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, 13-16, 46-49, 99-102, 105, 107 and 110 are pending.
Applicant’s election of Group I (claims 1, 13-16, 46-49, 99-102 and 105) that read on (A) HC of SEQ ID NO: 155 and (B) LC of SEQ ID NO: 157; (C) HCVR of SEQ ID NO: 140 and (D) LCVR of SEQ ID NO: 148; (E) HCDR1 of SEQ ID NO: 142, HCDR2 of SEQ ID NO: 144, HCDR3 of SEQ ID NO: 146, (F) LCDR1 of SEQ ID NO: 150, LCDR2 of GAS, and LCDR3 of SEQ ID NO:153, (G) polynucleotide molecular as the molecular cargo, and (H) Aducanumab as a further therapeutic agent in the reply filed of June 22, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 107 and 110 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1, 13-16, 46-49, 99-102 and 105, drawn to an antibody-drug conjugate that read on that read on (A) HC of SEQ ID NO: 155 and (B) LC of SEQ ID NO: 157; (C) HCVR of SEQ ID NO: 140 and (D) LCVR of SEQ ID NO: 148; (E) HCDR1 of SEQ ID NO: 142, HCDR2 of SEQ ID NO: 144, HCDR3 of SEQ ID NO: 146, (F) LCDR1 of SEQ ID NO: 150, LCDR2 of GAS, and LCDR3 of SEQ ID NO:153, (G) polynucleotide molecular as the molecular cargo, and (H) Aducanumab as further therapeutic agent, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/383,673, filed November 14, 2022, and 63/587,585, filed Oct 3, 2023, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on January 14, 2026, and June 28, 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 November 14, 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 objection
Claim 1 is objected to because of the following informality: “a molecular cargo” is inconsistence with the preamble “antibody-drug conjugate”. It is suggested that claim 1 be amended to recite “A conjugate” and dependent claims thereof recite “The conjugate”.
Claim 14 is objected to because of the following informality: “and/or” between (l) and (m) should have been “or”.
Claim 15 is objected to because of the following informality: “and/or” between (xii) and (xiii) should have been “or”.
Claim 16 is objected to because of the following informality: “and/or” between (l) and (m) should have been “or”.
Claim rejections under - 35 U.S.C. 112
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, 13-16, 46-49, 99-102 and 105 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).
Claim 1 encompasses an antibody-drug conjugate comprising an antibody or antigen- binding fragment thereof that binds to fibroblast growth factor receptor 3 (FGFR3) and is conjugated to a molecular cargo; wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region (HCVR) that comprises the heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, 22, 42, 62, 82, 102, 122, 140, 159, 169, 179, 199, or 219; and (ii) a light chain variable region (LCVR) that comprises the light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207, or 227.
Claim 13 encompasses the antibody-drug conjugate of claim 1, wherein the antibody or antigen-binding fragment thereof comprises:
(1) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2;and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10;
(2) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30;
(3) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50;
(4) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof); and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70;
(5) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90;
(6) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110;
(7) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof);
(8) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(9) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(10) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(11) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187;
(12) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207; or
(13) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227.
Claim 14 encompasses the antibody-drug conjugate of claim 13, wherein the antibody or antigen-binding fragment thereof comprises:
(a) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16;
(b) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 24, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36;
(c) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56;
(d) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 74, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76;
(e) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 94, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96;
(f) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 112, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 114, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116;
(g) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 134;
(h) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 144, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(i) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 163, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(j) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 171, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 173, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(k) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 181, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 189, an LCDR2 comprising the amino acid sequence ETS set forth in SEQ ID NO: 191, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193;
(1) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, an LCDR2 comprising the amino acid sequence KVF set forth in SEQ ID NO: 211, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213; and/or
(m) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 221, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76.
Claim 15 encompasses the antibody-drug conjugate of claim 13, wherein the antibody or antigen-binding fragment thereof comprises:
(i) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10;
(ii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30;
(iii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50;
(iv) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70;
(v) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90;
(vi) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110;
(vii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130;
(viii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140; and an LCVR that the amino acid sequence set forth in SEQ ID NO: 148;
(ix) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(x) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(xi) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187;
(xii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207; and/or
(xiii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227.
Claim 16 encompasses the antibody-drug conjugate of claim 13, wherein the antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 20;
(b) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 38, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 40;
(c) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 58, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 60;
(d) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 78, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 80;
(e) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 100;
(f) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 118, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 120;
(g) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 136, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 138;
(h) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 155, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(i) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 167, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(j) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 177, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(k) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 195, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 197;
(1) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 215, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 217; and/or
(m) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 229, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 231.
Claim 46 encompasses the antibody-drug conjugate of claim 1, wherein the molecular cargo comprises any polynucleotide molecule, any polypeptide molecule, any carrier, any viral particle, any viral capsid protein, or any small molecule.
Claim 47 encompasses the antibody-drug conjugate of claim 46, wherein the molecular cargo comprises any polynucleotide molecule.
Claim 48 encompasses the antibody-drug conjugate of claim 47, wherein the polynucleotide molecule is any interfering nucleic acid molecule, any guide RNA, any ribozyme, any aptamer, any mixmer, any multimer, or any mRNA.
Claim 49 encompasses the antibody-drug conjugate of claim 48, wherein the interfering nucleic acid molecule is any siRNA, any shRNA, any miRNA, any antisense oligonucleotide, or any gapmer.
Claim 99 encompasses a pharmaceutical composition comprising the antibody-drug conjugate of claim 1 and a pharmaceutically acceptable excipient or carrier.
Claim 100 encompasses a composition or kit comprising 1) the antibody-drug conjugate of A composition or kit comprising 1) the antibody-drug conjugate of 2) a further therapeutic agent.
Claim 101 encompasses a complex comprising the antibody-drug conjugate of claim 1 bound to fibroblast growth factor receptor 3 (FGFR3).
Claim 102 encompasses a method for making the antibody-drug conjugate of claim 1, comprising:(a) contacting the antibody or antigen-binding fragment thereof with the molecular cargo under the conditions favorable for conjugation of the antibody or antigen-binding fragment thereof to the molecular cargo; and(b) optionally, isolating the antibody-drug conjugate produced in step (a).
Claim 105 encompasses a vessel or injection device comprising the antibody-drug conjugate of claim 1.
Claim 107 encompasses a method for delivering a molecular cargo to a tissue or cell type expressing FGFR3 in the body of a subject comprising administering to the subject the antibody-drug conjugate of claim 1, or a pharmaceutical composition comprising said protein-drug conjugate and a pharmaceutically acceptable excipient or carrier.
The specification discloses 13 antibodies that bind to human fibroblast growth factor receptor 3 (FGFR3) wherein the antibodies each comprises a specific combination of a heavy chain variable region sequence and a light chain variable region sequence shown in table 1-3.
