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 1-6, 9, 12, 14, 16, 18-21, 25, 27 and 29 are pending.
Applicant’s election without traverse of Group I that read on the amino acid sequence of SEQ ID NO: 2, which selectively binds to immune cells that express CD16 as the species of targeting domain that selectively binds to a target in the reply filed on July 1, 2026 is acknowledged.
Claims 19-21 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-6, 9, 12, 14, 16, 18, 25, 27 and 29, drawn to a compound comprising a targeting domain that selectively binds to a target and an ADAM17-inhibiting domain and a linker operably linking the targeting domain and the ADAM17-inhibiting domain that read on the amino acid sequence of SEQ ID NO: 2, which selectively binds to immune cells that express CD16 as the species of targeting domain that selectively binds to a target, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/211,026, filed June 16, 2021, 63/211,033, filed June 16, 2021 and 63/211,041, filed June 16, 2021, is acknowledged.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 4 recites “a fragment thereof”. The phrase fragment can be as little as two amino acids or the antigen binding fragment or the Fc fragment. One skilled in the art could not determine the boundaries of the claimed invention in order to avoid infringing on the claim. Amending claim 4 to “antigen-binding fragment thereof” would obvious this rejection.
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 1-6, 9, 12, 14, 16, 18, 25, 27 and 29 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 any compound comprising: a targeting domain that selectively binds to any target; any ADAM17-inhibiting domain; and any linker operably linking the targeting domain and the ADAM 17-inhibiting domain.
Claim 2 encompasses the compound of claim 1, wherein the targeting domain selectively binds to any immune cell.
Claim 3 encompasses the compound of claim 2, wherein the immune cell is a T cell, a B cell, an NK cell, a monocyte, a macrophage, a dendritic cell, a myeloid-derived suppressor cell, or a mast cell.
Claim 4 encompasses the compound of claim 1, wherein the targeting domain comprises any antibody or any fragment thereof.
Claim 5 encompasses the compound of claim 4, wherein the antibody fragment comprises any scFv.
Claim 6 encompasses the compound of claim 4, wherein the antibody fragment comprises any single domain antibody.
Claim 9 encompasses the compound of claim l, wherein the targeting domain selectively binds to any cell infected by a virus.
Claim 12 encompasses the compound of claim l, wherein the targeting domain selectively binds to any cell infected by a bacterium.
Claim 14 encompasses the compound of claim l, wherein the targeting domain selectively binds to any cell infected by a parasite.
Claim 16 encompasses the compound of claim l, wherein the targeting domain selectively binds to any cell infected by a fungal cell.
Claim 18 encompasses the compound of claim l, wherein the targeting domain selectively binds to any tumor cell.
Claim 24 encompasses any human IgG4 antibody, or fragment thereof, comprising: at least one of SEQ ID NO:17-19; and amino acids 144-469 of SEQ ID NO:20.
Claim 27 encompasses any human IgG4 antibody, or fragment thereof, comprising: at least one of SEQ ID NO:13-15; and amino acids 128-234 of SEQ ID NO:21.
Claim 29 encompasses any therapeutic compound comprising: an anti-ADAM17 domain comprising the antibody, or fragment thereof, comprising:
at least one of SEQ ID NO:17-19 and amino acids 144-469 of SEQ ID NO:20, or
at least one of SEQ ID NO:13-15 and amino acids 128-234 of SEQ ID NO:21; and any targeting domain that specifically binds to a target of interest.
The specification discloses ADAM17-inhibiting antibody comprising a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 12 and a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 16, wherein the VL comprises CDRs1-3 of SEQ ID NO: 13 to 15 and wherein the VH comprises CDRs 1-3 of SEQ ID NO: 17 to 19, and a human anti-ADAM17 IgG4 antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprising the amino acid sequence of SEQ ID NO: 20 and a VL comprising the amino acid sequence of SEQ ID NO: 21.
Regarding targeting domain that binds to NK cells, the specification discloses just one sdAb that binds to CD16 comprising the amino acid sequence of SEQ ID NO: 2. These two domains are linked together by a linker. Exemplary CD16/ADAM17 TAB comprises the amino acid sequence of SEQ ID NO: 40.
However, this is not sufficiently representative of the broad range of compounds encompassed by instant claims. The specification does not describe structure-identifying information about all possible targeting domain that selectively binds to any and all possible target and ADAM17-inhibiting domain. The specification does not describe a representative number of species 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 compound. Thus one of skill in the art cannot "visualize or recognize" most members of the genus.
