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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 26, 2026 has been entered.
Claims 1-2, 6, 49-52, 62 and 63 are pending and being acted upon in this Office Action.
Priority
The Examiner’s concern about priority is moot in view of the claim amendment.
Applicant’ claim priority to provisional application 62/473,652, filed March 20, 2017, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on March 10, 2026 and January 26, 2026 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Claim Objection
Claim 49 is objected to because of the following informality: the plural CH2 domains should have been singular.
Rejection Withdrawn
The new matter rejection of claims 1-2, 4, 6, 8, 41 and 49-52 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of the claim amendment.
Claim Rejections - 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.
Claim 51 is 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.
The recitation of “the Fc domain” is indefinite because it is unclear if “the Fc domain” is referring to the Fc domain in the first polypeptide or the second polypeptide in claim 1. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.
Claim rejections under - 35 U.S.C. 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 6, 49-52, 62 and 63 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 MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding claims to a genus, MPEP § 2163 states that 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 and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus, See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406, M.P.E.P. § 2163, II, A, 3, (a), (ii).
Claim 1 encompasses any trispecific binding protein comprising:
(a) a first antigen-binding site comprising any heavy chain variable domain (VH) and any light chain variable domain (VL) of any anti-NKG2D antibody fragment antigen-binding region (Fab) that activates NKG2D;
(b) a second antigen-binding site comprising a VH and a VL of an anti-carcinoembryonic antigen (CEA) antibody single chain variable region fragment (scFv) that specifically binds to CEA; and
(c) a first polypeptide of an antibody Fc domain;
(d) a second polypeptide of the antibody Fc domain;
wherein the first polypeptide of the antibody Fc domain and the second polypeptide of the antibody Fc domain together bind CD16; wherein
the VH of the anti-NKG2D antibody is fused to a first heavy chain constant domain (CH1), and the first CH1 is fused to the N-terminus of the first polypeptide to form a first immunoglobulin heavy chain; the VL of the anti-NKG2D antibody is present on a first immunoglobulin light chain; the anti-CEA antibody scFv is fused to the N-terminus of the second polypeptide to form a second immunoglobulin heavy chain; and the VL of the anti-CEA antibody is present on a second immunoglobulin light chain;
wherein binding of NKG2D and CD16 on an NK cell results in synergistic activation of the NK cell, as determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay.
Claim 2 encompasses the trispecific binding protein of claim 1, wherein the first antigen-binding site binds to NKG2D in humans and non-human primates.
Claim 6 encompasses the trispecific binding protein of claim 1, wherein the VH and the VL of the anti-CEA antibody heavy chain variable domain and the light chain variable domain of the second antigen-binding site are present on the same polypeptide.
Claim 49 encompasses the trispecific binding protein according to claim 1, wherein the antibody Fc domain comprises hinge and CH2 domains of a human IgG1 antibody.
Claim 50 encompasses the trispecific binding protein according to claim 49, wherein the Fc domain comprises amino acids 234-332 of a human IgG1 antibody.
Claim 51 encompasses the trispecific binding protein according to claim 49, wherein the Fc domain comprises one or more substitutions selected from the group consisting of Q347, Y349, L351, S354, E356, E357, K360, Q362, S364, T366, L368, K370, N390, K392, T394, D399, S400, D401, F405, Y407, K409, T411, and K439 Q347E, Q347R, Y349S, Y349K, Y349T, Y349D, Y349E, Y349C, T350V, L351K, L351D, L351Y, S354C, E356K, E357Q, E357L, E357W, K360E, K360W, Q362E, S364K, S364E, S364H, S364D, T366V, T366I, T366L, T366M, T366K, T366W, T366S, L368E, L368A, L368D, K370S, N390D, N390E, K392L, K392M, K392V, K392F, K392D, K392E, T394F, T394W, D399R, D399K, D399V, S400K, S400R, D401K, F405A, F405T, Y407A, Y407I , Y407V, K409F, K409W, K409D, T411D, T411E, K439D, and K439E, all numbered according to the EU index.
Claim 52 encompasses a formulation comprising the trispecific binding protein of claim 1 and a pharmaceutically acceptable carrier.
Claim 62 encompasses the trispecific binding protein according claim 1, wherein the increased expression of one or both of CD107a and INFγ from the NK cell in the primary human NK cell activation assay is relative to a protein that binds to only NKG2D or only CD16 on the NK cell.
Claim 63 encompasses the protein according to claim 62, wherein the primary human NK cell activation assay comprises incubating a population of NK cells with the protein and measuring expression of one or both of CD107a and INFγ by flow cytometry.
The specification discloses a heterodimeric, multi-specific antibody including a first immunoglobulin heavy chain, a second immunoglobulin heavy chain and an immunoglobulin light chain (FIG. 2).
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The first immunoglobulin heavy chain includes a first Fc (hinge-CH2-CH3) domain fused via either a linker or an antibody hinge to a single-chain variable fragment (scFv) composed of a heavy chain variable domain and light chain variable domain which pair and bind NKG2D, or bind one of the tumor associated antigen CEA. The second immunoglobulin heavy chain includes a second Fc (hinge-CH2-CH3) domain, a second heavy chain variable domain and optionally a CH1 heavy chain domain. The immunoglobulin light chain includes a light chain variable domain and a light chain constant domain. The second immunoglobulin heavy chain pairs with the immunoglobulin light chain and binds to NKG2D or CEA. The first Fc domain and the second Fc domain together are able to bind to CD16 expressed on NK cell (FIG. 2).
Regarding heavy chain variable domain and light chain variable domain that bind to NKG2D, the specification discloses:
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Regarding heavy chain variable domain and light chain variable domain that bind to CEA, the specification discloses:
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Regarding binding of NKG2D and CD16 on NK cell results in synergistic activation of the NK cell as determined by increased expression of one or both of CD107a and IFNγ from primary human NK cell, the specification demonstrates only bispecific antibodies ADI-27705, ADI-27740, ADI-27743, ADI-28153, ADI-28226, ADI-28154, and ADI-28200 show synergistic activation of the NK cell as determined by increased expression of one or both of CD107a and IFNγ.
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FIGs. 19A-19C are bar graphs of synergistic activation of NK cells using CD16 and NKG2D binding. FIG. 19A demonstrates levels of CD 107a; FIG. 19B demonstrates levels of IFNγ; FIG. 19C demonstrates levels of CD107a and IFNγ. Graphs indicate the mean (n = 2) ± SD. Data are representative of five independent experiments using five different healthy donors.
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However, the specification does not describe the structure, e.g., amino acid sequences of any and all possible VH and VL of antibody Fabs that bind to NKG2D that correlated with the function of activates NKG2D. Likewise, the specification does not describe the structure, e.g., amino acid sequences of any and all possible VH and VL of a genus of scFv antibody that bind to CEA.