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The specification exemplifies:
[0248] FIGS. 1A-1B depict schematic representations of the general architecture of fibroblast growth factor receptor 3 (FGFR3), and isoforms FGFR3b and FGFR3c. Schematic showing the orientation of an FGFR dimer within the plasma membrane (FIG. 1A, top). The FGF3 receptor domain structure is comprised of an extracellular domain comprising a ligand binding site, a transmembrane domain, and an intracellular domain comprising spit tyrosine kinases. The receptor is depicted stabilized by a heparin/heparan sulfate (HS) chain of HS proteoglycan, HSPG. Schematic of the FGF monomer exemplifying the three IgG-like loops (Ig-I, Ig-II, and Ig-III) of the extracellular ligand-binding domain and the split kinase domain (FIG. 1A, bottom). Schematic showing a structural comparison of alternatively spliced FGFR3b and FGFR3c isoforms (FIG. 1B). Ig-I, Ig-II, and Ig-II loops of the extracellular domain ligand-binding domain are encoded by exons 7-9. FGFR3b includes exon 8, and excludes exon 9, whereas FGFR3c includes exon 9 and excludes exon 8. Thus, inclusion/exclusion of exon 8 and 9 directs expression of IIIb versus IIIc splice forms.
[0249] FIGS. 2A-2B illustrate FGFR3 is highly expressed on mouse and human astrocytes. Graphs of RNA sequencing (RNASeq) data depicting expression of FGFR1-FGFR4 transcript in mouse (FIG. 2A) and human (FIG. 2B) nervous and supporting cells.
[0250] FIG. 3 shows expression of total FGFR3, and FGFR3b and FGFR3c isoforms, in mouse brain, primary mouse astrocytes, and primary human astrocytes. Data are plotted as relative to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) Ct values, and normalized to the relative expression of each isoform from the mouse brain (1/2ΔΔCt, mean±standard deviation [SD]).
[0251] FIGS. 4A-4C illustrate FGFR3 antibodies internalize into live astrocytes as evidenced by perinuclear speckles (puncta). A schematic depicting an exemplary experimental timeline (FIG. 4A). Photomicrograph showing immunofluorescence detection of actin cytoskeleton and perinumclear FGFR3 puncta in human astrocytes using DEAD staining approaches described herein (FIG. 4B). Photomicrographs showing immunofluorescence detection of vimentin (VIM) cytoskeleton and perinuclear FGFR3 puncta in human and mouse astrocytes using LIVE staining approaches described herein (FIG. 4C). Non-degrader (H4H30063P) FGFR3 antibodies showed robust internalization as evidenced by prevalent puncta surrounding the nucleus.
[0252] FIGS. 5A-5C illustrate validation of FGFR3 expression and internalization in the U87-FGFR3b-FLuc-GFP line. A schematic depicting an exemplary experimental timeline (FIG. 5A). Photomicrographs showing immunofluorescent detection of FGFR3b and FelD1 (negative control) in GFP-positive U87 cells stained with DAPI (FIG. 5B). FGFR3 are visualized as prevalent fluorescent puncta surrounding the nucleus (DAPI staining), confirming FGFR3 expression and internalization in the U87-FGFR3b-FLuc-GFP line. A graph showing percent normalized TaqMan FGFR3 expression (mean±standard deviation [SD]) in U87 parental cells, and in U87 cell lines expressing human FGFR3b (U87-hFGFR3b), and human FGFR3c (U87-hFGFR3c) isoforms using hFGFR3b and hFGFR3c probes (FIG. 5C).
[0253] FIGS. 6A-6C shows GFP and luciferase siRNA knockdown of their respective targets in U87-FGFR3b/c-GFP-luciferase cells. Schematic depicting treatment of the U87-FGFR3b or U87-FGFR3c cell lines, including description of the GFP-P2A-FLuc mRNA (FIG. 6A). The schematic illustrates, in particular, that since luciferase and GFP are present within one contiguous mRNA, a GFP siRNA may knockdown luciferase expression and/or a luciferase siRNA may knockdown GFP expression. Graphs showing mean GFP fluorescence intensity (FIG. 6B) and luciferase activity (FIG. 6C) within the two different siRNA (GFP siRNA and luciferase siRNA) versus non-targeting siRNA, and as compared to untreated controls. Cells were treated with parental siRNA (i.e., unmodified siRNA), revealing that the GFP siRNA was more potent than luciferase siRNA (arrows), a finding which served as an impetus to advance the GFP siRNA via introduction of truncation modifications to this molecule described herein.
[0254] FIG. 7 shows exemplary GFP and luciferase siRNA sequences.
[0255] FIGS. 8A-8B illustrate modified GFP-targeting siRNA knockdown in U87-FGFR3b-GFP-luciferase cells. Schematic depicting treatment of the U87-FGFR3b cell line, including description of the GFP-P2A-FLuc mRNA (FIG. 8A). A graph showing luciferase activity within 3′-modified (mod) GFP siRNA (3′ truncated siRNA) and 5′-modified (mod) GFP siRNA (5′ truncated siRNA) cells versus GFP siRNA and untreated controls (FIG. 8B).
[0256] FIGS. 9A-9B show modified GFP-targeting siRNA molecules. Chemical structure of N6 linker (Horizon Discovery) (FIG. 9A, top), and corresponding N6 modified GFP siRNA sequence, based on reference sequence as described in Caplen et al., 2001 (FIG. 9A, bottom). Exemplary 5′ modified GFP siRNA sequence (truncated) (FIG. 9B, top). Exemplary 3′ modified GFP siRNA sequence (truncated) (FIG. 9B, bottom).
[0257] FIGS. 10A-10C illustrate internalized FGFR3b antibody H4H30105P2 co-localizes with early and late endosomes, but not Rab4-positive recycling endosomes, and internalized FGFR3b antibody H4H30063P co-localizes with early and late endosomes, lysosomes, as well as Rab-4 positive recycling endosomes. Schematic depicting treatment of the U87-FGFR3b cell line (FIG. 10A). Photomicrographs depicting immunofluorescent detection of FGFR3b and early endosome marker EEA1 (leftmost), recycling endosome marker Rab4 (left middle), late endosome marker Rab7 (right middle), and lysosome marker Lamp1 (rightmost) in GFP-positive U87 cells stained with DAPI (FIG. 10B). Endosomal trafficking of FGFR3b antibody H4H30105P2 (non-conjugated) illustrates achievement of robust internalization as evidenced by perinuclear speckles (puncta). FGFR3b antibody H4H30105P2 co-localized with the early endosomal marker EEA1 and the late endosomal marker Rab7, but not with the recycling endosomal marker Rab4. Photomicrographs depicting immunofluorescent detection of FGFR3b and early endosome marker EEA1 (leftmost), recycling endosome marker Rab4 (left middle), late endosome marker Rab7 (right middle), and lysosome marker Lamp1 (rightmost) in GFP-positive U87 cells stained with DAPI (FIG. 10C). Endosomal trafficking of FGFR3b antibody H4H30063P (non-conjugated) illustrates achievement of robust internalization as evidenced by perinuclear speckles (puncta). FGFR3b antibody H4H30063P co-localized with the early endosomal marker EEA1, the late endosomal marker Rab7, and the lysosomal marker Lamp1, as well as with the recycling endosomal marker Rab4.
[0258] FIG. 11 shows a schematic depicting potential fate(s) of FGFR3 receptors following internalization with FGFR3 antibody conjugated to a molecular cargo. It is not yet known which fate pathway (e.g., degradation or recycling) is most beneficial for delivery for antibody-conjugated molecular cargoes.
