binding loops in the region derived from the CH1 region and comprises an amino acid sequence of SEQ ID NO: 1, the phrase “an amino acid sequence” encompasses the full-length as well as any fragment thereof. The term “derived” encompasses any substitution, deletion, addition and a combination thereof. The specification discloses unmodified human IgG1 CH1 domain comprises the amino acid sequence of SEQ ID NO: 1. However, the specification does not teach antigen binding fragment comprises any fragment of human IgG1 CH1 and binds to any and all antigen.
Likewise, the specification does not teach binding fragment comprises any antigen fragment of human CL kappa region and binds to any and all antigen.
Regarding an amino acid sequence at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 1 or SEQ ID NO: 2, the specification does not teach where and what within the full-length sequence of SEQ ID NO: 1 or SEQ ID NO: 2 to be substituted, deleted, added or a combination thereof still maintains binding to second antigen.
Regarding replaces amino acid residues TSG of the CD loop and/or QSS of DE loop and/or S165 of CD loop of human IgG1 CH1 region, the specification does not disclose what changes being made in the CD loop and/or DE loop, such as TSG in the CD loop and/or QSS in the DE loop and/or S165 in the CD loop in the human IgG1 constant domain regions, and whether the said positions TSG being referred to are located within the amino acid sequence of SEQ ID NO: 1 (unmodified human IgG1 CH1).
Regarding replaces amino acid residues SGNS of the CD loop and/or SKD of DE loop and/or K169 of human CL kappa region, the specification does not disclose what changes in in the CD loop and/or DE loop and/or K169, such as SGNS in the CD loop, SKD in the DE loop and/or K169 of human CL kappa region that bind to any and all second antigen and whether the said positions are located within the amino acid sequence of SEQ ID NO: 2, which is an unmodified human CL kappa domain.
The specification does not teach the structure, e.g., amino acid sequences of the VH, VL CH1 and CL domains encompassed by the claimed binding molecule that correlated with binding to any and all first and second antigens. One skilled in the art cannot predict replaces with which combination of amino acids, such as 7 to 15 amino acid residues within the CD loop and/or DE loop of human IgG1 CH1 domain and/or CD loop and/or DE loop of human kappa CL domain maintains binding to which antigen.
Regarding pharmaceutical composition, given the lack of guidance as to the binding specificity of the binding molecule and the lack of in vivo working examples, it is unpredictable which any and all disease to be treated with the claimed pharmaceutical composition.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., 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).
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Barrios et al (J Molecular Recognition 17: 332-338, 2004; PTO 892) teach the amino acid residues in the CDRs and the length of the antibody heavy chain complementarity determining region (CDR3) are critical for antigen specific binding site (see abstract, in particular). The length of the amino acid sequence that links the CDRs of immunoglobulin light and heavy chains is important in maintaining their required conformation for binding and in vivo activity.
Wu et al (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.
Poosarla et al (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.)
There are no working example. One skilled in the art cannot predict replacement with which combination of amino acids, such as 7 to 15 amino acid residues within the CD loop and/or DE loop of human IgG1 CH1 domain and/or CD loop and/or DE loop of human kappa CL domain binds to which antigen.
Since the binding molecule is not enabled, neither is the claimed pharmaceutical composition (claim 18) or the nucleic acid encoding said binding molecule (claim 15), vector comprising said nucleic acid (claim 16) and method of making said binding molecule (claim 17) for treating any and all possible diseases that the uses the claimed binding molecule. As such, one skilled in the art cannot practice the invention with a reasonable expectation of success without undue experimentation.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Preyer et al (US20190048098 (published February 14, 2019; PTO 892).
Claim 1 recites a binding molecule comprising a region derived from a CH 1 region of an antibody heavy chain and/or a region derived from a CL region of an antibody light chain,
wherein the region derived from the CH1 region and/or the region derived from the CL region comprises one or more antigen binding loop(s), wherein:
A) the one or more antigen binding loop(s) in the region derived from the CH1 region are at CD and/or DE loop regions of the CH1 region; wherein the region derived from the CH1 region is a region derived from a human IgG1 CH1 region comprising an amino acid sequence of SEQ ID NO:1, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:1.
Claim 2 recites a binding molecule comprising:
a first polypeptide comprising a heavy chain variable region (VH) and a region derived from a CH1 region of an antibody heavy chain; and
(ii) a second polypeptide comprising a light chain variable region (VL) and a region derived from a CL region of an antibody light chain, wherein the region derived from the CH1 region and/or the region derived from the CL region comprises one or more antigen binding loop(s), wherein:
A) the one or more antigen binding loop(s) in the region derived from the CH1 region are at CD and/or DE loop regions of the CH1 region; wherein the region derived from the CH1 region is a region derived from a human IgG1 CH1 region comprising an amino acid sequence of SEQ ID NO:1, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:1.