Even assuming the compound comprising a targeting domain and an ADAM17-inibitging domain linked together by a linker is a bispecific antibody, the specification does not describe i. Complete structure, e.g., amino acid sequence of heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs and functional features share by members of the genus of targeting domains that correlated with binding to any and all potential target, and ADAM17-inhibiting domain encompassed by the claimed compound.
Even assuming the targeting domain binds to CD16 on NK cells, the specification discloses just one VHH comprising the amino acid sequence of SEQ ID NO: 2. The specification does not describe a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed antibody or antigen-binding fragment thereof that bind to CD16 and ADAM17.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., J Mol Biol. 2003 Nov 14;334(1): 103-118, found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Nguyen et al (EMBO Journal, 19(5): 921-930, 2000; PTO 892) teaches that VHH germline segments are highly diverse, leading to a broad structural repertoire of the antigen-binding loops. Seven VHH subfamilies have been recognized, of which 5 were confirmed to be expressed in vivo. Comparison of germline and cDNA sequences demonstrates that the rearranged VHHs are also extensively diversified by somatic mutations process, leading to an additional hypervariable region and a high incidence of nucleotide insertions or deletions. These diversification processes are drives by hypermutation and recombination hotspots embedded in the VHH germline genes at the regions affecting the structure of the antigen-binding loops. Germline segments of these antibodies are highly diverse, leading to a broad structural repertoire of the antigen-binding loops and such VHHs are even extensively diversified by somatic mutation processes.
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie). Thus the disclosure does not allow one of skill in the art to visualize or recognize the structure of such "compound" or "targeting domain" or "ADAM17-inhibiting domain" required to practice the claimed invention.
Regarding “fragment thereof” (claims 4, 25, 27, 29), the phrase “fragment” can be as little as two amino acids, or the Fc fragment. However, only the antigen binding fragment, e.g., Fab, F(ab)2, scFv can bind to a target.
Regarding the targeting domain selectively binds to any cell infected by any virus (claim 9), any cell infected by any bacterium (claim 12), any cell infected by any parasite (claim 14) or any tumor cell (claim 18), these claims are reached through claims because the binding specificity of the targeting domain to the target on such cells are not adequately described.
Regarding at least one of SEQ ID NO: 17-19 (claim 25, 29) or at least one of SEQ ID NO: 13-15 (claims 27 and 29), the specification discloses an ADAM17-inhibiting antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 16 wherein the light chain CDRs1-3 are set forth in SEQ ID NO: 13 to 15 and wherein the heavy chain CDRs 1-3 are set forth in SEQ ID NO: 17 to 19, see specification at p. 44.
However, the specification does not teach antibody comprising just heavy chain (claim 25, 29) or just light chain variable (claim 27, 29) and any one CDR from the light chain variable region paired with any one CDR from the heavy chain variable region (claims 25, 27 and 29) still maintains antigen binding.
Chiu et al (Antibodies 8: 55-80, 2019; PTO 892) teaches the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see p. 4, in particular). It is unlikely the claimed antibody in claims 25, 27 and 29 have the required antigen binding function.
Amgen Inc. v. Sanofi, 782 F.3d 1367, 1378 (Fed. Cir. 2017) (holding that an “adequate written description must contain enough information about the actual makeup of the claimed products”). Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010).
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.