[0259] FIGS. 12A-12B show screening of FGFR3 antibodies in the U87-FGFR3b-Fluc-GFP cell line. Photomicrographs depicting immunofluorescent detection of FGFR3b in GFP-positive U87 cells stained with DAPI illustrate robust internalization of FGFR3 antibodies in the U87-hFGFR3b cell line (FIG. 12A). Photomicrographs depicting immunofluorescent detection of FGFR3 in GFP-positive U87 cells stained with DAPI illustrate predominately surface staining with small diffuse puncta in the U87-hFGFR3c cell line for FGFR3 antibodies exhibiting best binder (i.e., strong surface binding), weak binders and non-binders properties (FIG. 12B).
[0260] FIG. 13 shows HDX epitope mapping results for anti-FGFR3b H4H30117P2, H4H30063P.
[0261] FIG. 14 shows HDX epitope mapping results for anti-FGFR3b H4H30045P and H4H30108P2.
[0262] FIG. 15 shows HDX protection by FGFR3 antibodies. Regions with above 20% and 25% HDX protection are shown.
[0263] FIGS. 16 and 17 show HDX epitope mapping of FGFR3 antibodies.
[0264] FIG. 18 shows HDX epitope mapping results for H4H30063P. Figure discloses SEQ ID NO: 238.
[0265] FIG. 19 shows HDX epitope mapping results for H4H30108P2. Figure discloses SEQ ID NO: 238.
[0266] FIG. 20 shows HDX epitope mapping results for H4H30117P2. Figure discloses SEQ ID NO: 238.
[0267] FIG. 21 shows HDX epitope mapping results for H4H30045P. Figure discloses SEQ ID NO: 238.
[0268] FIG. 22 shows exemplary Hydrogen-Deuterium Exchange Mass Spectrometry experimental process.
Regarding the use of the claimed antibody-drug conjugate, the specification discloses:
[0962] In some embodiments, anti-FGFR3 protein-drug conjugates described herein are used for treating or preventing a disease or disorder, such as but not limited to, a central nervous system (CNS) disease or disorder (e.g., a brain disease or disorder or a spinal cord disease or disorder), or an eye disease or disorder.
[0963] In some embodiments, anti-FGFR3 protein-drug conjugates described herein are used for treating or preventing a neurological disease or disorder. Non-limiting examples of neurological diseases or disorders include, but are not limited to, lysosomal storage diseases, amyloidosis, neuropathy, neurodegenerative diseases, leukodystrophy, neuropsychiatric diseases, traumatic brain injury, neurodevelopmental diseases, and neuromuscular diseases, seizure, behavioral disorders, ocular diseases or disorders, viral or microbial infections, inflammation, ischemia, and cancer. Specific examples of neurological disorders include, but are not limited to, neurodegenerative diseases (e.g., Lewy body disease, olivopontocerebellar atrophy, multiple system atrophy, postpoliomyelitis syndrome, Parkinson's disease, striatonigral degeneration, Shy-Draeger syndrome, tauopathies (e.g., Alzheimer disease and supranuclear palsy)), prion diseases (e.g., bovine spongiform encephalopathy, kuru, Creutzfeldt-Jakob syndrome, Gerstmann-Straussler-Scheinker disease, chronic wasting disease, fatal familial insomnia, and scrapie), bulbar palsy, motor neuron disease, and nervous system heterodegenerative disorders (e.g., Alexanders disease, Cockayne syndrome, Canavan disease, hepatolenticular degeneration, Huntington's disease, Halervorden-Spatz syndrome, neuronal ceroid-lipofuscinosis, Turette's syndrome, Menkes kinky hair syndrome, lafora disease, Rett syndrome, Lesch-Nyhan syndrome, and Unverricht-Lundborg syndrome), dementia (e.g., Pick's disease and spinocerebellar ataxia), cancer (e.g., central nervous system (CNS) cancers, including brain metastases resulting from cancer elsewhere in the body).
[0964] Exemplary neurological diseases that can be treated or prevented using the anti-FGFR3 protein-drug conjugates described herein are disclosed in Table 1-4. Corresponding genes that can be targeted for knockdown/knockout or knock-in replacement using, e.g., anti-FGFR3 protein-drug conjugates comprising interfering nucleic acids disclosed herein, or including a gene editing system or components of such systems disclosed herein, as well as other broad targeting options (e.g., using neuroprotective molecules), are also included.
TABLE-US-00011 TABLE 1-4 Exemplary Neurological Diseases and/or Disorders for Treatment or Prevention with Anti-FGFR3 Protein- Drug Conjugates and Corresponding Genes that can be targeted Knockdown/Knockout Multi- Knock-in/Replacement Specific for disease/indication Multi-disease/indication Disease disease targeting Specific for disease targeting Neuro- Alzheimer's ApoE risk alleles Stat3 Protective ApoE Neuroprotective molecules such degenerative disease (e.g., ApoE4) (PMID: 30322407) isoforms or gene as but not limited to below: Disease variants (e.g., ApoE2, a. Neurotrophic factors (CNTF, ApoE Christchurch, BDNF, NGF, GDNF, IGF, etc.) ApoE Jacksonville) PMID: 24340223; Parkinson's Atp13a2 (PMID: b. Antibodies and antibody disease 33046546) fragments/derivatives (e.g., full Huntington's antibodies, ScFv, F(ab), F(ab′)2 disease targeting pathological proteins, Amyotrophic lateral such as misfolded or aggregated sclerosis (ALS) Abeta or Tau in Alzheimer's Prion disease; alpha synuclein in (transmissible Parkinson's disease; huntingtin in spongiform Huntington's disease; SOD1, Fus, encephalopathies) TDP-43 in ALS; prion protein in Neuro- Alexander disease Gfap (PMID: Prion disease); developmental 34826654) c. Antibody receptor fusion disease Multiple sulfatase Sumf1 proteins (e.g., anti-amyloid beta deficiency (PMID: 22826245) Gas6 fusion protein for Autism Fmr1 (PMID: 22549954) Alzheimer's:PMID: 35927581); Epilepsy Glt1 (PMID: 34246771) also envisioned for other Rett syndrome MeCp2 (PMID: antibodies for other 29445033) neurodegenerative diseases; or Fragile X Fmr1 (PMID: 22549954) d. Socs3 (inhibition of Jak-Stat3 Physical Traumatic brain pathway a signaling pathway that injury leads to astrocyte activation) Spinal cord injury Stroke Brain edema Aqp4 (PMID: 16564496)
[0965] In some embodiments, the FGFR3 protein-drug conjugates described herein are used for treating or preventing, for example, without limitation, Alzheimer's disease, Alexander's disease, Parkinson's disease, Huntington's disease, prion diseases (transmissible spongiform encephalopathies), amyotrophic lateral sclerosis, Rett syndrome, fragile X mental retardation, multiple sulfatase deficiency (MSD), and stroke.
[0966] In some embodiments, the FGFR3 protein-drug conjugates described herein are used for treating or preventing a neuropsychiatric disease or disorder. Non-limiting examples of neuropsychiatric disease or disorders that can be treated with FGFR3 protein-drug conjugates of the present disclosure include major depressive disorder, anxiety disorders, and bipolar disorder by targeting proteins that modulate glioneuronal signaling and synaptic transmission, including but not limited to serotonin receptors (i.e., 5HT1a and 5HT7), noradrenaline receptors (i.e., ADRA1, ADRA2, ADRB1, ADRB2), serotonin transporter (SERT), noradrenaline transporter (NET), glutamine transporter (GLT1) and glutamine synthetase (GLUL), astrocytic gap junction proteins (i.e., GJB6 and GJA1), purinoceptor channels (i.e., P2RX family proteins), synaptic proteins (i.e., SNAP23, VAMP3).