The specification does not describe the structure common to members of the genus of VH and VL that bind to any NKG2D, much less human NKG2D and non-human primate NKG2D (claim 2) to enable one of skill in the art to visualize members of the genus.
At the time the invention was made, Briney et al (of record, Nature 566: 393, 2019; PTO 892) teaches antibodies are incredibly diverse, at p. 397, left col, in particular.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. 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 (of record, Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al. (of record, J Mol Biol.334(1): 103-118, Nov 14, 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).
Kjellev et al (of record, Eur. J Immunol 37: 1397-1406, 2007; PTO 892) demonstrate that NKG2D binding CX5 mAb is capable of inhibiting NK cell function, and at p. 1402. Kjellev et al. teach that not only does CX5 block the binding of NKG2D to its ligands, CX5 also mediates internalization of the receptor. This suggest that not all antibodies that interfere with the binding of NKG2D are suitable for use when preparing multi-specific binding proteins that elicit NK cell-mediated lysis, at least because some antibodies, such as CX5, have been shown to both inhibit the interaction between NKG2D and its ligands and induce the internalization of NKG2D, which would further interfere with the function of NKG2D.
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 small group of species of binding site that binds to just human NKG2D and CEA, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigens NKG2D, e.g., human and non-human primate NKG2D, CEA and CD16 (as held in Abbvie).
Regarding first and second polypeptide of the antibody each comprises Fc domain from any isotype that together binds to CD16 (claim 1), the specification discloses just human IgG1 Fc, see para. [0125], [0126].
However, the specification does not describe the Fc domain from different isotype, e.g., IgE, IgM, IgA, and/or different species.
Regarding the first antigen-binding site binds to NKG2D in humans and any non-human primates (claim 2), while the specification discloses several antibodies ADI-27705, ADI-27740, ADI-27743, ADI-28153, ADI-28226, ADI-28154, and ADI-28200 that bind to human NKG2D, these antibodies are not known to bind to non-human primates, e.g., Cynomolgus or Rhesus monkeys, apes (e.g., chimpanzees, orangutans, gorillas, bonobos, and gibbons), and lemurs NKG2D.
Regarding antibody Fc domain comprises hinge and CH2 domains of a human IgG1 domain (claim 50), the specification discloses each Fc domain of the first polypeptide and the second polypeptide comprises a hinge, a CH2 domain, and a CH3 domain, see p. 22, para. [0090].
However, the specification does not disclose antibody Fc domain comprises multiple CH2 domains.
Regarding one or more substitutions in the Fc domain such as the ones recited in claim 51, the specification discloses specific pairing of the first polypeptide having the particular combination of substitution in the Fc domain paired with the second polypeptide comprises the particular combination of substitutions within the Fc domain, see Tables 8, 9, 10, 11, 14.
The phrase “one or more substitutions” encompasses one amino acid substitution or more than one substitutions.
However, the specification does not describe Fc domain from each of the first and the second polypeptide comprises multiple substitutions such as
Q347E, Q347R, Y349S, Y349K, Y349T, Y349D, Y349E, Y349C, T350V, L351K, L351D, L351Y, S354C, E356K, E357Q, E357L, E357W, K360E, K360W, Q362E, S364K, S364E, S364H, S364D, T366V, T366I, T366L, T366M, T366K, T366W, T366S, L368E, L368A, L368D, K370S, N390D, N390E, K392L, K392M, K392V, K392F, K392D, K392E, T394F, T394W, D399R, D399K, D399V, S400K, S400R, D401K, F405A, F405T, Y407A, Y407I , Y407V, K409F, K409W, K409D, T411D, T41lE, K439D, and K439E, all numbered according to the EU index.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
While methods of screening phage library is known in the art, the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co.. Inc.. 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Therefore, only (A) a trispecific binding protein comprising:
(a) a first antigen-binding site comprising any heavy chain variable domain (VH) and any light chain variable domain (VL) of an anti-NKG2D antibody fragment antigen-binding region (Fab) that activates NKG2D;
(b) a second antigen-binding site comprising a VH and a VL of an anti-carcinoembryonic antigen (CEA) antibody single chain variable region fragment (scFv) that specifically binds to CEA; and
(c) a first polypeptide of an antibody human IgG1 Fc domain;
(d) a second polypeptide of the antibody human IgG1 Fc domain;
wherein the first polypeptide of the antibody Fc domain and the second polypeptide of the antibody Fc domain together bind CD16; wherein
the VH of the anti-NKG2D antibody is fused to a first heavy chain constant domain (CH1), and the first CH1 is fused to the N-terminus of the first polypeptide to form a first immunoglobulin heavy chain; the VL of the anti-NKG2D antibody is present on a first immunoglobulin light chain; the anti-CEA antibody scFv is fused to the N-terminus of the second polypeptide to form a second immunoglobulin heavy chain; and the VL of the anti-CEA antibody is present on a second immunoglobulin light chain;
wherein binding of NKG2D and CD16 on an NK cell results in synergistic activation of the NK cell, as determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay,
wherein the first antigen-binding site (Fab) comprises:
(1) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 2;
(2) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO :6;
(3) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 10;
(4) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14; and
wherein the second antigen-binding binding site (scFv) comprises:
(1) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 195 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 196;
(2) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 203 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 204;
(3) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 211 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 212;
(B) The trispecific binding protein above wherein the first Fc domain and second Fc domain each comprises a hinge, a CH2 domain and a CH3 domain,
(C) The trispecific binding protein above wherein the first polypeptide and the second polypeptide comprise the particular combination of substitutions shown in Tables 8, 9, 10, 11, 14,
(D) a formulation comprising the trispecific binding protein above and a pharmaceutically acceptable carrier, 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).
Applicant’s arguments filed January 26, 2026 have been fully considered but are not found persuasive.
Applicant respectfully submits that instant claim 1 does not recite "or portion thereof." As such, this rejection is moot. Therefore, Applicant requests that the Examiner reconsider and withdraw this rejection.
Sequence identity to VH and VL of claims 8 and 41
On page 13 of the Office Action, it is alleged that "the specification does not disclose a representative of species of antibodies having at least 10% sequence identity to the VH and VL as set forth in claims 8 and 41 still [maintaining] binding to NKG2D and CEA."
Applicant respectfully disagrees.
However, without acquiescing to the rejection and solely to expedite prosecution, previously pending claims 8 and 41 are cancelled herein, rendering the rejection moot.
Applicant requests that the Examiner reconsider and withdraw this rejection.
Claim 50 Sequence with 90% identity to amino acids 234-332 of IgG1 Fc
On page 13 of the Office Action, the Examiner alleges that the specification does not teach an IgG1 Fc having 90% sequence identity to amino acids 234-332 of human IgG1, still maintaining binding to CD 16, as set forth in claim 50.
Applicant respectfully disagrees. Solely to expedite prosecution and without acquiescing to the rejection, claim 50 is amended herein to remove the 90% sequence identity limitation.
