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 .
Priority
The instant application is claiming the benefit as a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US20/46181, filing date 08/13/2020, which claims the benefit of the prior-filed United States Provisional Patent Application No. 62/887,523, filing date 08/15/2019.
Status of Application/Claims
The amendment, filed 09/15/2025, is acknowledged. Claims 1-53 are canceled. Claims 56-57, and 59 are currently amended. Claims 60-64 are new. Claims 54-64 are currently pending and are examined on the merits herein.
Withdrawn Objections/Rejections
Regarding the claim 55 and 57 objections for minor informalities, applicant amendment has addressed the issues. Thus, the objections are withdrawn.
Regarding the rejection for claim 59 under 35 U.S.C. 112(b) for indefiniteness: Applicant amendment and remarks submitted 09/15/2025 have addressed the rejection. Thus, the rejection is withdrawn.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 64 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 64 recites that the OKT3, M5A, and CC49 antibodies each comprise an Fc region. Claim 64 is dependent on claim 54 which recites that the bispecific antibody is comprised of an OKT3 antibody bound to an M5A or CC49 antibody. An “antibody,” by definition, comprises an Fc region, as evidenced by the instant specification as follows:
“The Fc… is used herein according to its plain and ordinary meaning in the art and refers to the “base” or “tail” of an immunoglobulin.” -p.35, lines 9-10
“…the Fc region ensures that each antibody generates an appropriate immune response for a given antigen by binding to specific proteins… various cell receptors…and other immune molecules…” -p.35, lines 15-18
Thus, claim 64 fails to further limit claim 54.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Maintained in Modified Form
Claims 54, 56, 5758-59, 62-63, and 64 are rejected under 35 U.S.C. 103 as being unpatentable over June et al., US 2018/0243341 (published 08/30/2018; herein referred to as June), and further in view of Kaufmann et al., US 2018/0194859 (published 12/07/2018; herein referred to as Kaufmann); and, as evidenced by Muraro, et al. Generation and characterization of B72.3 second generation monoclonal antibodies reactive with the tumor-associated glycoprotein 72 antigen. Cancer Res. 1988, 15:48(16), p.4588-4596 (herein referred to as Muraro).
June teaches a method of treating cancer in a subject comprising administering a bispecific antibody bound to a T cell (abstract, paras 0009 and 0013 and 0239). June teaches bispecific antibodies comprising a combination of antibodies selected from the group consisting of anti-CD3 including muromonab-CD3 (i.e., humanized OKT3 as evidenced by instant disclosure p.42, lines 4-5; June p.1, [0009]; June p.24, [0261], and June p. 25, [0279]), anti-IgD Fc, and anti-IgA Fc. June teaches that the bispecific antibody is chemically hetero-conjugated (i.e., covalently bound) to an antibody specific for a tumor-associated antigen (TAA), wherein the T cells specifically bind the TAA antibody (i.e., each “antibody” comprises its own Fc domain; p.1, [0009], p.3, [0049], and p.4, [0053]). June further teaches that bispecific antibodies can be OKT3 and specific to any tumor antigen of choice (p.12, [0151], p.25, [0279]; Figs.14-15). June teaches that the antibodies can be of various forms, including polyclonal antibodies, monoclonal antibodies (e.g., M5A or CC49), Fv, Fab, scFv, and humanized antibodies (p.3, [0049]; p.6, [0081]; p.11, [0149; p.13, [0163]; p.14 – p.15, [0181] – [0186]); and that the bispecific antibodies can each bind the same antigen or different antigens (p.4, [0053]). June additionally teaches assessment of cytotoxicity in SK-BR3 (i.e., a breast cancer cell line) and HCT-8 (a colon cancer cell line) tumor cells after treatment of bispecific antibodies comprising HER2 antibody (i.e., HER2Bi) or EGFR antibody (i.e., EGFRBi; Figs.6 and Fig.15, p.2, [0020] – [0021]). June teaches the T cells of the invention may be autologous (p.22, [0247]). June also teaches techniques for engineering and expressing bispecific antibodies which includes recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities, “knob-in-hole” engineering, cross-linking two or more antibodies or fragments, using leucine zippers, using “diabody” technology; and using single-chain Fv dimers, preparing trispecific (p.11 – p.12, [0150]).
June does not explicitly teach that the OKT3/CD3 antibody is covalently bound to M5A or CC49 (instant claim 54 and 56); linking the antibodies via a linker or wherein the linker attached to a cysteine within the hinge region of each antibody (instant claims 54 and 56); that the OKT3 and CC49 antibodies each have Fc domains (instant claim 64); or, that the OKT3 antibody Fc and CC49 antibody Fc regions are oriented in opposite directions for a 6-lobed bispecific antibody morphology (instant claims 57 and 62). June also does not teach:
Instant claims 58 and 63:
“…a linker that has the formula -L1-L2-L3-L4-L5-, and wherein L1, L2, L3, L4, and L5 are independently a bond, -O-, -S-, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2NH-, -NH-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene,”
or instant claim 59:
“…wherein:
L1 is substituted heteroalkylene;
L2 is unsubstituted fused heterocycloalkylene, unsubstituted fused arylene, or unsubstituted fused heteroarylene;
L3 is unsubstituted heteroalkylene;
L4 is a bond; and
L5 is unsubstituted alkylene.