[0967] Additional diseases or disorders are described in Zhao, et al. Front Mol Neurosci. 2019 Jun. 5; 12:136, which is incorporated herein by reference in its entity. As an example, astrocyte numbers or density have been reported to be affected in neuropsychiatric disorders. Either too little or too many astrocytes could be modulating by targeting astrocytes with an FGFR3 protein conjugated with a proliferative agent (if too few astrocytes), or a cytotoxic agent (if too many).
[0968] In some embodiments, anti-FGFR3 protein-drug conjugates of the present disclosure are used for treating or preventing a cancer, e.g., brain cancer. In some embodiments, anti-FGFR3 protein-drug conjugates of the present disclosure are used for treating or preventing a glioma (e.g., astrocytoma, glioblastoma) where dysregulation of FGFR3 expression is implicated (Lasorella et al., Neuro Oncol. 2017 Apr. 1; 19(4):475-483, which is incorporated herein by reference in its entity).
[0969] In some embodiments, anti-FGFR3 protein-drug conjugates described herein are used for treating or preventing glioblastoma multiforme (GBM). Glioblastoma multiforme (GBM) is a rapidly-growing type of tumor typically of the brain or spinal cord. It is the most common type of primary malignant brain tumor in adults. Only 25% of glioblastoma patients survive more than one year and 5% of patients survive more than five years. Symptoms of can depend on the brain region where the glioblastoma is located. For instance, the tumor can grow in areas of the brain that lead to difficulties in forming words or in moving limbs. Expanding tumors can increase pressure within the skull, leading to headaches. Other symptoms include impaired vision, nausea and vomiting, loss of appetite; mood swings; loss of balance, problems with memory or concentration, problems speaking and/or seizures.
Regarding subject, the specification defines subject as follow:
[0970] As used herein, the term “subject” refers to a mammal (e.g., rat, mouse, cat, dog, cow, sheep, horse, goat, rabbit), preferably a human, for example, in need of prevention and/or treatment of a disease or disorder described herein.
However, the specification does not describe the chemical structures or nucleic acid sequences of any and all molecular cargo (claim 1), any molecular cargo such as any polynucleotide molecule, any polypeptide molecule, any carrier, any viral particle, any viral capsid protein, any small molecule (claims 46, 47), any interfering nucleic acid molecule, any guide RNA, any ribozyme, any aptamer, any mixmer, any multimer, any mRNA (claim 48), any siRNA, any shRNA, any miRNA, any anti-sense oligomer, or any gapmer (claim 49) conjugated to any antibody or antigen-binding fragment thereof that binds to fibroblast growth factor receptor 3 (FGFR3) wherein the antibody or antigen-binding fragment thereof comprises any heavy chain variable region comprises the sequences set forth in claim 1 randomly paired with any light chain variable region comprises the sequence set forth in claim 1. The specification fails to disclose the structures common to all members of the genus of molecular cargo. The specification does not describe a representative number of species of antibody-drug conjugate falling within 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 antibody-drug conjugate themselves. There are no in vivo working examples. It is unpredictable which undisclosed antibody-drug conjugate is effective as a pharmaceutical composition for treating, much less preventing any and all potential neurological disease or disorder.
At the time the invention was made, it was known in the art that the location or site of conjugation on the drug and the antibody affect conjugate stability, and pharmacokinetics of antibody drug conjugates.
For example, Strop et al (Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
Furthermore, the art teaches antibody that binds to a protein from one species, e.g., human may not bind to protein from another species, e.g., rat, mouse, cat, dog, cow, sheep, horse, goat, rabbit.
For example, Yu et al (Investigative Ophthalmology & Visual Science 49(2): 522-527, February 2008; PTO 892) teach bevacizumab, which is a humanized anti-human VEGF-A mAb A.4.6.1 binds specifically to human VEGF-A, the same antibody does not bind to mouse VEGF-A (see page 522, right col., page 523, Figure 1, in particular).
“Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Regents of the University of California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997).
The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406.
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.
Given the size of the genus of molecule cargos conjugated to antibody or antigen binding fragment thereof having random pairing heavy and light chain variable region, the absence of sufficient disclosure of relevant identifying characteristics for the claimed class of the genus of encompassed the claimed antibody-drug conjugates as a pharmaceutical composition for treating or preventing any and all neurological disease or disorder in any subject, the specification at best describes a plan for making such antibody conjugate having the claimed attributes or limitations, and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
Therefore, only (1) a conjugate antibody comprising an antibody or antigen-binding fragment thereof that bind to fibroblast growth factor receptor 3 (FGFR3) wherein the antibody or antigen-binding fragment thereof is conjugated to a molecular cargo, wherein the antibody or antigen-binding fragment thereof comprises
(i) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10;
(ii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30;
(iii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50;
(iv) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70;
(v) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90;
(vi) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110;
(vii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130;
(viii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140; and an LCVR that the amino acid sequence set forth in SEQ ID NO: 148;
(ix) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(x) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(xi) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187;
(xii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207; and/or
(xiii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227 and wherein the molecular cargo is a liposome, a lipid nanoparticle (LNP), a detectable label, or a bead,
(2) The antibody conjugate above wherein the antibody or antigen-binding fragment thereof comprises:
(a) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2;and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10;
(b) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30;
(c) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50;
(d) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof); and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70;
(e) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90;
(f) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110;
(g) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof);
(h) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(i) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(j) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(k) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187;
(l) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207; or
(m) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227,
(3) the conjugate above wherein the antibody or antigen-binding fragment thereof comprises:
(a) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16;
(b) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 24, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36;
(c) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56;
(d) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 74, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76;
(e) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 94, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96;
(f) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 112, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 114, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116;
(g) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 134;
(h) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 144, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(i) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 163, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(j) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 171, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 173, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(k) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 181, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 189, an LCDR2 comprising the amino acid sequence ETS set forth in SEQ ID NO: 191, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193;
(1) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, an LCDR2 comprising the amino acid sequence KVF set forth in SEQ ID NO: 211, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213; or
(m) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 221, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76,
(4) the conjugate above wherein the antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 20;
(b) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 38, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 40;
(c) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 58, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 60;
(d) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 78, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 80;
(e) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 100;
(f) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 118, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 120;
(g) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 136, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 138;
(h) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 155, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(i) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 167, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(j) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 177, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(k) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 195, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 197;
(1) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 215, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 217; and/or
(m) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 229, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 231,
(5) a composition comprising said antibody conjugate and a pharmaceutically acceptable excipient or carrier,
(6) a kit comprising said antibody conjugate,
(7) a complex comprising said antibody conjugate bound to fibroblast growth factor receptor 3 (FGFR3),
(8) a method for making said antibody conjugate comprising a) contacting the antibody or antigen-binding fragment thereof above with the molecular cargo under the conditions favorable for conjugation of the antibody or antigen-binding fragment thereof to the molecular cargo; and (b) optionally, isolating the antibody-drug conjugate produced in step (a),
(9) a vessel or injection device comprising the antibody conjugate above.
