DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Restriction/Election
Applicant’s election without traverse of Group I, drawn to a recombinant antibody construct that binds selectively to MUC1-C/ECD, wherein said antibody construct binds to another antigen, and corresponding to claims 1-20 in the reply filed 07/13/2026 is acknowledged.
Applicant has further elected examination of the following species:
Additional Target – CD3
Valency – Trivalent (claim 3)
Linked Moiety - None
Claim Status
Claims 1-33 are pending. Claims 21-33 are withdrawn for being directed to non-elected inventions. Claims 2, 4, and 11-16 are withdrawn for being directed to non-elected species, as no linked moiety has been elected.
Claims 1, 3, 5-10, and 17-20 are under examination.
Claim Objections
Claims 17 and 18 are objected to for the use of the term “wherein said antibody construct comprises a sequence of SEQ ID NOS: 22-24” because the term “a sequence of” can read on a fragment of any or all of the claimed sequences.
Claim Rejections - 35 USC § 112(b)
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 7, 17-18, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 recites the antibody construct of claim 1 contains one or more mutations permitting two distinct antibody chains to lock, but does not provide a sequence or structure (e.g. Fc region of IgG) in which the mutations are occurring.
Claims 17 and 18 are directed to a Markush grouping of 20 different sequences which should be written as a closed grouping of alternatives (MPEP2173.05(h)). In the instant case, it is not clear if the claims are directed to the sequences in the alternative or if all the sequences are required to meet the limitations of the claim. If the claim is intended to be directed the sequences in the alternative, they could be amended to state: “wherein said antibody construct comprises the sequence of any one of SEQ ID NOs: 22-24.”
Claim 20 recites the limitation "induction of cell death" in Line 1. There is insufficient antecedent basis for this limitation in the claim. The following is a recommended amendment to claim 20: --The antibody construct of claim 1, wherein the antibody construct induces cell death by antibody-dependent cell cytotoxicity or complement-mediated cytotoxicity.--
Claim Rejections - 35 USC § 112(a)
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, 3, 5, 7-10, and 17-20 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The instant invention is directed to a recombinant antibody construct that binds selectively to MUC1-C extracellular domain (MUC1-C/ECD) defined by SEQ ID NO: 2 and wherein said antibody construct also binds to CD3. While antibodies that bind CD3 are known in the art and readily identifiable by those having ordinary skill in the art, it is not clear how to identify a genus of MUC1-C antibodies that binds the epitope defined by SEQ ID NO: 2.
The specification discloses two clones of anti-MUC1-C antibodies, 7B8-1 and 3D1 (Specification, Pg. 6 and Fig. 1). The CDRs for these clones are claimed in claim 6.
The state of the prior art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
The prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Similarly, Herold et al. (Sci Rep. 2017 Sep 25;7(1):12276) performed single- and double-point mutations in exemplary antibodies and found that a single point mutation in the VH CDR region can completely abolish antigen binding (Page 8, Paragraph 1, Line 11).
In all, the art shows that in order to define an antibody requires the identification of all 6 CDRs that define the binding regions of both heavy and light chain variable regions.
Claim analysis
In light of the teachings of the specification and the state of the relevant art, the claims have the following written description issues:
Claim 1 defines the MUC1-C/ECD binding region defined only by the epitope set forth in SEQ ID NO: 2 and does not provide CDRs required for binding the epitope.
Claim 5 claims two different distinct binding specificities without defining two different binding regions by claiming at a minimum 6 CDRs for each binding region.
Claim 17 and 18 claim the antibody construct comprises a sequence of SEQ ID NO: 22-42, where the specification teaches that not all the claimed sequences comprise 6 CDRs of the MUC1-C-specific antibody. Additionally, claim 18 claiming by percent identity allows for mutations within the CDR sequences.
Because these claims do not define all 6 CDRs of the heavy and light chain binding domains, one of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed. There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus from the disclosure.
That is, the specification provides neither a representative number of the encompassed antibodies, nor does it provide a descriptive of structural features that are common to the encompassed antibodies.
Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed antibodies and non-antibody proteins and therefore Applicant was not in possession of the instant claimed invention.
Dependent claims 3, 7-10, and 19-20 are also rejected under 35 U.S.C. 112(a) for being dependent on rejected claims and not providing limitations for overcoming the written description rejection.
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, 6, 9-10, and 19-20 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by “Kufe 2016" (US2016/0340442A1, published 11/24/2016, effectively filed 01/29/2014).
The disclosure of Kufe is directed to antibodies binding to MUC1-C/extracellular domain (MUC1-C/ECD) and methods of using such antibodies to treat cancers that express the MUC1 antigen (see Abstract).
Regarding claim 1, pertaining to a recombinant antibody construct that binds selectively to MUC1-C extracellular domain (MUC1-C/ECD) defined by SEQ ID NO: 2, wherein said antibody construct also binds to the elected species CD3, Kufe discloses a fusion protein comprising (i) a first single chain antibody that binds selectively to MUC1-C/ECD defined by SEQ ID NO: 2 (identical to instant SEQ ID NO:2) and (ii) a second single chain antibody that binds CD3 (Pg. 72, claims 51-52 and [0009], Lines 1-4). The term “fusion protein” reasonably reads on the recombinant antibody construct of the instant claims. Importantly, Kufe 2016 also teaches embodiments in which the MUC1-C binding domain is formulated in a bispecific T cell engager with a domain that binds CD3 ([02282]-[0287], in particular [0284], Lines 4-6 which states “one of the scFvs binds to T cells via the CD3 receptor, and the other to a tumor cell via a tumor specific molecule, in this case MUC1”.)
Regarding claim 6, wherein the antibody construct has MUC1 binding specificity arising from heavy CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 3, 5, and 7, respectively, and light chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS; 4, 6, and 8, respectively; and/or MUC1 binding specificity arising from heavy CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 9, 11, and 13, respectively, and light chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS; 10, 12, and 14, respectively, Kufe 2016 claims the MUC1 antibody comprises a variable heavy chain SEQ ID NO: 60 (comprising instant SEQ ID NO: 3, 5, 7) or SEQ ID NO: 73 (comprising instant SEQ ID NO: 9, 11, 13) and a variable light chain SEQ ID NO: 70 (comprising instant SEQ ID NO: 4, 6, 8) or SEQ ID NO: 75 (comprising instant SEQ ID NO: 10, 12, 14). The sequences alignments are shown at the end of the rejection.
Instant
Kufe (US2016/0340442A1)
7B8-1 Heavy Chain
SEQ ID NO: 3, 5, 7
SEQ ID NO: 60
7B8-1 Light Chain
SEQ ID NO: 4, 6, 8
SEQ ID NO: 70
3D1 Heavy Chain
SEQ ID NO: 9, 11, 13
SEQ ID NO: 73
3D1 Light Chain
SEQ ID NO: 10, 12, 14
SEQ ID NO: 75
PNG
media_image1.png
501
1091
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Greyscale
SEQ ID NO: 3, 5, 7 and SEQ ID NO:4, 6, 8
SEQ ID NO: 9, 11, 13 and SEQ ID NO:10, 12, 14
PNG
media_image2.png
501
1061
media_image2.png
Greyscale
Regarding claims 9 and 10, wherein the antibody of claim 1 is a humanized version of a murine antibody (claim 9) and wherein the humanized antibody construct contains IgG sequences (claim 10), Kufe 2016 discloses that the MUC1-C antibody of the disclosure is a humanized antibody (Pg. 71, claim 9) and that the humanized antibody is an IgG (Pg. 71, claim 10).
Regarding claim 19, wherein the antibody construct of claim 1 is conjugated to a nanoparticle or a liposome, Kufe 2016 discloses the antibody is conjugated to a nanoparticle or liposome (Pg. 71, claim 19).
Regarding claim 20, wherein induction of cell death comprises antibody-dependent cell cytotoxicity or complement-mediated cytotoxicity, Kufe 2016 discloses the antibody induces cell death via antibody-dependent cell cytotoxicity or complement-mediated cytotoxicity (Pg. 71, claim 20).