Therefore, only (1) a human IgG4 anti-AMAM17 antibody comprising a heavy chain comprising a heavy CDR1 (HCDR1), a HCDR2 and a HCDR3 and a light chain comprising a light chain CDR1 (LCDR1), a LCDR2, and a LCDR3 wherein the heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and wherein the light chain comprising the amino acid sequence of SEQ ID NO: 21, (2) Said human IgG4 anti-AMAM17 antibody wherein the HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 17, 18 and 19, respectively, and wherein the LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 13, 14 and 15, respectively, (3) a targeted ADAM17 blocker (TAB) compound comprising a targeting domain and an ADAM17-inhibiting domain and a linker operably linking the targeting domain and the ADAM17-inhibiting domain wherein the compound comprises the amino acid sequence of SEQ ID NO: 40, (4) the said targeted ADAM17 blocker (TAB) compound wherein the targeting domain comprises the amino acid sequence of SEQ ID NO: 2, (5) targeted ADAM17 blocker (TAB) compound comprising a targeting domain and an ADAM17-inhibiting domain and a linker operably linking the targeting domain and the ADAM17-inhibiting domain wherein the compound comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 36, 37, 38, 39, 40, 41, 42, 43 and 44, 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 1-6, 9, 12, 14, 16, 18, 25, 27 and 29 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 human IgG4 anti-AMAM17 antibody comprising a heavy chain comprising a heavy CDR1 (HCDR1), a HCDR2 and a HCDR3 and a light chain comprising a light chain CDR1 (LCDR1), a LCDR2, and a LCDR3 wherein the heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and wherein the light chain comprising the amino acid sequence of SEQ ID NO: 21, (2) Said human IgG4 anti-AMAM17 antibody wherein the HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 17, 18 and 19, respectively, and wherein the LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 13, 14 and 15, respectively, (3) a targeted ADAM17 blocker (TAB) compound comprising a targeting domain and an ADAM17-inhibiting domain and a linker operably linking the targeting domain and the ADAM17-inhibiting domain wherein the compound comprises the amino acid sequence of SEQ ID NO: 40, (4) the said targeted ADAM17 blocker (TAB) compound wherein the targeting domain comprises the amino acid sequence of SEQ ID NO: 2, (5) targeted ADAM17 blocker (TAB) compound comprising a targeting domain and an ADAM17-inhibiting domain and a linker operably linking the targeting domain and the ADAM17-inhibiting domain wherein the compound comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 36, 37, 38, 39, 40, 41, 42, 43 and 44, does not reasonably provide enablement for any and all compound as set forth in claims 1-6, 9, 12, 14, 16 and 18, and human IgG4 antibody as set forth in claims 25, 27 and 29. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses any compound comprising: a targeting domain that selectively binds to any target; any ADAM17-inhibiting domain; and any linker operably linking the targeting domain and the ADAM 17-inhibiting domain.
Claim 2 encompasses the compound of claim 1, wherein the targeting domain selectively binds to any immune cell.
Claim 3 encompasses the compound of claim 2, wherein the immune cell is a T cell, a B cell, an NK cell, a monocyte, a macrophage, a dendritic cell, a myeloid-derived suppressor cell, or a mast cell.
Claim 4 encompasses the compound of claim 1, wherein the targeting domain comprises any antibody or any fragment thereof.
Claim 5 encompasses the compound of claim 4, wherein the antibody fragment comprises any scFv.
Claim 6 encompasses the compound of claim 4, wherein the antibody fragment comprises any single domain antibody.
Claim 9 encompasses the compound of claim l, wherein the targeting domain selectively binds to any cell infected by a virus.
Claim 12 encompasses the compound of claim l, wherein the targeting domain selectively binds to any cell infected by a bacterium.
Claim 14 encompasses the compound of claim l, wherein the targeting domain selectively binds to any cell infected by a parasite.
Claim 16 encompasses the compound of claim l, wherein the targeting domain selectively binds to any cell infected by a fungal cell.
Claim 18 encompasses the compound of claim l, wherein the targeting domain selectively binds to any tumor cell.
Claim 24 encompasses any human IgG4 antibody, or fragment thereof, comprising: at least one of SEQ ID NO:17-19; and amino acids 144-469 of SEQ ID NO:20.
Claim 27 encompasses any human IgG4 antibody, or fragment thereof, comprising: at least one of SEQ ID NO:13-15; and amino acids 128-234 of SEQ ID NO:21.
Claim 29 encompasses any therapeutic compound comprising: an anti-ADAM17 domain comprising the antibody, or fragment thereof, comprising:
at least one of SEQ ID NO:17-19 and amino acids 144-469 of SEQ ID NO:20, or
at least one of SEQ ID NO:13-15 and amino acids 128-234 of SEQ ID NO:21; and any targeting domain that specifically binds to a target of interest.
The specification discloses ADAM17-inhibiting antibody comprising a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 12 and a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 16, wherein the VL comprises CDRs1-3 of SEQ ID NO: 13 to 15 and wherein the VH comprises CDRs 1-3 of SEQ ID NO: 17 to 19, and a human anti-ADAM17 IgG4 antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprising the amino acid sequence of SEQ ID NO: 20 and a VL comprising the amino acid sequence of SEQ ID NO: 21.
Regarding targeting domain that binds to NK cells, the specification discloses just one sdAb that binds to CD16 comprising the amino acid sequence of SEQ ID NO: 2. These two domains are linked together by a linker. Exemplary CD16/ADAM17 TAB comprises the amino acid sequence of SEQ ID NO: 40.
However, the specification does not teach the structure-identifying information about all possible targeting domain that selectively binds to any and all possible target and ADAM17-inhibiting domain to enable one of skill in the art to make and use without undue experimentation.