Accordingly, Applicant respectfully requests reconsideration and withdrawal of the rejection.
Claim 1 as amended recites synergistic antibodies activating NKG2D
On page 10-11 of the Office Action, it is alleged that the specification only discloses a
limited number of NKG2D and CEA binding domains that are not representative of the genus for each binding domain.
In support of the written description rejection, the Office cites Kjellev which allegedly teaches the CX5 antibody that blocks binding of NKG2D to ligands and mediates internalization of the receptor. It is further alleged that not all antibodies that interfere with the binding of NKG2D are suitable for use when preparing the instantly claimed multi-specific binding proteins that elicit NK cell-mediated lysis.
The Office further states at page 22 that the synergistic activation of NK cells that was argued by the Applicant in the prior response of April 7, 2025, is not recited in the rejected claims.
Applicant respectfully submits that the claimed invention is not about which anti- NKG2D antigen-binding site or anti-CEA antigen-binding site is used, but rather about a class of proteins in which combining an anti-NKG2D antigen-binding site, an anti-CEA antigen-binding site, and a CD16-binding Fc domain in a single protein facilitates destruction of CEA-expressing target cells through synergistic NK cell activation through co-stimulation of NKG2D and CD16.
Thus, solely to expedite prosecution and without acquiescing to the rejection, instant claim 1 requires "binding of NKG2D and CD16 on an NK cell results in synergistic activation of the NK cell, as determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay."
As such, this rejection is moot. Therefore, Applicant requests that the Examiner reconsider and withdraw this rejection.
In response, the amendment to claims 1, 8 and 41 is acknowledged.
Although the amended claim 1 now recites a trispecific binding protein comprising:
(a) a first antigen-binding site comprising any heavy chain variable domain (VH) and any light chain variable domain (VL) of any anti-NKG2D antibody fragment antigen-binding region (Fab) that activates NKG2D;
(b) a second antigen-binding site comprising a VH and a VL of an anti-carcinoembryonic antigen (CEA) antibody single chain variable region fragment (scFv) that specifically binds to CEA; and
(c) a first polypeptide of an antibody Fc domain;
(d) a second polypeptide of the antibody Fc domain;
wherein the first polypeptide of the antibody Fc domain and the second polypeptide of the antibody Fc domain together bind CD16; wherein
the VH of the anti-NKG2D antibody is fused to a first heavy chain constant domain (CH1), and the first CH1 is fused to the N-terminus of the first polypeptide to form a first immunoglobulin heavy chain; the VL of the anti-NKG2D antibody is present on a first immunoglobulin light chain; the anti-CEA antibody scFv is fused to the N-terminus of the second polypeptide to form a second immunoglobulin heavy chain; and the VL of the anti-CEA antibody is present on a second immunoglobulin light chain;
wherein binding of NKG2D and CD16 on an NK cell results in synergistic activation of the NK cell, as determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay, the specification does not describe sufficient number of structure, e.g., amino acid sequence of heavy and light chain variable regions that bind to any NKG2D and any CEA in the format shown in Fig 2 or common structure share by members of the genus that bind to NKG2D and CEA wherein binding of NKG2D and CD16 on NK cells results in synergistic activation of NK cell.
The specification demonstrates that only bispecific antibodies ADI-27705, ADI-27740, ADI-27743, ADI-28153, ADI-28226, ADI-28154, and ADI-28200 show synergistic activation of the NK cell as determined by increased expression of one or both of CD107a and IFNγ.
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FIGs. 19A-19C are bar graphs of synergistic activation of NK cells using CD16 and NKG2D binding. FIG. 19A demonstrates levels of CD 107a; FIG. 19B demonstrates levels of IFNγ; FIG. 19C demonstrates levels of CD107a and IFNγ. Graphs indicate the mean (n = 2) ± SD. Data are representative of five independent experiments using five different healthy donors.
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Regarding heavy chain variable domain and light chain variable domain of such antibodies that bind to NKG2D, the specification discloses:
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Regarding heavy chain variable domain and light chain variable domain that bind to CEA, the specification discloses:
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However, the specification does not describe the structure, e.g., amino acid sequences of any and all possible VH and VL of antibody Fabs that bind to NKG2D that correlated with the function of activates NKG2D. Likewise, the specification does not describe the structure, e.g., amino acid sequences of any and all possible VH and VL of a genus of scFv antibody that bind to CEA.
The specification does not describe the structure common to members of the genus of VH and VL that bind to any NKG2D, much less human NKG2D and non-human primate NKG2D (claim 2) to enable one of skill in the art to visualize members of the genus.
At the time the invention was made, Briney et al (of record, Nature 566: 393, 2019; PTO 892) teaches antibodies are incredibly diverse, at p. 397, left col, in particular.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. 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 (of record, Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al. (of record, J Mol Biol.334(1): 103-118, Nov 14, 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).
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 small group of species of binding site that binds to just human NKG2D and CEA, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigens NKG2D, e.g., human and non-human primate NKG2D, CEA and CD16 (as held in Abbvie).
Regarding first and second polypeptide of the antibody each comprises Fc domain from any isotype that together binds to CD16 (claim 1), the specification discloses just human IgG1 Fc, see para. [0125], [0126].
However, the specification does not describe the Fc domain from different isotype, e.g., IgE, IgM, IgA, and/or different species.
Regarding the first antigen-binding site binds to NKG2D in humans and any non-human primates (claim 2), while the specification discloses several antibodies ADI-27705, ADI-27740, ADI-27743, ADI-28153, ADI-28226, ADI-28154, and ADI-28200 that bind to human NKG2D, these antibodies are not known to bind to non-human primates, e.g., Cynomolgus or Rhesus monkeys, apes (e.g., chimpanzees, orangutans, gorillas, bonobos, and gibbons), and lemurs NKG2D.
While the specification discloses human CEA protein comprising the amino acid sequence of SEQ ID NO: 219, possession may not be shown by merely described how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
Regarding antibody Fc domain comprises hinge and CH2 domains of a human IgG1 domain (claim 50), the specification discloses each Fc domain of the first polypeptide and the second polypeptide comprises a hinge, a CH2 domain, and a CH3 domain, see p. 22, para. [0090].
However, the specification does not disclose antibody Fc domain comprises multiple CH2 domains.
Regarding one or more substitutions in the Fc domain such as the ones recited in claim 51, the specification discloses specific pairing of the first polypeptide having the particular combination of substitution in the Fc domain paired with the second polypeptide comprises the particular combination of substitutions within the Fc domain, see Tables 8, 9, 10, 11, 14.
The phrase “one or more substitutions” encompasses one amino acid substitution or more than one substitutions.