Preyer teaches binding molecule, e.g., bispecific antibody or antigen-binding fragment thereof that comprises a first heavy chain variable domain (first VH) and a first light chain variable domain (first VL), wherein the first VH and the first VL pair to form a first variable region that binds specifically to a first epitope of a first antigen. The bispecific antibody further comprises a second Fab comprising a second VH and a second VL, wherein the second VH and the second VL pair to form a second variable region, and wherein the second VH is either (i) directly linked or (ii) linked via a linker to a CH1 domain and the second VL is either (i) directly linked or (ii) linked via a linker to a CL domain, see para. [0008].
The reference CH1 domain comprises the amino acid sequence of SEQ ID NO: 91 that is 100% identical to the claimed SEQ ID NO: 2, see sequence alignment below:
Query Match 100.0%; Score 534; Length 113;
Best Local Similarity 100.0%;
Matches 103; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
Qy 61 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 103
|||||||||||||||||||||||||||||||||||||||||||
Db 61 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 103
The term “or” does not require CL region.
Although the reference does not specifically teach that the one or more antigen binding loops in the CH1 region, a chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure as claimed, the properties applicant discloses and/or claims are necessarily present. "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Thus, the reference teachings anticipate the claimed invention.
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 1, 4-5 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 6,294,654 (issued September 25, 2001; PTO 892) in view of US Patent No. 7,381,794 (issued June 3, 2008; PTO 892).
Claim 1 recites a binding molecule comprising a region derived from a CH 1 region of an antibody heavy chain and/or a region derived from a CL region of an antibody light chain,
wherein the region derived from the CH1 region and/or the region derived from the CL region comprises one or more antigen binding loop(s), wherein:
A) the one or more antigen binding loop(s) in the region derived from the CH1 region are at DE loop regions of the CH1 region; wherein the region derived from the CH1 region is a region derived from a human IgG1 CH1 region comprising an amino acid sequence of SEQ ID NO:1, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:1,
a) the antigen binding loop at the DE loop region of the CH1 region replaces amino acid residues QSS of the DE loop of the human IgG1 CH1 region.
Claim 2 recites a binding molecule comprising:
a first polypeptide comprising a heavy chain variable region (VH) and a region derived from a CH1 region of an antibody heavy chain; and
a second polypeptide comprising a light chain variable region (VL) and a region derived from a CL region of an antibody light chain, wherein the region derived from the CH1 region and/or the region derived from the CL region comprises one or more antigen binding loop(s), wherein:
A) the one or more antigen binding loop(s) in the region derived from the CH1 region are at DE loop regions of the CH1 region; wherein the region derived from the CH1 region is a region derived from a human IgG1 CH1 region comprising an amino acid sequence of SEQ ID NO:1, and comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO:1,
a) the antigen binding loop at the DE loop region of the CH1 region replaces amino acid residues QSS of the DE loop of the human IgG1 CH1 region
Claim 4 recites the binding molecule of claim 1, wherein: (i) the region derived from the CH1 region comprises one or two antigen binding loop(s); and/or (ii) the region derived from the CL region comprises one or two antigen binding loop(s).
Claim 5 recites the binding molecule of claim 1, wherein: (i) the region derived from the CH1 region comprises one antigen binding loop at the CD loop region of the CH1 region; and/or (ii) the region derived from the CH1 region comprises one antigen binding loop at the DE loop region of the CH1 region.
Claim 12 recites the binding molecule of claim 1, wherein each of the one or more antigen binding loop(s) comprises any 7 to 15 amino acid residues.
Regarding claims 1, 2, 5, the ‘654 patent teaches binding molecule, e.g., antibodies can be made in which a peptide antigen, e.g., ras peptide can be incorporated into one or more non-CDR loops of CH1 or CL (aka Ckappa) of immunoglobulin (Ig), see entire document, col., 3, lines 28-42, claims1-3, in particular. Examples of immunoglobulin or Ig molecule include human IgG1, IgG2, IgG3, IgG4, see col. 4, lines 39-41, col. 7, lines 53, in particular. The ‘654 patent teaches replaces amino acid residues QSS residues in loop 2 (aka instant DE loop) of human IgG, see Fig. 1B, in particular. The non-CDR loops may be in the CH.sub.1 or C.sub.K region between the hinge region and the variable region. This would apply particularly where the Ig is a Fab fragment, see col. 4, line 42-44, in particular. The term “or” does not require replacing amino acid residues TSG of the CD loop and/or the S165 of the CD loop of human IgG1 CH1 region. The term “or” does not require replacing one or more loops such as SGNS of CD loop and/or SKD of DE loop and/or K169 of DE loop of human CL kappa region.