(10) a method for delivering a molecular cargo to a tissue or cell expressing FGFR3 in the body of a subject comprising administering to the subject the antibody conjugate of claim 1, or a composition comprising said antibody drug conjugate and a pharmaceutically acceptable excipient or carrier meet the written description requirement, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1, 13-16, 46-49, 99-102 and 105 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 conjugate antibody comprising an antibody or antigen-binding fragment thereof that bind to fibroblast growth factor receptor 3 (FGFR3) wherein the antibody or antigen-binding fragment thereof is conjugated to a molecular cargo, wherein the antibody or antigen-binding fragment thereof comprises
(i) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10;
(ii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30;
(iii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50;
(iv) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70;
(v) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90;
(vi) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110;
(vii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130;
(viii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140; and an LCVR that the amino acid sequence set forth in SEQ ID NO: 148;
(ix) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(x) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(xi) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187;
(xii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207; and/or
(xiii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227 and wherein the molecular cargo is a liposome, a lipid nanoparticle (LNP), a detectable label, or a bead,
(2) The antibody conjugate above wherein the antibody or antigen-binding fragment thereof comprises:
(a) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2;and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10;
(b) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30;
(c) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50;
(d) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof); and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70;
(e) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90;
(f) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110;
(g) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof);
(h) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(i) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(j) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(k) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187;
(l) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207; or
(m) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227,
(3) the conjugate above wherein the antibody or antigen-binding fragment thereof comprises:
(a) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16;
(b) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 24, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36;
(c) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56;
(d) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 74, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76;
(e) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 94, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96;
(f) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 112, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 114, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116;
(g) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 134;
(h) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 144, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(i) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 163, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(j) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 171, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 173, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(k) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 181, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 189, an LCDR2 comprising the amino acid sequence ETS set forth in SEQ ID NO: 191, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193;
(1) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, an LCDR2 comprising the amino acid sequence KVF set forth in SEQ ID NO: 211, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213; or
(m) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 221, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76,
(4) the conjugate above wherein the antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 20;
(b) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 38, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 40;
(c) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 58, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 60;
(d) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 78, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 80;
(e) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 100;
(f) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 118, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 120;
(g) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 136, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 138;
(h) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 155, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(i) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 167, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(j) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 177, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(k) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 195, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 197;
(1) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 215, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 217; and/or
(m) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 229, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 231,
(5) a composition comprising said antibody conjugate and a pharmaceutically acceptable excipient or carrier,
(6) a kit comprising said antibody conjugate,
(7) a complex comprising said antibody conjugate bound to fibroblast growth factor receptor 3 (FGFR3),
(8) a method for making said antibody conjugate comprising a) contacting the antibody or antigen-binding fragment thereof above with the molecular cargo under the conditions favorable for conjugation of the antibody or antigen-binding fragment thereof to the molecular cargo; and (b) optionally, isolating the antibody-drug conjugate produced in step (a),
(9) a vessel or injection device comprising the antibody conjugate above and
(10) a method for delivering a molecular cargo to a tissue or cell expressing FGFR3 in the body of a subject comprising administering to the subject said antibody conjugate, or a composition comprising said antibody conjugate and a pharmaceutically acceptable excipient or carrier, does not reasonably provide enablement for any antibody-drug conjugate as set forth in claims 1, 13-16, 46-49, 99-102 and 105. 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 an antibody-drug conjugate comprising an antibody or antigen- binding fragment thereof that binds to fibroblast growth factor receptor 3 (FGFR3) and is conjugated to a molecular cargo; wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region (HCVR) that comprises the heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, 22, 42, 62, 82, 102, 122, 140, 159, 169, 179, 199, or 219; and (ii) a light chain variable region (LCVR) that comprises the light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207, or 227.
Claim 13 encompasses the antibody-drug conjugate of claim 1, wherein the antibody or antigen-binding fragment thereof comprises:
(1) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2;and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10;
(2) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30;
(3) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50;
(4) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof); and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70;
(5) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90;
(6) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110;
(7) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof);
(8) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(9) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(10) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(11) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187;
(12) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207; or
(13) an HCVR comprising the HCDR1, HCDR2 and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219; and an LCVR comprising the LCDR1, LCDR2 and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227.
Claim 14 encompasses the antibody-drug conjugate of claim 13, wherein the antibody or antigen-binding fragment thereof comprises:
(a) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16;
(b) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 24, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36;
(c) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56;
(d) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 74, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76;
(e) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 94, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96;
(f) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108; and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 112, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 114, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116;
(g) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 134;
(h) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 144, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(i) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 163, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(j) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 171, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 173, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an LCDR2 comprising the amino acid sequence GAS set forth in SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;
(k) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 181, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 189, an LCDR2 comprising the amino acid sequence ETS set forth in SEQ ID NO: 191, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193;
(1) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, an LCDR2 comprising the amino acid sequence KVF set forth in SEQ ID NO: 211, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213; and/or
(m) an HCVR that comprises: an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 221, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225, and an LCVR that comprises: an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, an LCDR2 comprising the amino acid sequence AAS set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76.
Claim 15 encompasses the antibody-drug conjugate of claim 13, wherein the antibody or antigen-binding fragment thereof comprises:
(i) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10;
(ii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 22; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 30;
(iii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50;
(iv) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 62; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 70;
(v) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90;
(vi) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 102; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 110;
(vii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130;
(viii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 140; and an LCVR that the amino acid sequence set forth in SEQ ID NO: 148;
(ix) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 159; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(x) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 169; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 148;
(xi) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 179; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 187;
(xii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 199; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 207; and/or
(xiii) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 219; and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 227.
Claim 16 encompasses the antibody-drug conjugate of claim 13, wherein the antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 20;
(b) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 38, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 40;
(c) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 58, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 60;
(d) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 78, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 80;
(e) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 100;
(f) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 118, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 120;
(g) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 136, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 138;
(h) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 155, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(i) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 167, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(j) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 177, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 157;
(k) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 195, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 197;
(1) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 215, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 217; and/or
(m) a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO: 229, and a light chain that comprises the amino acid sequence set forth in SEQ ID NO: 231.
Claim 46 encompasses the antibody-drug conjugate of claim 1, wherein the molecular cargo comprises any polynucleotide molecule, any polypeptide molecule, any carrier, any viral particle, any viral capsid protein, or any small molecule.
Claim 47 encompasses the antibody-drug conjugate of claim 46, wherein the molecular cargo comprises any polynucleotide molecule.
Claim 48 encompasses the antibody-drug conjugate of claim 47, wherein the polynucleotide molecule is any interfering nucleic acid molecule, any guide RNA, any ribozyme, any aptamer, any mixmer, any multimer, or any mRNA.
Claim 49 encompasses the antibody-drug conjugate of claim 48, wherein the interfering nucleic acid molecule is any siRNA, any shRNA, any miRNA, any antisense oligonucleotide, or any gapmer.
Claim 99 encompasses a pharmaceutical composition comprising the antibody-drug conjugate of claim 1 and a pharmaceutically acceptable excipient or carrier.
Claim 100 encompasses a composition or kit comprising 1) the antibody-drug conjugate of A composition or kit comprising 1) the antibody-drug conjugate of 2) a further therapeutic agent.