However, the specification does not describe Fc domain from each of the first and the second polypeptide comprises multiple substitutions such as
Q347E, Q347R, Y349S, Y349K, Y349T, Y349D, Y349E, Y349C, T350V, L351K, L351D, L351Y, S354C, E356K, E357Q, E357L, E357W, K360E, K360W, Q362E, S364K, S364E, S364H, S364D, T366V, T366I, T366L, T366M, T366K, T366W, T366S, L368E, L368A, L368D, K370S, N390D, N390E, K392L, K392M, K392V, K392F, K392D, K392E, T394F, T394W, D399R, D399K, D399V, S400K, S400R, D401K, F405A, F405T, Y407A, Y407I , Y407V, K409F, K409W, K409D, T411D, T41lE, K439D, and K439E, all numbered according to the EU index.
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.).
In Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), the court explained in Amgen that when an antibody is claimed, 35 U.S.C § 112(a) requires adequate written description of the antibody itself. 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).
Applicant is reminded that in order to demonstrate that Applicant has invented what is claimed, the specification must adequately describe representative species of antibodies that reflect the structural diversity of the claimed genus (see Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of the material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived”).
For these reasons, the rejection is maintained.
Claims 1-2, 6, 49-52, 62 and 63 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 (A) a trispecific binding protein comprising:
(a) a first antigen-binding site comprising a heavy chain variable domain (VH) and any light chain variable domain (VL) of an anti-human NKG2D antibody fragment antigen-binding region (Fab) that activates human NKG2D;
(b) a second antigen-binding site comprising a VH and a VL of an anti-carcinoembryonic antigen (CEA) antibody single chain variable region fragment (scFv) that specifically binds to human CEA; and
(c) a first polypeptide of an antibody human IgG1 Fc domain;
(d) a second polypeptide of the antibody human IgG1 Fc domain;
wherein the first polypeptide of the antibody Fc domain and the second polypeptide of the antibody Fc domain together bind human CD16; wherein
the VH of the anti-NKG2D antibody is fused to a first heavy chain constant domain (CH1), and the first CH1 is fused to the N-terminus of the first polypeptide to form a first immunoglobulin heavy chain; the VL of the anti-NKG2D antibody is present on a first immunoglobulin light chain; the anti-CEA antibody scFv is fused to the N-terminus of the second polypeptide to form a second immunoglobulin heavy chain; and the VL of the anti-CEA antibody is present on a second immunoglobulin light chain;
wherein binding of NKG2D and CD16 on an NK cell results in synergistic activation of the human NK cell, as determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay,
wherein the first antigen-binding site (Fab) comprises:
(1) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 2;
(2) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO :6;
(3) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 10;
(4) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14; and
wherein the second antigen-binding binding site (scFv) comprises:
(1) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 195 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 196;
(2) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 203 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 204;
(3) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 211 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 212;
(B) The trispecific binding protein above wherein the first Fc domain and second Fc domain each comprises a hinge, a CH2 domain and a CH3 domain,
(C) The trispecific binding protein above wherein the first polypeptide and the second polypeptide comprise the particular combination of substitutions shown in Tables 8, 9, 10, 11, 14,
(D) a formulation comprising the trispecific binding protein above and a pharmaceutically acceptable carrier, does not reasonably provide enablement for any trispecific binding protein as set forth in claims 1-2, 6, 49-52, 62 and 63. 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/use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The Wands 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 and 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 trispecific binding protein comprising:
(a) a first antigen-binding site comprising any heavy chain variable domain (VH) and any light chain variable domain (VL) of any anti-NKG2D antibody fragment antigen-binding region (Fab) that activates NKG2D;
(b) a second antigen-binding site comprising a VH and a VL of an anti-carcinoembryonic antigen (CEA) antibody single chain variable region fragment (scFv) that specifically binds to CEA; and
(c) a first polypeptide of an antibody Fc domain;
(d) a second polypeptide of the antibody Fc domain;
wherein the first polypeptide of the antibody Fc domain and the second polypeptide of the antibody Fc domain together bind CD16; wherein
the VH of the anti-NKG2D antibody is fused to a first heavy chain constant domain (CH1), and the first CH1 is fused to the N-terminus of the first polypeptide to form a first immunoglobulin heavy chain; the VL of the anti-NKG2D antibody is present on a first immunoglobulin light chain; the anti-CEA antibody scFv is fused to the N-terminus of the second polypeptide to form a second immunoglobulin heavy chain; and the VL of the anti-CEA antibody is present on a second immunoglobulin light chain;
wherein binding of NKG2D and CD16 on an NK cell results in synergistic activation of the NK cell, as determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay.
Claim 2 encompasses the trispecific binding protein of claim 1, wherein the first antigen-binding site binds to NKG2D in humans and non-human primates.
Claim 6 encompasses the trispecific binding protein of claim 1, wherein the VH and the VL of the anti-CEA antibody heavy chain variable domain and the light chain variable domain of the second antigen-binding site are present on the same polypeptide.
Claim 49 encompasses the trispecific binding protein according to claim 1, wherein the antibody Fc domain comprises hinge and CH2 domains of a human IgG1 antibody.
Claim 50 encompasses the trispecific binding protein according to claim 49, wherein the Fc domain comprises amino acids 234-332 of a human IgG1 antibody.
Claim 51 encompasses the trispecific binding protein according to claim 49, wherein the Fc domain comprises one or more substitutions selected from the group consisting of Q347, Y349, L351, S354, E356, E357, K360, Q362, S364, T366, L368, K370, N390, K392, T394, D399, S400, D401, F405, Y407, K409, T411, and K439 Q347E, Q347R, Y349S, Y349K, Y349T, Y349D, Y349E, Y349C, T350V, L351K, L351D, L351Y, S354C, E356K, E357Q, E357L, E357W, K360E, K360W, Q362E, S364K, S364E, S364H, S364D, T366V, T366I, T366L, T366M, T366K, T366W, T366S, L368E, L368A, L368D, K370S, N390D, N390E, K392L, K392M, K392V, K392F, K392D, K392E, T394F, T394W, D399R, D399K, D399V, S400K, S400R, D401K, F405A, F405T, Y407A, Y407I , Y407V, K409F, K409W, K409D, T411D, T411E, K439D, and K439E, all numbered according to the EU index.
Claim 52 encompasses a formulation comprising the trispecific binding protein of claim 1 and a pharmaceutically acceptable carrier.
Claim 62 encompasses the trispecific binding protein according claim 1, wherein the increased expression of one or both of CD107a and INFγ from the NK cell in the primary human NK cell activation assay is relative to a protein that binds to only NKG2D or only CD16 on the NK cell.
Claim 63 encompasses the protein according to claim 62, wherein the primary human NK cell activation assay comprises incubating a population of NK cells with the protein and measuring expression of one or both of CD107a and INFγ by flow cytometry.
The specification teaches that only bispecific antibodies ADI-27705, ADI-27740, ADI-27743, ADI-28153, ADI-28226, ADI-28154, and ADI-28200 show synergistic activation of the NK cell as determined by increased expression of one or both of CD107a and IFNγ.