Claims 1, 6, 9-10, and 17-20 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by “Kufe 2018" (US2018/0036441A1, published 02/08/2018, effectively filed 08/05/2016).
The disclosure of Kufe 2018 is directed to antibodies binding to MUC1-C/extracellular domain (MUC1-C/ECD) and methods of using such antibodies to treat cancers that express the
MUC1 antigen (see Abstract).
Regarding claim 1, pertaining to a recombinant antibody construct that binds selectively to MUC1-C extracellular domain (MUC1-C/ECD) defined by SEQ ID NO: 2, wherein said antibody construct also binds to the elected species CD3, Kufe 2018 discloses a fusion protein comprising (i) a first single chain antibody that binds selectively to MUC1-C/ECD and (ii) a second single chain antibody that binds a T cell (Pg. 59, claim 31). The term “fusion protein” reasonably reads on the recombinant antibody construct of the instant claims. Importantly, Kufe 2018 also teaches an embodiment in which the MUC1-C binding domain is formulated in a bispecific T cell engager (BiTE®) with a domain that binds CD3 ([0227]-[0231], in particular [0228], Lines 4-6 which states “one of the scFvs binds to T cells via the CD3 receptor, and the other to a tumor cell via a tumor specific molecule, in this case MUC1”.)
Regarding claim 6, wherein the antibody construct has MUC1 binding specificity arising from heavy CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 9, 11, 13, respectively, and light chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS; 10, 12, 14, respectively, , Kufe claims the MUC1 antibody comprises a variable heavy chain SEQ ID NO: 3 (comprising instant SEQ ID NO: 9, 11, 13) or and a variable light chain SEQ ID NO: 14 (comprising instant SEQ ID NO: 10, 12, 14), and teaches the combination of SEQ ID NO: 3 + SEQ ID NO: 14 (Pg. 6, Table 1)
Instant
Kufe (US2016/0340442A1)
3D1 Heavy Chain
SEQ ID NO: 9, 11, 13
SEQ ID NO: 3
3D1 Light Chain
SEQ ID NO: 10, 12, 14
SEQ ID NO: 14
SEQ ID NO: 3, 5, 7 and SEQ ID NO: 4, 6, 8
PNG
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471
1060
media_image3.png
Greyscale
Regarding claims 9 and 10, wherein the antibody of claim 1 is a humanized version of a murine antibody (claim 9) and wherein the humanized antibody construct contains IgG sequences (claim 10), Kufe 2018 discloses that the MUC1-C antibodies of the disclosure are humanized and that the humanized antibody is an IgG (Pg. 30, Example 1- Antibody Humanization)
Regarding claims 17 and 18, wherein the antibody construct of claim 1 comprises a sequence of any one of SEQ ID NO: 22-42 (claim 17) or wherein the antibody construct of claim 1 comprises a sequence having 80%, 85%, 90%, 95% or 99% homology to SEQ ID NOS: 22-42, Kufe 2018 disclose SEQ ID NO: 26, with 99.7% homology to instant SEQ ID NO: 31, and corresponding to VL of humanized anti-MUC1 antibody 3D1 and CL of human IgG1.
PNG
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738
660
media_image4.png
Greyscale
Pertaining specifically to claim 17, which is interpreted herein to require 100% homology to any one of the listed sequences pending further clarification from the applicant, it is believed that the serine at position 144 of instant SEQ ID NO: 31 is an error in the disclosure and sequence listing. The wild-type sequence of IgG CL in the art comprises an alanine in that position, as seen in Kufe 2018 SEQ ID NO: 26. A sequence search does not support this S144A mutation as a known variant of IgG CL. In support of this interpretation, the instant specification discloses other sequences comprising IgG CL and they do not have the serine at that location. See, for example instant SEQ ID NO: 33 attached below.
Instant Specification, Pg. 78
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237
922
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Greyscale
Regarding claim 19, wherein the antibody construct of claim 1 is conjugated to a nanoparticle or a liposome, Kufe discloses the antibody is conjugated to a nanoparticle or liposome (Pg. 71, claim 19).