Claim 101 encompasses a complex comprising the antibody-drug conjugate of claim 1 bound to fibroblast growth factor receptor 3 (FGFR3).
Claim 102 encompasses a method for making the antibody-drug conjugate of claim 1, comprising:(a) contacting the antibody or antigen-binding fragment thereof with the molecular cargo under the conditions favorable for conjugation of the antibody or antigen-binding fragment thereof to the molecular cargo; and(b) optionally, isolating the antibody-drug conjugate produced in step (a).
Claim 105 encompasses a vessel or injection device comprising the antibody-drug conjugate of claim 1.
Claim 107 encompasses a method for delivering a molecular cargo to a tissue or cell type expressing FGFR3 in the body of a subject comprising administering to the subject the antibody- drug conjugate of claim 1, or a pharmaceutical composition comprising said protein-drug conjugate and a pharmaceutically acceptable excipient or carrier.
The specification discloses 13 antibodies that bind to human fibroblast growth factor receptor 3 (FGFR3) wherein the antibodies each comprises a specific combination of a heavy chain variable region sequence and a light chain variable region sequence shown in table 1-3.
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[0248] FIGS. 1A-1B depict schematic representations of the general architecture of fibroblast growth factor receptor 3 (FGFR3), and isoforms FGFR3b and FGFR3c. Schematic showing the orientation of an FGFR dimer within the plasma membrane (FIG. 1A, top). The FGF3 receptor domain structure is comprised of an extracellular domain comprising a ligand binding site, a transmembrane domain, and an intracellular domain comprising spit tyrosine kinases. The receptor is depicted stabilized by a heparin/heparan sulfate (HS) chain of HS proteoglycan, HSPG. Schematic of the FGF monomer exemplifying the three IgG-like loops (Ig-I, Ig-II, and Ig-III) of the extracellular ligand-binding domain and the split kinase domain (FIG. 1A, bottom). Schematic showing a structural comparison of alternatively spliced FGFR3b and FGFR3c isoforms (FIG. 1B). Ig-I, Ig-II, and Ig-II loops of the extracellular domain ligand-binding domain are encoded by exons 7-9. FGFR3b includes exon 8, and excludes exon 9, whereas FGFR3c includes exon 9 and excludes exon 8. Thus, inclusion/exclusion of exon 8 and 9 directs expression of IIIb versus IIIc splice forms.
[0249] FIGS. 2A-2B illustrate FGFR3 is highly expressed on mouse and human astrocytes. Graphs of RNA sequencing (RNASeq) data depicting expression of FGFR1-FGFR4 transcript in mouse (FIG. 2A) and human (FIG. 2B) nervous and supporting cells.
[0250] FIG. 3 shows expression of total FGFR3, and FGFR3b and FGFR3c isoforms, in mouse brain, primary mouse astrocytes, and primary human astrocytes. Data are plotted as relative to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) Ct values, and normalized to the relative expression of each isoform from the mouse brain (1/2ΔΔCt, mean±standard deviation [SD]).
[0251] FIGS. 4A-4C illustrate FGFR3 antibodies internalize into live astrocytes as evidenced by perinuclear speckles (puncta). A schematic depicting an exemplary experimental timeline (FIG. 4A). Photomicrograph showing immunofluorescence detection of actin cytoskeleton and perinumclear FGFR3 puncta in human astrocytes using DEAD staining approaches described herein (FIG. 4B). Photomicrographs showing immunofluorescence detection of vimentin (VIM) cytoskeleton and perinuclear FGFR3 puncta in human and mouse astrocytes using LIVE staining approaches described herein (FIG. 4C). Non-degrader (H4H30063P) FGFR3 antibodies showed robust internalization as evidenced by prevalent puncta surrounding the nucleus.
[0252] FIGS. 5A-5C illustrate validation of FGFR3 expression and internalization in the U87-FGFR3b-FLuc-GFP line. A schematic depicting an exemplary experimental timeline (FIG. 5A). Photomicrographs showing immunofluorescent detection of FGFR3b and FelD1 (negative control) in GFP-positive U87 cells stained with DAPI (FIG. 5B). FGFR3 are visualized as prevalent fluorescent puncta surrounding the nucleus (DAPI staining), confirming FGFR3 expression and internalization in the U87-FGFR3b-FLuc-GFP line. A graph showing percent normalized TaqMan FGFR3 expression (mean±standard deviation [SD]) in U87 parental cells, and in U87 cell lines expressing human FGFR3b (U87-hFGFR3b), and human FGFR3c (U87-hFGFR3c) isoforms using hFGFR3b and hFGFR3c probes (FIG. 5C).
[0253] FIGS. 6A-6C shows GFP and luciferase siRNA knockdown of their respective targets in U87-FGFR3b/c-GFP-luciferase cells. Schematic depicting treatment of the U87-FGFR3b or U87-FGFR3c cell lines, including description of the GFP-P2A-FLuc mRNA (FIG. 6A). The schematic illustrates, in particular, that since luciferase and GFP are present within one contiguous mRNA, a GFP siRNA may knockdown luciferase expression and/or a luciferase siRNA may knockdown GFP expression. Graphs showing mean GFP fluorescence intensity (FIG. 6B) and luciferase activity (FIG. 6C) within the two different siRNA (GFP siRNA and luciferase siRNA) versus non-targeting siRNA, and as compared to untreated controls. Cells were treated with parental siRNA (i.e., unmodified siRNA), revealing that the GFP siRNA was more potent than luciferase siRNA (arrows), a finding which served as an impetus to advance the GFP siRNA via introduction of truncation modifications to this molecule described herein.
[0254] FIG. 7 shows exemplary GFP and luciferase siRNA sequences.
[0255] FIGS. 8A-8B illustrate modified GFP-targeting siRNA knockdown in U87-FGFR3b-GFP-luciferase cells. Schematic depicting treatment of the U87-FGFR3b cell line, including description of the GFP-P2A-FLuc mRNA (FIG. 8A). A graph showing luciferase activity within 3′-modified (mod) GFP siRNA (3′ truncated siRNA) and 5′-modified (mod) GFP siRNA (5′ truncated siRNA) cells versus GFP siRNA and untreated controls (FIG. 8B).
[0256] FIGS. 9A-9B show modified GFP-targeting siRNA molecules. Chemical structure of N6 linker (Horizon Discovery) (FIG. 9A, top), and corresponding N6 modified GFP siRNA sequence, based on reference sequence as described in Caplen et al., 2001 (FIG. 9A, bottom). Exemplary 5′ modified GFP siRNA sequence (truncated) (FIG. 9B, top). Exemplary 3′ modified GFP siRNA sequence (truncated) (FIG. 9B, bottom).