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FIGs. 19A-19C are bar graphs of synergistic activation of NK cells using CD16 and NKG2D binding. FIG. 19A demonstrates levels of CD 107a; FIG. 19B demonstrates levels of IFNγ; FIG. 19C demonstrates levels of CD107a and IFNγ. Graphs indicate the mean (n = 2) ± SD. Data are representative of five independent experiments using five different healthy donors.
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Regarding heavy chain variable domain and light chain variable domain of such antibodies that bind to NKG2D, the specification discloses:
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Regarding heavy chain variable domain and light chain variable domain that bind to CEA, the specification discloses:
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However, the specification does not teach the structure, e.g., amino acid sequences of any and all possible VH and VL of antibody Fabs that bind to NKG2D that correlated with the function of activates NKG2D. Likewise, the specification does not describe the structure, e.g., amino acid sequences of any and all possible VH and VL of a genus of scFv antibody that bind to CEA to enable one of skill in the art to make and use without undue experimentation.
At the time the invention was made, Briney et al (of record, Nature 566: 393, 2019; PTO 892) teaches antibodies are incredibly diverse, at p. 397, left col, in particular.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. 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 (of record, Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al. (of record, J Mol Biol.334(1): 103-118, Nov 14, 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).
Kjellev et al (of record, Eur. J Immunol 37: 1397-1406, 2007; PTO 892) demonstrate that NKG2D binding CX5 mAb is capable of inhibiting NK cell function, and at p. 1402. Kjellev et al. teach that not only does CX5 block the binding of NKG2D to its ligands, CX5 also mediates internalization of the receptor. This suggest that not all antibodies that interfere with the binding of NKG2D are suitable for use when preparing multi-specific binding proteins that elicit NK cell-mediated lysis, at least because some antibodies, such as CX5, have been shown to both inhibit the interaction between NKG2D and its ligands and induce the internalization of NKG2D, which would further interfere with the function of NKG2D.
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 small group of species of binding site that binds to just human NKG2D and CEA, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigens NKG2D, e.g., human and non-human primate NKG2D, CEA and CD16.
Regarding first and second polypeptide of the antibody each comprises Fc domain from any isotype that together binds to CD16 (claim 1), the specification discloses just human IgG1 Fc, see para. [0125], [0126].
However, the specification does not teach the Fc domain from different isotype, e.g., IgE, IgM, IgA, and/or different species, much less binding of CD16 (FcγRIII) and activates CD16 on NK cell synergistically with binding to NKG2D.
Regarding the first antigen-binding site binds to NKG2D in humans and any non-human primates (claim 2), while the specification discloses several antibodies ADI-27705, ADI-27740, ADI-27743, ADI-28153, ADI-28226, ADI-28154, and ADI-28200 that bind to human NKG2D, these antibodies are not known to bind to non-human primates, e.g., Cynomolgus or Rhesus monkeys, apes (e.g., chimpanzees, orangutans, gorillas, bonobos, and gibbons), and lemurs NKG2D.
Regarding antibody Fc domain comprises hinge and CH2 domains of a human IgG1 domain (claim 50), the specification discloses each Fc domain of the first polypeptide and the second polypeptide comprises a hinge, a CH2 domain, and a CH3 domain, see p. 22, para. [0090].
However, the specification does not disclose antibody Fc domain comprises multiple CH2 domains.
Regarding one or more substitutions in the Fc domain such as the ones recited in claim 51, the specification discloses specific pairing of the first polypeptide having the particular combination of substitution in the Fc domain paired with the second polypeptide comprises the particular combination of substitutions within the Fc domain, see Tables 8, 9, 10, 11, 14.
The phrase “one or more substitutions” encompasses one amino acid substitution or more than one substitutions.
However, the specification does not teach Fc domain from each of the first and the second polypeptide comprises any and all substitutions such as
Q347E, Q347R, Y349S, Y349K, Y349T, Y349D, Y349E, Y349C, T350V, L351K, L351D, L351Y, S354C, E356K, E357Q, E357L, E357W, K360E, K360W, Q362E, S364K, S364E, S364H, S364D, T366V, T366I, T366L, T366M, T366K, T366W, T366S, L368E, L368A, L368D, K370S, N390D, N390E, K392L, K392M, K392V, K392F, K392D, K392E, T394F, T394W, D399R, D399K, D399V, S400K, S400R, D401K, F405A, F405T, Y407A, Y407I , Y407V, K409F, K409W, K409D, T411D, T41lE, K439D, and K439E, all numbered according to the EU index.
There are insufficient working examples. It is unpredictable which trispecific binding protein that binds to any NKG2D and any CEA and any CD16 is effective for synergistic activation of NK cell.
As such, it would take undue trials and errors to practice the claimed invention as broadly as claimed.
In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute.
Applicant's arguments filed January 26, 2026 have been fully considered but they are not persuasive.
Applicant respectfully submits claim 1(i), claim 8, and claim 41 are canceled herein.
Moreover, and as indicated above, Applicant respectfully submits that the claimed invention is not about which anti-NKG2D antigen-binding site or anti-CEA antigen-binding site is used, but rather about a class of proteins in which combining an anti-NKG2D antigen-binding site, an anti-CEA antigen-binding site, and a CD16-binding Fc domain in a single protein facilitates destruction of CEA-expressing target cells through synergistic NK cell activation through co-stimulation of NKG2D and CD16.
Thus, solely to expedite prosecution and without acquiescing to the rejection, instant claim 1 requires "binding of NKG2D and CD16 on an NK cell results in synergistic activation of the NK cell, as determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay."
As such, this rejection is moot. Therefore, Applicant requests that the Examiner reconsider and withdraw this rejection.
In response, the amendment to claims 1, 8 and 41 is acknowledged.
Although the amended claim 1 now recites a trispecific binding protein comprising:
(a) a first antigen-binding site comprising any heavy chain variable domain (VH) and any light chain variable domain (VL) of any anti-NKG2D antibody fragment antigen-binding region (Fab) that activates NKG2D;
(b) a second antigen-binding site comprising a VH and a VL of an anti-carcinoembryonic antigen (CEA) antibody single chain variable region fragment (scFv) that specifically binds to CEA; and
(c) a first polypeptide of an antibody Fc domain;
(d) a second polypeptide of the antibody Fc domain;
wherein the first polypeptide of the antibody Fc domain and the second polypeptide of the antibody Fc domain together bind CD16; wherein
the VH of the anti-NKG2D antibody is fused to a first heavy chain constant domain (CH1), and the first CH1 is fused to the N-terminus of the first polypeptide to form a first immunoglobulin heavy chain; the VL of the anti-NKG2D antibody is present on a first immunoglobulin light chain; the anti-CEA antibody scFv is fused to the N-terminus of the second polypeptide to form a second immunoglobulin heavy chain; and the VL of the anti-CEA antibody is present on a second immunoglobulin light chain;
wherein binding of NKG2D and CD16 on an NK cell results in synergistic activation of the NK cell, as determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay, the specification does not teach the structure, e.g., amino acid sequence of heavy and light chain variable regions that bind to any NKG2D and any CEA in the format shown in Fig 2 wherein the binding of NKG2D and CD16 on NK cells results in synergistic activation of NK cell.