Regarding claim 20, wherein induction of cell death comprises antibody-dependent cell cytotoxicity or complement-mediated cytotoxicity, discloses the antibody induces cell death via antibody-dependent cell cytotoxicity or complement-mediated cytotoxicity (Pg. 71, claim 20).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3, 5-10, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over “Kufe 2018" (US2018/0036441A1, published 02/08/2018, effectively filed 08/05/2016) as applied to claims 1, 6, 9-10, and 17-20 above, and further in view of Liu (Mol Ther Oncolytics. 2019 Apr 2;14:66-73).
The teachings of Kufe 2018 as set forth in the 35 U.S.C. 102 rejection above are incorporated herein. Kufe teaches a fusion protein comprising a first single chain antibody that binds MUC1-C/ECD and a second single chain antibody that binds CD3.
The disclosure of Kufe does not teach: (1) the antibody construct is trivalent or (2) the antibody construct has two distinct binding specificities for MUC1-C/ECD binding, (3) the antibody has mutations permitting two distinct antibody chains to lock, or (4) the antibody comprises IgG sequences.
These deficiencies are taught by Liu.
The disclosure of Liu is directed to the development and use of a novel biparatopic anti-HER2 bispecific antibody constructed by linking a single anti-CD3 Fab with two different anti-HER2 single-domain antibodies targeting non-overlapping epitopes of HER2 (see Abstract). They generated the anti-HER2 biparatopic T cell engager based on of previous evidence that the biparatopic HER2 antibody had enhanced anti-tumor activity (Pg. 66, Right column, Full paragraph 1, Lines 10-12). They found the biparatopic T cell engager antibody demonstrated significant anti-tumor activity in a mouse xenograft with low-to-medium HER2 expression (Fig 6A). The biparatopic T cell engager also exhibited higher tumor inhibition activity than trastuzumab (Figure 6A, described on Pg. 68, In Vivo Tumor Suppression Induced by Bispecific Antibody).
Regarding claims 3 and 5, wherein the construct of claim 1 is trivalent (claim 3), and wherein the antibody construct has two distinct binding specificities for MUC1-C/ECD binding (claim 5), the biparatopic T cell engager is trivalent comprising two distinct binding domains for the same tumor-associated antigen and one CD3 binding domain (Abstract).
Regarding claim 7, wherein the antibody construct of claim 1 contains one or more mutations permitting two distinct antibody chains to lock, as the claim does not provide a structure or any specific mutations, this limitation is met by the antibody of Liu which is formed by heterodimerization of VH-CH1-VHH2 and VL-CL-VHH1, as anti-Her2 VHH1 and anti-Her2 VHH2 bind to different epitopes on Her2 protein (Fig. 1B).
Regarding claim 8, wherein the antibody construct of claim 7 contains IgG sequences, Liu teaches the construct comprises the CL or CH1 region of the IgG1 anti-CD3 antibody UCHT1 (Pg. 67, Left column, Lines 1-4).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the MUC1-C and CD3 fusion protein of Kure by (1) using a trivalent antibody construct, (2) wherein the antibody construct has two distinct binding specificities for MUC1-C/ECD, (3) wherein the antibody has mutations permitting two distinct antibody chains to lock, and (4) wherein the antibody comprises IgG sequences. One would have been motivated to do so because Liu provides a bispecific antibody that binds two non-overlapping epitopes on a tumor antigen and CD3 and provides evidence that the biparatopic antibody has in vivo anti-tumor effect in tumors expressing low levels of the tumor-associated antigen. There would be an expectation of success in combining the teachings because Liu distills to practice the generation and in vivo use of a biparatopic bispecific T cell engager antibody.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 9-10, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. US10,059,775. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference teaches fusion protein comprising a MUC1-C binding doman and a CD3 binding domain. The reference also claims the instantly claimed CDRs of clone anti-MUC1 antibody clone 3D1.