Even assuming the compound comprising a targeting domain and an ADAM17-inibitging domain linked together by a linker is a bispecific antibody, the specification does not teach i. Complete structure, e.g., amino acid sequence of heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs and functional features share by members of the genus of targeting domains that correlated with binding to any and all potential target, and ADAM17-inhibiting domain encompassed by the claimed compound.
Even assuming the targeting domain binds to CD16 on NK cells, the specification discloses just one VHH comprising the amino acid sequence of SEQ ID NO: 2. The specification does not teach a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can make and use member of the genus of the actual claimed antibody or antigen-binding fragment thereof that bind to CD16 and ADAM17 for treating any disease.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009, PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., J Mol Biol. 334(1): 103-118, 2003; PTO 892, found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Nguyen et al (EMBO Journal, 19(5): 921-930, 2000; PTO 892) teaches that VHH germline segments are highly diverse, leading to a broad structural repertoire of the antigen-binding loops. Seven VHH subfamilies have been recognized, of which 5 were confirmed to be expressed in vivo. Comparison of germline and cDNA sequences demonstrates that the rearranged VHHs are also extensively diversified by somatic mutations process, leading to an additional hypervariable region and a high incidence of nucleotide insertions or deletions. These diversification processes are drives by hypermutation and recombination hotspots embedded in the VHH germline genes at the regions affecting the structure of the antigen-binding loops. Germline segments of these antibodies are highly diverse, leading to a broad structural repertoire of the antigen-binding loops and such VHHs are even extensively diversified by somatic mutation processes.
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen. Thus the disclosure does not allow one of skill in the art to predict the structure of such "compound" or "targeting domain" or "ADAM17-inhibiting domain" required to practice the claimed invention.
Regarding “fragment thereof” (claims 4, 25, 27, 29), the phrase “fragment” can be as little as two amino acids, or the Fc fragment. However, only the antigen binding fragment, e.g., Fab, F(ab)2, scFv can bind to a target.
Regarding the targeting domain selectively binds to any cell infected by any virus (claim 9), any cell infected by any bacterium (claim 12), any cell infected by any parasite (claim 14) or any tumor cell (claim 18), these claims are reached through claims because it us nit clear the targeting domain that binds to CD16 can also bind any other cells infected by any virus, any bacterium, any parasite or any tumor.
Regarding at least one of SEQ ID NO: 17-19 (claim 25, 29) or at least one of SEQ ID NO: 13-15 (claims 27 and 29), the specification discloses an ADAM17-inhibiting antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 16 wherein the light chain CDRs1-3 are set forth in SEQ ID NO: 13 to 15 and wherein the heavy chain CDRs 1-3 are set forth in SEQ ID NO: 17 to 19, see specification at p. 44.
However, the specification does not teach antibody comprising just heavy chain (claim 25, 29) or just light chain variable (claim 27, 29) and any one CDR from the light chain variable region paired with any one CDR from the heavy chain variable region (claims 25, 27 and 29) still maintains antigen binding.
Chiu et al (Antibodies 8: 55-80, 2019; PTO 892) teaches the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see p. 4, in particular). It is unlikely the claimed antibody in claims 25, 27 and 29 have the required antigen binding function.
There are no in vivo working examples. It is unpredictable which undisclosed compound above is effective for treating any and all possible disease.
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).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5 are rejected under 35 U.S.C. 102 (a)(1)as being anticipated by Yamamoto et al (of record, Biochem J 445: 135-144, 2012; PTO 892).
1. (Original) A compound comprising: a targeting domain that selectively binds to a target; an ADAM17-inhibiting domain; and a linker operably linking the targeting domain and the ADAM 17-inhibiting domain.
2. (Original) The compound of claim 1, wherein the targeting domain selectively binds to an immune cell.
3. (Original) The compound of claim 2, wherein the immune cell is a T cell, a B cell, an NK cell, a monocyte, a macrophage, a dendritic cell, a myeloid-derived suppressor cell, or a mast cell.
4. (Currently Amended) The compound of claim 1 any preceding claim, wherein the targeting domain comprises an antibody or a fragment thereof.
5. (Original) The compound of claim 4, wherein the antibody fragment comprises an scFv.
Regarding claim 1, Yamamoto teaches a compound, e.g., A300E-BITE bispecific single-chain antibody comprising a targeting domain, e.g., scFv that binds to CD3 and an ADAM17-inhibiting domain, e.g., scFv that binds to ADAM17 and a linker operably linking the CD3 targeting domain and the ADMA17-inhibiting domain, see entire document, Fig 2A, in particular.