[0257] FIGS. 10A-10C illustrate internalized FGFR3b antibody H4H30105P2 co-localizes with early and late endosomes, but not Rab4-positive recycling endosomes, and internalized FGFR3b antibody H4H30063P co-localizes with early and late endosomes, lysosomes, as well as Rab-4 positive recycling endosomes. Schematic depicting treatment of the U87-FGFR3b cell line (FIG. 10A). Photomicrographs depicting immunofluorescent detection of FGFR3b and early endosome marker EEA1 (leftmost), recycling endosome marker Rab4 (left middle), late endosome marker Rab7 (right middle), and lysosome marker Lamp1 (rightmost) in GFP-positive U87 cells stained with DAPI (FIG. 10B). Endosomal trafficking of FGFR3b antibody H4H30105P2 (non-conjugated) illustrates achievement of robust internalization as evidenced by perinuclear speckles (puncta). FGFR3b antibody H4H30105P2 co-localized with the early endosomal marker EEA1 and the late endosomal marker Rab7, but not with the recycling endosomal marker Rab4. Photomicrographs depicting immunofluorescent detection of FGFR3b and early endosome marker EEA1 (leftmost), recycling endosome marker Rab4 (left middle), late endosome marker Rab7 (right middle), and lysosome marker Lamp1 (rightmost) in GFP-positive U87 cells stained with DAPI (FIG. 10C). Endosomal trafficking of FGFR3b antibody H4H30063P (non-conjugated) illustrates achievement of robust internalization as evidenced by perinuclear speckles (puncta). FGFR3b antibody H4H30063P co-localized with the early endosomal marker EEA1, the late endosomal marker Rab7, and the lysosomal marker Lamp1, as well as with the recycling endosomal marker Rab4.
[0258] FIG. 11 shows a schematic depicting potential fate(s) of FGFR3 receptors following internalization with FGFR3 antibody conjugated to a molecular cargo. It is not yet known which fate pathway (e.g., degradation or recycling) is most beneficial for delivery for antibody-conjugated molecular cargoes.
[0259] FIGS. 12A-12B show screening of FGFR3 antibodies in the U87-FGFR3b-Fluc-GFP cell line. Photomicrographs depicting immunofluorescent detection of FGFR3b in GFP-positive U87 cells stained with DAPI illustrate robust internalization of FGFR3 antibodies in the U87-hFGFR3b cell line (FIG. 12A). Photomicrographs depicting immunofluorescent detection of FGFR3 in GFP-positive U87 cells stained with DAPI illustrate predominately surface staining with small diffuse puncta in the U87-hFGFR3c cell line for FGFR3 antibodies exhibiting best binder (i.e., strong surface binding), weak binders and non-binders properties (FIG. 12B).
[0260] FIG. 13 shows HDX epitope mapping results for anti-FGFR3b H4H30117P2, H4H30063P.
[0261] FIG. 14 shows HDX epitope mapping results for anti-FGFR3b H4H30045P and H4H30108P2.
[0262] FIG. 15 shows HDX protection by FGFR3 antibodies. Regions with above 20% and 25% HDX protection are shown.
[0263] FIGS. 16 and 17 show HDX epitope mapping of FGFR3 antibodies.
[0264] FIG. 18 shows HDX epitope mapping results for H4H30063P. Figure discloses SEQ ID NO: 238.
[0265] FIG. 19 shows HDX epitope mapping results for H4H30108P2. Figure discloses SEQ ID NO: 238.
[0266] FIG. 20 shows HDX epitope mapping results for H4H30117P2. Figure discloses SEQ ID NO: 238.
[0267] FIG. 21 shows HDX epitope mapping results for H4H30045P. Figure discloses SEQ ID NO: 238.
[0268] FIG. 22 shows exemplary Hydrogen-Deuterium Exchange Mass Spectrometry experimental process.
Regarding the use of the claimed antibody-drug conjugate, the specification discloses:
[0962] In some embodiments, anti-FGFR3 protein-drug conjugates described herein are used for treating or preventing a disease or disorder, such as but not limited to, a central nervous system (CNS) disease or disorder (e.g., a brain disease or disorder or a spinal cord disease or disorder), or an eye disease or disorder.
[0963] In some embodiments, anti-FGFR3 protein-drug conjugates described herein are used for treating or preventing a neurological disease or disorder. Non-limiting examples of neurological diseases or disorders include, but are not limited to, lysosomal storage diseases, amyloidosis, neuropathy, neurodegenerative diseases, leukodystrophy, neuropsychiatric diseases, traumatic brain injury, neurodevelopmental diseases, and neuromuscular diseases, seizure, behavioral disorders, ocular diseases or disorders, viral or microbial infections, inflammation, ischemia, and cancer. Specific examples of neurological disorders include, but are not limited to, neurodegenerative diseases (e.g., Lewy body disease, olivopontocerebellar atrophy, multiple system atrophy, postpoliomyelitis syndrome, Parkinson's disease, striatonigral degeneration, Shy-Draeger syndrome, tauopathies (e.g., Alzheimer disease and supranuclear palsy)), prion diseases (e.g., bovine spongiform encephalopathy, kuru, Creutzfeldt-Jakob syndrome, Gerstmann-Straussler-Scheinker disease, chronic wasting disease, fatal familial insomnia, and scrapie), bulbar palsy, motor neuron disease, and nervous system heterodegenerative disorders (e.g., Alexanders disease, Cockayne syndrome, Canavan disease, hepatolenticular degeneration, Huntington's disease, Halervorden-Spatz syndrome, neuronal ceroid-lipofuscinosis, Turette's syndrome, Menkes kinky hair syndrome, lafora disease, Rett syndrome, Lesch-Nyhan syndrome, and Unverricht-Lundborg syndrome), dementia (e.g., Pick's disease and spinocerebellar ataxia), cancer (e.g., central nervous system (CNS) cancers, including brain metastases resulting from cancer elsewhere in the body).
[0964] Exemplary neurological diseases that can be treated or prevented using the anti-FGFR3 protein-drug conjugates described herein are disclosed in Table 1-4. Corresponding genes that can be targeted for knockdown/knockout or knock-in replacement using, e.g., anti-FGFR3 protein-drug conjugates comprising interfering nucleic acids disclosed herein, or including a gene editing system or components of such systems disclosed herein, as well as other broad targeting options (e.g., using neuroprotective molecules), are also included.
TABLE-US-00011 TABLE 1-4 Exemplary Neurological Diseases and/or Disorders for Treatment or Prevention with Anti-FGFR3 Protein- Drug Conjugates and Corresponding Genes that can be targeted Knockdown/Knockout Multi- Knock-in/Replacement Specific for disease/indication Multi-disease/indication Disease disease targeting Specific for disease targeting Neuro- Alzheimer's ApoE risk alleles Stat3 Protective ApoE Neuroprotective molecules such degenerative disease (e.g., ApoE4) (PMID: 30322407) isoforms or gene as but not limited to below: Disease variants (e.g., ApoE2, a. Neurotrophic factors (CNTF, ApoE Christchurch, BDNF, NGF, GDNF, IGF, etc) ApoE Jacksonville) PMID: 24340223; Parkinson's Atp13a2 (PMID: b. Antibodies and antibody disease 33046546) fragments/derivatives (e.g., full Huntington's antibodies, ScFv, F(ab), F(ab′)2 disease targeting pathological proteins, Amyotrophic lateral such as misfolded or aggregated sclerosis (ALS) Abeta or Tau in Alzheimer's Prion disease; alpha synuclein in (transmissible Parkinson's disease; huntingtin in spongiform Huntington's disease; SOD1, Fus, encephalopathies) TDP-43 in ALS; prion protein in Neuro- Alexander disease Gfap (PMID: Prion disease); developmental 34826654) c. Antibody receptor fusion disease Multiple sulfatase Sumf1 proteins (e.g., anti-amyloid beta deficiency (PMID: 22826245) Gas6 fusion protein for Autism Fmr1 (PMID: 22549954) Alzheimer's:PMID: 35927581); Epilepsy Glt1 (PMID: 34246771) also envisioned for other Rett syndrome MeCp2 (PMID: antibodies for other 29445033) neurodegenerative diseases; or Fragile X Fmr1 (PMID: 22549954) d. Socs3 (inhibition of Jak-Stat3 Physical Traumatic brain pathway a signaling pathway that injury injury leads to astrocyte activation) Spinal cord injury Stroke Brain edema Aqp4 (PMID: 16564496)
[0965] In some embodiments, the FGFR3 protein-drug conjugates described herein are used for treating or preventing, for example, without limitation, Alzheimer's disease, Alexander's disease, Parkinson's disease, Huntington's disease, prion diseases (transmissible spongiform encephalopathies), amyotrophic lateral sclerosis, Rett syndrome, fragile X mental retardation, multiple sulfatase deficiency (MSD), and stroke.