Regarding claims 1 and 6, pertaining to a recombinant antibody construct that binds selectively to MUC1-C extracellular domain (MUC1-C/ECD) defined by SEQ ID NO: 2, wherein said antibody construct also binds to the elected species CD3 (claim 1) and wherein the antibody construct has MUC1 binding specificity arising from heavy CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 9, 11, 13, respectively, and light chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS; 10, 12, 14, respectively (claim 6), ‘775 claims 19 and 33 disclose a fusion protein comprising (i) a first single chain antibody that binds MUC1-C and (ii) a second single chain antibody binding region that binds to a T cell, specifically CD3 and wherein the MUC1-C binding region comprises the CDRs of the instant claimed antibody clone 3D1.
Regarding claims 9 and 10, wherein the antibody of claim 1 is a humanized version of a murine antibody (claim 9) and wherein the humanized antibody construct contains IgG sequences (claim 10), ‘775 claims 7 and 8 disclose the antibody of the disclosure is humanized IgG.
Regarding claim 19, wherein the antibody construct of claim 1 is conjugated to a nanoparticle or a liposome, ‘775 claim 14 claims the antibody of the disclosure is conjugated to a nanoparticle of liposome.
Claims 1, 3, 5-10, and 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. US10,059,775 as applied to claims 1, 6, 9-10 and 19 above and further in view of Liu (Mol Ther Oncolytics. 2019 Apr 2;14:66-73) and “Kufe 2018" (US2018/0036441A1, published 02/08/2018, effectively filed 08/05/2016).
‘775 does not teach: (1) the antibody construct is trivalent, (2) the antibody construct has two distinct binding specificities for MUC1-C/ECD binding, (3) the antibody has mutations permitting two distinct antibody chains to lock, (4) the antibody comprises IgG sequences, or (5) the antibody construct of claim 1 comprises a sequence of any one of SEQ ID NO: 22-42.
These teachings are provided by Liu and Kufe 2018. The teachings of Liu and Kufe 2018 from the rejections above are incorporated herein in their entirety.
Liu:
Regarding instant claims 3, 5, and 7-8 pertaining to the trivalent bispecific antibody comprising two distinct MUC1-C binding specificities, Liu teaches a biparatopic bispecific antibody that targets two different non-overlapping epitopes of the same antigen and CD3. Liu additionally teaches all other components of the bispecific antibody, including IgG isotype and mutations that allow for heterodimerization of two distinct chains.
Kufe 2018:
Regarding claims 17 and 18, wherein the antibody construct of claim 1 comprises a sequence of any one of SEQ ID NO: 22-42 (claim 17) or wherein the antibody construct of claim 1 comprises a sequence having 80%, 85%, 90%, 95% or 99% homology to SEQ ID NOS: 22-42, Kufe 2018 disclose SEQ ID NO: 26, with 99.7% homology to instant SEQ ID NO: 31, and corresponding to VL of a humanized anti-MUC1 antibody 3D1 and CL of human IgG1.
Regarding claim 20, wherein induction of cell death comprises antibody-dependent cell cytotoxicity or complement-mediated cytotoxicity, Kufe 2018 discloses the antibody induces cell death via antibody-dependent cell cytotoxicity or complement-mediated cytotoxicity (Pg. 71, claim 20).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the MUC1-C and CD3 fusion protein of ‘775 by: (1) generating a trivalent antibody construct (2) wherein the antibody construct has two distinct binding specificities for MUC1-C/ECD, (3) wherein the antibody has mutations permitting two distinct antibody chains to lock, (4) wherein the antibody comprises IgG sequences and (5) using the VL-CL structure of Kufe comprising the VL of antibody clone 3D1. One would have been motivated to do so because Liu provides a bispecific antibody that binds two non-overlapping epitopes on a tumor antigen and CD3 and provides evidence that the biparatopic antibody can an in vivo anti-tumor effect. There would be an expectation of success in combining the teachings because Liu distills to practice the use of a biparatopic bispecific T cell engager antibody and Kufe teaches a known anti-MUC1 VL comprising the CDRs of ‘775 that could readily be incorporated into the fusion protein.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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