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Regarding claims 2-4, the reference BITE scFv binds to immune cell, e.g., CD3 expressing human T cells, see p. 140-141, in particular.
Regarding claim 5, the reference antibody fragment comprises scFv, see caption of Fig 2, and Fig. 2 above, in particular. Thus, the reference teachings anticipate the claimed invention.
Claims 1-6 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by Felices et al (US20230203166, claimed earliest priority to June 3, 2020; PTO 892).
1. (Original) A compound comprising: a targeting domain that selectively binds to a target; an ADAM17-inhibiting domain; and a linker operably linking the targeting domain and the ADAM 17-inhibiting domain.
2. (Original) The compound of claim 1, wherein the targeting domain selectively binds to an immune cell.
3. (Original) The compound of claim 2, wherein the immune cell is a T cell, a B cell, an NK cell, a monocyte, a macrophage, a dendritic cell, a myeloid-derived suppressor cell, or a mast cell.
4. (Currently Amended) The compound of claim 1 any preceding claim, wherein the targeting domain comprises an antibody or a fragment thereof.
5. (Original) The compound of claim 4, wherein the antibody fragment comprises an scFv.
6. The compound of claim 4, wherein the antibody fragment comprises any single domain antibody.
Regarding claims 1, 2, 3, 5, 6, Felices teaches a compound such as bispecific killer cell engager or T cell engager comprising a targeting domain, e.g., scFv or single domain antibody (sdAb, para. [0040]) and (b) an ADAM17 blocker wherein the two domains are operably linked by a linker (see para. [0051], [0055]) to target ADAM17 to T cells or NK cells, see para. [0033].
Examples of NK cell targeting/engaging domain that binds to NK cell target includes anti-CD16 receptor antibody, see para. [0061], [0064]. The binding domain can be linked to another binding domain through a peptide linker, see para. [0050].
Regarding claims 5 and 6, Felices teaches the NK cell engaging/targeting domain comprises an scFv or a single domain antibody (sdAb), see para. [0066].
Thus, the reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 6, 9 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al (of record, Biochem J 445: 135-144, 2012; PTO 892) in view of Miller et al (WO2020/081841, published April 23, 2020; PTO 892) and Damschroder et al (WO2016089888, published June 9, 2016; PTO 892).
The teachings of Yamamoto have been discussed supra.
Yamamoto does not teach the targeting domain comprises a single domain antibody as per claim 6 selectively binds to CD16 comprising the amino acid sequence of SEQ ID NO: 2 (elected species).
However, Miller teaches a single domain antibody, e.g., humanized VHH (para. [008, [0061]) that binds to CD16 (FcγRIIIa) on NK cells and comprises the amino acid sequence of SEQ ID NO: 8, which is 100% identical to the claimed SEQ ID NO: 2. See para. [0014], sequence alignment below.
Query Match 100.0%; Score 643; Length 122;
Best Local Similarity 100.0%;
Matches 122; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGLVQPGGSLRLSCAASGLTFSSYNMGWFRQAPGQGLEAVASITWSGRDTFY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGLVQPGGSLRLSCAASGLTFSSYNMGWFRQAPGQGLEAVASITWSGRDTFY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAANPWPVAAPRSGTYWGQGTLVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAANPWPVAAPRSGTYWGQGTLVTV 120
Qy 121 SS 122
||
Db 121 SS 122
The NK engaging domain, e.g., anti-CD16a that binds to Fc receptors (FcγRIIIa) that expressed on NK cells and on neutrophils, see para. [0058]. Miller teaches that BiKE or compound comprising the targeting domain is useful in composition for inducing NK-mediated killing of target cell, stimulating expansion of NK cells in vivo in the subject, stimulating immune response, inducing apoptosis, and treating cancer in a subject, see entire document, abstract, p. 3, 11, in particular.
Regarding claim 9, Miller teaches that targeting domain that can selectively bind to a target on a cell infected by a virus, e.g., EBV, HBV, HCV, and/or HPV, see para. [0072].