The specification demonstrates that only bispecific antibodies ADI-27705, ADI-27740, ADI-27743, ADI-28153, ADI-28226, ADI-28154, and ADI-28200 show synergistic activation of the NK cell as determined by increased expression of one or both of CD107a and IFNγ.
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FIGs. 19A-19C are bar graphs of synergistic activation of NK cells using CD16 and NKG2D binding. FIG. 19A demonstrates levels of CD 107a; FIG. 19B demonstrates levels of IFNγ; FIG. 19C demonstrates levels of CD107a and IFNγ. Graphs indicate the mean (n = 2) ± SD. Data are representative of five independent experiments using five different healthy donors.
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Regarding heavy chain variable domain and light chain variable domain of such antibodies that bind to NKG2D, the specification discloses:
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Regarding heavy chain variable domain and light chain variable domain that bind to CEA, the specification discloses:
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However, the specification does not teach the structure, e.g., amino acid sequences of any and all possible VH and VL of antibody Fabs that bind to NKG2D that correlated with the function of activates NKG2D. Likewise, the specification does not describe the structure, e.g., amino acid sequences of any and all possible VH and VL of a genus of scFv antibody that bind to CEA.
The specification does not teach the structure common to members of the genus of VH and VL that bind to any NKG2D, much less human NKG2D and non-human primate NKG2D (claim 2) to enable one of skill in the art to make and use without undue experimentation.
At the time the invention was made, Briney et al (of record, Nature 566: 393, 2019; PTO 892) teaches antibodies are incredibly diverse, at p. 397, left col, in particular.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. 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 (of record, Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al. (of record, J Mol Biol.334(1): 103-118, Nov 14, 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).
Kjellev et al (of record, Eur. J Immunol 37: 1397-1406, 2007; PTO 892) demonstrate that NKG2D binding CX5 mAb is capable of inhibiting NK cell function, and at p. 1402. Kjellev et al. teach that not only does CX5 block the binding of NKG2D to its ligands, CX5 also mediates internalization of the receptor. This suggest that not all antibodies that interfere with the binding of NKG2D are suitable for use when preparing multi-specific binding proteins that elicit NK cell-mediated lysis, at least because some antibodies, such as CX5, have been shown to both inhibit the interaction between NKG2D and its ligands and induce the internalization of NKG2D, which would further interfere with the function of NKG2D.
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 small group of species of binding site that binds to just human NKG2D and CEA, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigens NKG2D, e.g., human and non-human primate NKG2D, CEA and CD16.
Regarding first and second polypeptide of the antibody each comprises Fc domain from any isotype that together binds to CD16 (claim 1), the specification discloses just human IgG1 Fc, see para. [0125], [0126].
However, the specification does not describe the Fc domain from different isotype, e.g., IgE, IgM, IgA, and/or different species.
Regarding the first antigen-binding site binds to NKG2D in humans and any non-human primates (claim 2), while the specification discloses several antibodies ADI-27705, ADI-27740, ADI-27743, ADI-28153, ADI-28226, ADI-28154, and ADI-28200 that bind to human NKG2D, these antibodies are not known to bind to non-human primates, e.g., Cynomolgus or Rhesus monkeys, apes (e.g., chimpanzees, orangutans, gorillas, bonobos, and gibbons), and lemurs NKG2D.
Regarding antibody Fc domain comprises hinge and CH2 domains of a human IgG1 domain (claim 50), the specification discloses each Fc domain of the first polypeptide and the second polypeptide comprises a hinge, a CH2 domain, and a CH3 domain, see p. 22, para. [0090].
However, the specification does not teach antibody Fc domain comprises multiple CH2 domains as claimed.
Regarding one or more substitutions in the Fc domain such as the ones recited in claim 51, the specification discloses specific pairing of the first polypeptide having the particular combination of substitution in the Fc domain paired with the second polypeptide comprises the particular combination of substitutions within the Fc domain, see Tables 8, 9, 10, 11, 14.
The phrase “one or more substitutions” encompasses one amino acid substitution or more than one substitutions.
However, the specification does not teach Fc domain from each of the first and the second polypeptide comprises any and all substitutions such as
Q347E, Q347R, Y349S, Y349K, Y349T, Y349D, Y349E, Y349C, T350V, L351K, L351D, L351Y, S354C, E356K, E357Q, E357L, E357W, K360E, K360W, Q362E, S364K, S364E, S364H, S364D, T366V, T366I, T366L, T366M, T366K, T366W, T366S, L368E, L368A, L368D, K370S, N390D, N390E, K392L, K392M, K392V, K392F, K392D, K392E, T394F, T394W, D399R, D399K, D399V, S400K, S400R, D401K, F405A, F405T, Y407A, Y407I , Y407V, K409F, K409W, K409D, T411D, T41lE, K439D, and K439E, all numbered according to the EU index.
There are insufficient working examples. It is unpredictable which trispecific binding protein that binds to any NKG2D and any CEA and any CD16 is effective for synergistic activation of NK cell.
As such, it would take undue trials and errors to practice the claimed invention as broadly as claimed.
For these reasons, the rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 6, 49, 50, 51, 52, 62 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Moore et al (WO2014145806, published September 18, 2014; PTO 892) as evidenced by Bryceson et al (Blood 107(1): 159-166, 2006; PTO 892) in view of Thibault et al (US20100167315, published July 1, 2010; PTO 892), Alter et al (Journal of Immunological Methods 294: 15-22, 2004; PTO 892) and Kefer et al (US20040038339, published February 26, 2004; PTO 892).
Claim 1. A trispecific binding protein comprising:
(a) a first antigen-binding site comprising any heavy chain variable domain (VH) and any light chain variable domain (VL) of any anti-NKG2D antibody fragment antigen-binding region (Fab) that activates NKG2D;
(b) a second antigen-binding site comprising a VH and a VL of an anti-carcinoembryonic antigen (CEA) antibody single chain variable region fragment (scFv) that specifically binds to CEA; and
(c) a first polypeptide of an antibody Fc domain;
(d) a second polypeptide of the antibody Fc domain;
wherein the first polypeptide of the antibody Fc domain and the second polypeptide of the antibody Fc domain together bind CD16; wherein
the VH of the anti-NKG2D antibody is fused to a first heavy chain constant domain (CH1), and the first CH1 is fused to the N-terminus of the first polypeptide to form a first immunoglobulin heavy chain; the VL of the anti-NKG2D antibody is present on a first immunoglobulin light chain; the anti-CEA antibody scFv is fused to the N-terminus of the second polypeptide to form a second immunoglobulin heavy chain; and the VL of the anti-CEA antibody is present on a second immunoglobulin light chain;
wherein binding of NKG2D and CD16 on an NK cell results in synergistic activation of the NK cell, as determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay.