[0966] In some embodiments, the FGFR3 protein-drug conjugates described herein are used for treating or preventing a neuropsychiatric disease or disorder. Non-limiting examples of neuropsychiatric disease or disorders that can be treated with FGFR3 protein-drug conjugates of the present disclosure include major depressive disorder, anxiety disorders, and bipolar disorder by targeting proteins that modulate glioneuronal signaling and synaptic transmission, including but not limited to serotonin receptors (i.e., 5HT1a and 5HT7), noradrenaline receptors (i.e., ADRA1, ADRA2, ADRB1, ADRB2), serotonin transporter (SERT), noradrenaline transporter (NET), glutamine transporter (GLT1) and glutamine synthetase (GLUL), astrocytic gap junction proteins (i.e., GJB6 and GJA1), purinoceptor channels (i.e., P2RX family proteins), synaptic proteins (i.e., SNAP23, VAMP3).
[0967] Additional diseases or disorders are described in Zhao, et al. Front Mol Neurosci. 2019 Jun. 5; 12:136, which is incorporated herein by reference in its entity. As an example, astrocyte numbers or density have been reported to be affected in neuropsychiatric disorders. Either too little or too many astrocytes could be modulating by targeting astrocytes with an FGFR3 protein conjugated with a proliferative agent (if too few astrocytes), or a cytotoxic agent (if too many).
[0968] In some embodiments, anti-FGFR3 protein-drug conjugates of the present disclosure are used for treating or preventing a cancer, e.g., brain cancer. In some embodiments, anti-FGFR3 protein-drug conjugates of the present disclosure are used for treating or preventing a glioma (e.g., astrocytoma, glioblastoma) where dysregulation of FGFR3 expression is implicated (Lasorella et al., Neuro Oncol. 2017 Apr. 1; 19(4):475-483, which is incorporated herein by reference in its entity).
[0969] In some embodiments, anti-FGFR3 protein-drug conjugates described herein are used for treating or preventing glioblastoma multiforme (GBM). Glioblastoma multiforme (GBM) is a rapidly-growing type of tumor typically of the brain or spinal cord. It is the most common type of primary malignant brain tumor in adults. Only 25% of glioblastoma patients survive more than one year and 5% of patients survive more than five years. Symptoms of can depend on the brain region where the glioblastoma is located. For instance, the tumor can grow in areas of the brain that lead to difficulties in forming words or in moving limbs. Expanding tumors can increase pressure within the skull, leading to headaches. Other symptoms include impaired vision, nausea and vomiting, loss of appetite; mood swings; loss of balance, problems with memory or concentration, problems speaking and/or seizures.
Regarding subject, the specification defines subject as follow:
[0970] As used herein, the term “subject” refers to a mammal (e.g., rat, mouse, cat, dog, cow, sheep, horse, goat, rabbit), preferably a human, for example, in need of prevention and/or treatment of a disease or disorder described herein.
However, the specification does not teach the chemical structures or nucleic acid sequences of any and all molecular cargo (claim 1), any molecular cargo such as any polynucleotide molecule, any polypeptide molecule, any carrier, any viral particle, any viral capsid protein, any small molecule (claims 46, 47), any interfering nucleic acid molecule, any guide RNA, any ribozyme, any aptamer, any mixmer, any multimer, any mRNA (claim 48), any siRNA, any shRNA, any miRNA, any anti-sense oligomer, or any gapmer (claim 49) conjugated to any antibody or antigen-binding fragment thereof that binds to fibroblast growth factor receptor 3 (FGFR3) wherein the antibody or antigen-binding fragment thereof comprises any heavy chain variable region comprises the sequences set forth in claim 1 randomly paired with any light chain variable region comprises the sequence set forth in claim 1.
The specification does not teach a representative number of species of antibody-drug conjugate falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can make and use the claimed antibody-drug conjugate themselves for treating or preventing any and all possible neurological diseases.
At the time the invention was made, it was known in the art that the location or site of conjugation on the drug and the antibody affect conjugate stability, and pharmacokinetics of antibody drug conjugates.
For example, Strop et al (Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
Furthermore, the art teaches antibody that binds to a protein from one species, e.g., human may not bind to the same protein from another species, e.g., rat, mouse, cat, dog, cow, sheep, horse, goat, rabbit.
For example, Yu et al (Investigative Ophthalmology & Visual Science 49(2): 522-527, February 2008; PTO 892) teach bevacizumab, which is a humanized anti-human VEGF-A mAb A.4.6.1 binds specifically to human VEGF-A, the same antibody does not bind to mouse VEGF-A (see page 522, right col., page 523, Figure 1, in particular).
There are no in vivo working examples. It is unpredictable which undisclosed antibody-drug conjugate is effective as a pharmaceutical composition for treating any and all potential neurological disease or disorder, much less preventing all neurological disease or disorder.
As such, it would require undue experimentation of one skilled in the art to practice the claimed invention. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 13-16, 46-49, 99-102 and 105 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 13-17 of copending Application No. 18/509,136. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Appl. 136 teach:
Copending claim 1 recites an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof comprising: a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2, 22, 42, 62, 82 ,102, 122, 140, 159, 169, 179, 199 or 219 and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207, or 227.
18/509,030
18/509,136
Heavy chain (HC)
SEQ ID NO: 155
SEQ ID NO: 155
Light chain (LC)
SEQ ID NO: 157
SEQ ID NO: 157
Heavy chain variable Region (HCVR)
SEQ ID NO: 140
SEQ ID NO: 140
Light chain variable region (LCVR)
SEQ ID NO: 148
SEQ ID NO: 148
SEQ ID NO: 142
GYSFTSYW
GYSFTSYW
SEQ ID NO: 144
IYPGDSDT
IYPGDSDT
SEQ ID NO: 146
ARLDYSGSWFDY
ARLDYSGSWFDY
SEQ ID NO: 150
QSVSSSY
QSVSSSY
GAS
GAS
SEQ ID NO: 153
QQYGSSPWT
QQYGSSPWT
The copending application also teaches immunoconjugates, see para. [0250].
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
SEQ ID NO: 2, 22, 42, 62, 82, 102, 122, 140, 159, 169, 179, 199, 219, 10, 130, 18, 20, 38, 40, 58, 60, 78, 98, 118, 136, 138, 155, 167, 177, 195, 197, 215, 217, 229 are 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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