Regarding claim 18, Miller teaches various targeting domains that tumor cell, e.g., an anti-tumor antibody such as rituximab (anti-CD20), afutuzumab (anti-CD20), trastuzumab (anti-HER2/neu), pertuzumab (anti-HER2/neu), labetuzumab (anti-CEA), adecatumumab (anti-EpCAM), citatuzumab bogatox (anti-EpCAM), edrecolomab (anti-EpCAM), arcitumomab (anti-CEA), bevacizumab (anti-VEGF-A), cetuximab (anti-EGFR), nimotuzumab (anti-EGFR), panitumumab (anti-EGFR), zalutumumab (anti-EGFR), gemtuzumab ozogamicin (anti-CD33), lintuzumab (anti-CD33), etaracizumab (anti-integrin αvβ3), intetumumab (anti-CD51), ipilimumab (anti-CD152), oregovomab (anti-CA-125), votumumab (anti-tumor antigen CTAA16.88), or pemtumumab (anti-MUCl), anti-CD19, anti-CD22, anti-CD133, anti-CD38 anti-mesothelin, anti-ROR1, CSPG4, SS1, or IGFR1. Any tumor marker can be targeted. In some embodiments, the targeting domain, or tumor-associated antigen targeted, can include CD133, CD20, HER2, CEA, EpCAM, VEGF-A, EGFR, CD33, integrin αVβ3, CD51, CD152, CD125, CTAA16.88, MUC1, CD19, CD22, CD38, mesothelin, ROR1, CSPG4, SS1, or IGFR1, NKG2 family members, including but not limited to 2A, 2B, 2C, and the like, BCMA, APRIL, B7H3, and PSMA, by way of example, see para. [0070] to [0072].
Miller does not teach the ADAM17-inhibiting domain comprises a heavy chain variable region and a light chain variable region wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 16 and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 12.
However, Damschroder teaches antibody, e.g., B07 or antigen binding fragment thereof, which binds to ADAM7 (also known as TACE), and which is a potent inhibitor of ADAM17 that can be used in treatment of disease, e.g., tumor in humans by inhibits shedding of ADAM17-dependent ligands from the stromal component of tumors, see p. 27, Example 3, p. 31.
The reference anti-ADAM17 antibody (ADAM17 inhibitor) comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 3, which is identical to instant SEQ ID NO: 12, see sequence alignment below, the 3CDRs are in bold.
Query Match 100.0%; Score 551; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRSSQSIPSYLNWYQQKPGKAPKLLIYAASRLQSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRSSQSIPSYLNWYQQKPGKAPKLLIYAASRLQSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK 107
And a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2, which is identical to instant SEQ ID NO: 16, see sequence alignment below, the 3 CDRs are in bold.
Query Match 100.0%; Score 626; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMNWVRQAPGKGLEWVSYISPFGGMTDY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMNWVRQAPGKGLEWVSYISPFGGMTDY 60
Qy 61 ATSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAMRGAEVDYWGQGTLVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ATSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAMRGAEVDYWGQGTLVTVSS 119
The ADAM17 inhibitor is a full-length antibody or antigen binding fragment thereof, e.g., Fab, Fv, scFv, dAb, Fd, Fab’ or F(ab’)2, see p. 9, in particular. The tumor suppressor activity could be abrogated by ADAM17-mediated shedding of ligand or receptor, see p. 31-32.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to fuse Miller’s humanized VHH with Damschroder’s ADAM17 inhibitor, just like that of Yamamoto’s bispecific antibody comprising a cell targeting domain and a ADAM17 binding domain to arrive at the claimed invention with a reasonable expectation of success, e.g., targeting ADAM17 inhibitor to CD16 expressing NK, macrophage or neutrophils to block the drownregulation (shedding) of CD16 on activated cells for treating cancer.
One of ordinary skill in the art would have been motivated to and had a reasonable expectation of success at the time the invention was made to make such products because linking humanized VHH antibody that binds to CD16 with ADAM17 inhibitor, just like that of Yamamoto, is expected to target ADAM17 inhibitor to CD16 expressing NK cells for treating cancer and the small humanized VHH that binds to CD16 is expected to be non-immunogenic when administering to human subject.
One of ordinary skill in the art would have been motivated to do so because Yamamoto teaches that ADAM17 is a potential immunotherapeutic target and bispecific antibody can target CD3 expressing T cells to ADAM17 expressing cancer cells, Damschroder teaches that the ADAM17 inhibitor combine with other antibody that binds to tumor cell is useful for treating cancer by inhibiting ADAM17 mediated cleavage of activated cell surface receptor and Miller teaches that humanized VHH that binds to CD16 (FcγRIIIa) on NK cells, which is taught in the art useful for targeting CD16 expressing NK cells to ADAM17 expressing cancer cells.
“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Conclusion
SEQ ID NO: 36, 37, 38, 39, 40, 41, 42, 43, 44, 20, 21 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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