Regarding claim 1, Moore teaches trispecific (para. [0082]) triple binding protein comprising (a) a Fab antigen binding (Ag. 2) comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), (b) a scFv antigen binding domain (Ag. 1), (c) a first polypeptide comprises an antibody Fc domain, and (d) a second polypeptide comprises an antibody Fc domain, wherein the first Fc and second Fc domain form Fc region that bind to FcγRIII (CD16, see entire document, Figure 1, "triple F" format (sometimes also referred to as the "bottle-opener", abstract, para. [0021]. Typically, "triple F" construct is a scFv region-hinge-Fc domain and the other is (VH-CH1-hinge- CH2-CH3 plus associated light chain). See para. [00155], [00162], Fig 1B below.
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Moore teaches that the "triple F" format is particularly beneficial for targeting two (or more) distinct antigens and virtually any antigen may be targeted, see para. [00125], [00188], [010190]. Example of antigen include CEA, see para. [00191], and NKG2D, see para. [00195]. The multispecific antibody bind to two different antigens simultaneously, see para. [0082]. Moore teaches that the Fc (para. [00150]) binds to its receptor, e.g., FcγRIII (CD16), see para. [00119], [00120]. Moore teaches that it is known that Increased binding to FcγRIII (activating receptor) generally results in increase ADCC activity (antibody dependent cell-mediated cytotoxicity, see para. [00105], [00229].
Claim 6 is included because Moore teaches that scFv comprising a VH and a VL are linked together via a linker on the same polypeptide (scFv), see Figure 2, in particular.
Regarding claim 49, Moore teaches that antibody Fc comprises a hinge, a CH2 and a CH3 domain in each polypeptide as there are two Fc polypeptides to form an Fc domain that binds to CD16 (FcγRIII).
Regarding claim 50, Moore teaches that the antibody Fc domain is from a human IgG1 isotype, see para. [00288], [00289]. The reference full-length human IgG1 is expected to comprise amino acids 234 to 332.
Regarding claim 51, Moore teaches that first and/or second Fc domain of the antibody further comprises amino acid substitution(s), e.g., Q347E in Fc monomer 1, and E357Q in Fc monomer 2 to form heterodimer, see Figure 12E, in particular.
Regarding claim 52, Moore teaches formulation comprising the reference trispecific binding protein and a pharmaceutical acceptable carrier, see p. 76, para. [00257].
The advantages of "triple F" format by fusing scFv antibody to IgG are that it increases in size, high stability, longer half-life in serum; it double the half-life of scFv from 3 to 6 days, see para. [003], [0057].
Given Moore teaches the same antibody format as shown in instant Fig 2 and binds to NKG2D and CD16, the binding of the reference antibody to NKG2D and CD16 on NK cells intrinsically activated NK cells synergistically.
Evidentiary reference Bryceson teaches that antibody-mediated crosslinking of NL cell receptors has demonstrated that colligation of several activating NK cell receptors, including NKG2D can act synergistically with signals through CD16 to enhance NK cell calcium flux. Bryceson teaches that antibody to CD16 (clone 3G8), and NKG2D (clone 1D11) each augmented lysis of P815 target cells in the presence of IL-2 activated NK cells, see Fig. 1A. Bryceson teaches that synergistic activation of intracellular Ca2+ mobilization in resting NK cells by single anti-CD16 (clone 3G8) and anti-NKG2D (clone 1D11) by the combined of both receptors, see p. Co-crosslinking CD16 with NKG2D enhanced the peak Ca2+ , see p. 160, Antibodies, and p, 163, Figure 3A, red line show activation, in particular. Cross-linking of CD16 and NKG2D resulted in a more sustained elevation in Ca2+ in most cells, see p. 163, Figure 4D, in particular. Synergistic Ca2+ flux correlated with degranulation by measuring CD107a expression on NK cells, see p. 163, right col., Figure 5, CD16+NKG2D, in particular.
Moore does not explicitly teach synergistic activation of the NK cell is determined by increased expression of one or both of CD107a and INFγ from the NK cell in a primary human NK cell activation assay as per claim 1, wherein the increased activation of one or both of CD107a and INFγ in primary human NK cell activation assay as per claim 62 and wherein the primary NK cell activation comprises incubating a population of NK cells with the protein and measuring expression of one or both of CD107a and INFγ by flow cytometry as per claim 63.
However, Thibault teaches that NK cell activation was assessed by quantification of cell surface CD107a by flow cytometry, see para. see para. [0067], Examples 1-3, in particular. The primary NK cells were isolated from blood samples of donors, see para. [0053] to [0055]. The NK cells were stimulated with appropriate antibody, see para. [0056] to [0057]. The NK cells were labeled with anti-CD107-PECy5, see para. [0058], and detection of intracellular IFNγ, see para. [0062], [0065]. Thibault teaches that flow cytometry technique is well known to those skilled in the art, who will be able to choose suitable labels for distinguishing the various molecules to be measured. In particular, it is advantageous to choose, as labels coupled to the anti-CD107, anti-IFN.gamma., and anti-CD16 monoclonal antibodies, fluorochromes which emit at distinct wavelengths. By way of nonlimiting examples, mention may be made of fluorescein isothiocyanate (FITC), Alexa Fluor 488, Alexa Fluor 405, phycoerythrin (PE), peridinin chlorophyll protein (PerCP), phycoerythrin cyanin 5 (PC5), phycoerythrin cyanin 5.5 (PC5.5), phycoerythrin Taxas Red.RTM. (ECD), phycoerythrin cyanin 7 (PC7), allophycocyanin (APC), Alexa Fluor 647, Alex Fluor 700, phycoerythrin Alexa Fluor 700 (PAF7), Alexa Fluor 700 and APC cyanin 7 (APC7), see para. [0017]. The primary NK cells were isolated from blood samples of donors, see para. [0053] to [0055]. The NK cells were stimulated with appropriate antibody, see para. [0056] to [0057]. The NK cells were labeled with anti-CD107-PECy5, see para. [0058], and detection of intracellular IFNγ, see para. [0062], [0065]. Thibault teaches that simultaneous quantification of cell surface CD107a and synthesis of IFN.gamma by NK cells stimulated with various agents using flow cytometry, see Examples 4, 8, 11.