Claims 4-5 are included as the ‘654 patent teaches one or more non-CDR loops of CH1 are replaced. The term “comprises” is open ended. It expands the one or two antigen binding loops in CH1 domain to include more than one, e.g., 1 to 3 loops. The term “or” in claim 4 does not require the CL region. The term “or” in claim 5 does not require the CD loop region of CH1.
Regarding claim 12, the ‘654 patent teaches that the size of the inserted peptide is probably not critical; generally an 11 amino acids will suffice, which is within the claimed range of between 7 and 15, see col. 4, lines 10-14. The ‘654 patent teaches that the L1, L2 and L3 loops of CH1 domain comprises seven, seven and four amino acids, see FIG 1, in particular. The reference L2 loop correspond to the claimed DE loop, which comprises QSS residues, see Fig. 1B, in particular.
The ‘654 patent teaches that the size of the inserted peptide is generally 11 amino acids, but typically about 11-20 amino acids in length, see col. 4, lines . The ras peptide is 11 amino acids in length, see Fig. 1B. The antigenic peptide could be inserted into just one non-CDR loop, but it may be desirable to incorporate an antigenic peptide into more than one such loop, see col. 4, line 17-19, in particular. This could be the same peptide, so as to increase the amount of antigenic peptide that is carried into the APC; or different antigenic peptides could be incorporated.
The ’654 patent teaches the advantages of such modified antibody include it retained antigen-binding specificity for the APC (preferably a dendritic cell), potentially greater binding affinity to APCs than Fc-FcR binding. It provides potentially divalent binding, which can increase the likelihood of being taken up by and degraded within the APC. It provides the possibility of the Ig molecules being cross-linked by their constant regions, thereby further increasing the likelihood of being taken up by the APC.
It provides the possibility (in the case of bispecific antibodies) of the Ig molecules being cross-linked by their variable domains, thereby increasing the likelihood of being taken up and correctly processed by the APC, since FcRs are primarily adapted to take up immune complexes. It can substantially prevent the Ig from being targeted to the wrong site. It allows one in principle to target any of the surface epitopes of the APC, and in particular epitopes specific to dendritic cells, see col. 5, in particular.
The ’654 patent does not teach the CH1 region derived from the CH1 region of human IgG1 CH1 and comprises an amino acid sequence having at least 70% identity to SEQ ID NO: 1 as per claims 1 and 2.
However, the ‘794 patent teaches the wild type human IgG1 CH1 wherein the CH1 domain comprises the amino acid sequence of SEQ ID NO: 48, that is 100% identical to the claimed SEQ ID NO: 1, see sequence alignment below, the QSS residue in the DE loop is in bold, see sequence in Fig. 2A, reference SEQ ID NO: 48, in particular. The amino acid sequence numbers 118 to 215 are based on the Eu index of Kabat, see Fig. 1A, col. 4, line 18-29, in particular. The QSS residues correspond to Q175, S176 and S177, numbering according to EU index.
Query Match 100.0%; Score 534; Length 103;
Best Local Similarity 100.0%;
Matches 103; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
Qy 61 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 103
|||||||||||||||||||||||||||||||||||||||||||
Db 61 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 103
Given that the wild type (un-modified) CH1 domain has 103 amino acid residues in length, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to have determined the sequence identity to SEQ ID NO: 1 in the antibody or antigen binding fragment thereof of ’654 patent in view of the ‘794 patent as a % amino acid sequence identity value is determined by dividing (a) the number of matching identical amino acid residues between the amino acid sequence of the immunoglobulin domain of interest having a sequence derived from the native immunoglobulin domain and the comparison amino acid sequence of interest (i.e., the sequence against which the immunoglobulin domain of interest is being compared which may be the unmodified immunoglobulin domain) with a reasonable expectation success, e.g., 92/103 x 100 or 89% sequence identity to SEQ ID NO: 1 if there are 11 amino acids substitution or 83/103 x 100 or 81% if there are 20 amino acids substitution.
One of ordinary skill in the art would have been motivated to do so because the ‘654 patent teaches that one or more foreign antigen peptides, typically about 11-20 amino acids, can be incorporated into one or more non-CDR loops in the CH1 or Ck region of the antibody (Ab) and the advantages of such modified antibody are retained antigen-binding specificity, potentially divalent binding, and allows one in principle to target any of the surface epitopes of the APC, and in particular epitopes specific to dendritic cells, see col. 5, in particular
“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
The antigen binding loop consisting of the amino acid sequence selected from the group consisting of SEQ ID NO: 1-5, 7-10, 12, 14, 15, 16 to 42 is free of prior art.
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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