Likewise, Alter teaches the use of multi-parameter flow cytometry to measure NK cell activation by measuring CD107a expression and IFN-γ secretion, see entire document, Fig. 2A, in particular. Alter teaches that CD107a is upregulated on NK cells following stimulation. CD107a induction is expressed in concert with cytokine secretion and target cell lysis. Moreover, multi-parameter flow cytometry can be performed to detect simultaneous degranulation and cytokine secreting NK cells on a single cell level. Given the expression of this marker on the surface of both cytokine secreting and non-secreting cells, it will be possible to sort out the role of these two subsets of NK effector populations and explore their role in diverse models, see p. 21, in particular. Alter teaches that CD107a as a marker of NK cell functional activity may allow for the identification of a large fraction of activated NK cells that may degranulate in the absence of cytokine secretion, see abstract, in particular.
Kufer teaches NK cells are usually recruited through engagement of CD16, forming the major extracellular part of the Fc.gamma.-receptor IIIA complex, see para. [0011]. Kufer teaches single chain bispecific antibody comprising a first antibody domain comprising VH and VL that binds to NKG2D and a second binding domain, e.g., VH and VL that binds to a tumor associated antigens, e.g., CEA, or EPCAM, see para. [0036], [0038], [0050], Fig. 2,, Example 3, in particular. The VH and VL that binds to NKG2D on human lymphocytes are from monoclonal antibodies such as 6E5, 8G7, and 11B2, see example 2, in particular. Kufer teaches that multifunctional NKG2D-directed polypeptides, which differentially recruit CD8.sup.+ T-cells and NK-cells to cancer cells for cell mediated lysis and target cell elimination, see para. [0022], claims in particular.
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 have produced a trispecific binding protein having the format
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having Fab that binds to NKG2D, and the other binding site, scFv that binds to a tumor antigen, e.g., CEA and also binds to CD16 through the intact human IgG1 Fc as disclosed by Moore wherein the synergistic activation of human primary NK cells can be determined by increased expression of one or both CD107a and IFNγ by flow cytometry as taught by Thibault and/or Alter to arrive at the claimed invention with a reasonable expectation of success, e.g., targeting NKG2D expressing NK cells to CEA expressing tumor cell as taught by Kufer and synergistic activation of NK cells by antibody that binds to NKG2D and CD16 by antibody receptor crosslinking as shown by Bryceson.
One of ordinary skill in the art would have had a reasonable expectation of success to do so because Thibault teaches that flow cytometry technique is well known to those skilled in the art and detecting NK cells activation can be measured by the increased expression of the CD107 marker on NK cells using anti-CD107 antibody coupled to a PE label and IFN-gamma using anti-IFN-Gamma monoclonal antibody coupled to a different label FITC.
One of ordinary skill in the art would have been motivated to do so because Alter teaches that multi-parameter flow cytometry can be used to detect simultaneous NK cell degranulation as measured by increase CD107a expression and cytokine secreting NK cells on a single cell level, see p. 21, in particular.
One of ordinary skill in the art would have been motivated to do so because Moore teaches that
advantages of "triple F" format by fusing scFv antibody to IgG are that it increases in size, high stability, longer half-life in serum; it double the half-life of scFv from 3 to 6 days, see para. [003], [0057].
“The test of obviousness is not express suggestion of the claimed 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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Moore et al (WO2014145806, published September 18, 2014; PTO 892) as evidenced by Bryceson et al (Blood 107(1): 159-166, 2006; PTO 892) in view of Thibault et al (US20100167315, published July 1, 2010; PTO 892), Alter et al (Journal of Immunological Methods 294: 15-22, 2004; PTO 892) and Kefer et al (US20040038339, published February 26, 2004; PTO 892) as applied to claims 1, 6, 49, 50, 51, 52, 62 and 63 mentioned above and further in view of Urso et al (US20100056764, published March 4, 2010; PTO 892) or Rader et al (of record, U.S. Patent No. 9,273,136, issued March 1, 2016; PTO892 ).
The combine teachings of Moore, Bryceson, Thibault and Alter have been discussed supra.
The references above do not teach the trispecific binding protein wherein the first antigen-binding site (Fab) binds to NKG2D in humans and non-human primates as per claim 2.
However, Urso teaches fully human or humanized antibodies against human NKG2D, see para. [0070] and one or more non-primate, such as cynomolgus or rhesus NKG2D and such antibodies have the advantage of allowing for toxicity testing in the most suitable animal model (or models) prior to use in humans, see entire document, para. [0069]. in particular. Urso teaches typically, the antibodies are fully human or humanized to minimize the risk for immune responses against the antibodies when administered to a patient, see para. [0008].
Likewise, Rader teaches a fully human anti-human NKG2D IgG1 monoclonal antibody, e.g., KYK-2.0 IgG1 that binds to human NKG2D (col. 13, line 27-29) for treating cancer, see entire document, Fig. 2B, col. 4, line 5-36, Examples 3-4, 6, reference claim 8, in particular. Rader further teaches mouse anti-human NKG2D mAb 149810, see col. 15, in particular. The reference anti-hNKG2D antibodies are useful for treating various disease, e.g., cancer, see Example 6, in particular.
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 have produced a trispecific binding protein having the format
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having Fab that binds to NKG2D, and the other binding site, scFv that binds to a tumor antigen, e.g., CEA and also binds to CD16 through the intact human IgG1 Fc as disclosed by Moore by substituting the binding site comprising a VH and VL that binds to NKG2D of Moore for the VH and VL from any one of the antibodies that binds to human and/or non-human primate NKG2D as taught by Urso or Rader with to arrive at the claimed invention with a reasonable expectation success, i.e., non-immunogenic scFv-Fc IgG bispecific antibody that binds to human and cynomolgus or rhesus NKG2D and CEA wherein the full-length IgG Fc binds to FcγRIII such as CD16.
One of ordinary skill in the art would have been motivated to do so because Urso teaches that fully human or humanized antibodies can minimize the risk for immune responses against the antibodies when administered to a patient, see para. [0008] and antibody that binds to human and cynomolgus or rhesus NKG2D have the advantage of allowing for toxicity testing in the most suitable animal model (or models) prior to use in humans, see para. [0060].
One of ordinary skill in the art would have had a reasonable expectation of success in making the claimed antibody because Rader teaches how to prepare a fully human monoclonal antibody that binds to human NKG2D of IgG1 using the reference VH and VL amino acid sequences, see Examples 1 and 3, in particular.
One of ordinary skill in the art would have been motivated to do so because Rader teaches fully human anti-NKG2D antibody is expected to minimize immunogenicity and damage to non-diseased cells that expressed NKG2D receptors and the antibody can have specificity for a tumor antigen, see entire document, col. 4, lines 50-3, reference claim 10, in particular.
One of ordinary skill in the art would have been motivated to do so because Hansen teaches humanized MN-14 monoclonal antibody binding domain that binds to CEA does not engender an adverse immune response (aka circulating human anti-mouse antibody immune responses or HAMA) in a patient, see col. 1, line 55-56.
Furthermore, the combination does not change the operation of antibody of Moore. It merely improves upon the scFv-Fc bispecific antibody by reducing its immunogenicity when administering to a human subject with cancer.
“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 claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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