Kaufmann teaches linked dual antibodies conjugated at the hinge region (abstract and Fig.1) that can be used to target T-cells to a target, including tumor-associated antigens (p.1, [0003 – 0004]). Kaufman teaches that the dual antibodies can be comprised of full-length humanized monoclonal antibodies including muromonab-CD3 (i.e., OKT3) and minretumomab (i.e., humanized anti-TAG-72 (CC49) as evidenced by Muraro p.1-2; Kaufman p.2, [0034]; p.11, col.1, lines 29 and 26, respectively). Kaufmann teaches a linker molecule comprising a first hinge-joining moiety that covalently links both cysteine residues of a disulfide bond-forming cysteine pair of the first hinge and a second hinge of two antibodies (p.1, [0006-0013] and p.10, [0068]). Kaufman teaches that linkers with click chemistry handles (e.g., dibromomaleimide-PEG4-azide/DBM-PEG4-azide and DBM-PEG4-DBCO) can be used for the purpose of conjugating one hinge-containing antibody molecule to another hinge-containing antibody molecule to create a bispecific antibody (p.12, [0076]), which allows for the generation of dual antibodies from native, pre-existing monoclonal antibodies that have binding specificities to two different targets (p.1, [0005]). Kaufmann also teaches the specific linker dibromomaleimide-PEG4-azide (DBM-PEG4-azide; Fig.2A; p.12, [0076]) which comprises, in order: a substituted heteroalkylene (instant L1), an unsubstituted (fused) heterocycloalkylene (instant L2), an unsubstituted heteroalkylene (instant L3), an ether bond (instant L4 = “a bond”) and an unsubstituted alkylene (instant L5); thus, the linker reads on instant claims 58-59 (see Kaufmann DBM-PEG4-azide linker with instant application linkage notations below):
[AltContent: textbox (Kaufmann DBM-PEG4-azide with applicant L1-5 designations noted
[img-media_image1.png])] Further, Kaufman teaches methods for functionalizing hinge-containing antibody molecules comprising: reducing an antibody interchain disulfide bond in a hinge region of an antibody to produce two sulfhydryl groups; contacting the antibody with a linker wherein the linker comprises a sulfhydryl-reactive moiety and a biorthogonal moiety; and wherein the sulfhydryl reactive moiety comprises a DBM moiety and the biorthogonal moiety comprises a click chemistry handle comprising one or more moieties selected from an azide, nitrone, cyclooctyne, aldehyde, ketone, tetrazine, cyclooctene, isonitrile, quadricyclane, nickel bi(dithiolene), and DBCO (p.1, [0006] – p.2, [0015]; Figs.2A and 2B).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of June and Kaufman by producing a bispecific antibody (as taught by June and Kaufman) to comprise a humanized anti-CD3/OKT3 antibody (as taught by June; and also taught as “muromonab” by Kaufman) and a humanized anti-CC49/TAG-72 antibody (i.e., a TAA; as taught by Kaufman as “minretumomab”; i.e., CC49 as evidenced by Muraro) using the DBM-PEG4-azide linker (as taught by Kaufmann) that binds a cysteine within the hinge region of the OKT antibody and a cysteine within the hinge region of a second antibody (as taught by Kaufmann) in order to recruit T-cells to tumor associated antigens (as taught by June and Kaufman). One of ordinary skill in the art would have been motivated to make such modifications and expect success because Kaufmann teaches the benefit of using click chemistry to join native monoclonal bispecific antibodies using linkers. One skilled in the art would also be motivated to use to linker taught by Kaufman because Kaufman teaches that a linker containing click chemistry functionalizing molecules like DBM-PEG4-azide and DBCO could be used to join the two antibodies which would predictably result in the formation of a bispecific antibody that brings T-cells and tumor cells into close proximity in order for the T-cells to therapeutically target the tumor cells. Regarding the morphology of the dual bispecific antibody wherein the Fc regions of each antibody are oriented in opposite directions and wherein the dual bispecific antibody has a 6-lobed morphology (instant claims 57, 60, 62): these claims describe inherent properties of the known dual bispecific antibody taught by the combination of June and Kaufman that does not render the claim patentably new (see MPEP §2112). The instant dual bispecific antibody comprising two antibodies functionalized by DBCO and PEGn-azide necessarily possesses the same linker connection as the dual bispecific antibody comprising two antibodies (taught by June and Kaufman) functionalized by DBCO and PEG4-azide click chemistry molecules forming the linker taught by Kaufman. As evidenced by the instant specification, a dual bispecific antibody formed by this linker would produce a main product wherein the Fc molecules are oriented in opposite directions and the molecule has a 6-lobed structure, wherein 4 lobes are formed by the Fabs of each of the first and second antibodies, 1 lobe each is formed by the Fc regions each antibody (see instant specification p.2, [0008] and Figs.1A-1B). Thus, the combination of June and Kaufman also teaches instant claims 57, 60, and 62 based on inherent structure/function properties.
Maintained in Modified Form
Claims 54-55, 57 and 58-59, 60-61, 64 are rejected under 35 U.S.C. 103 as being unpatentable over June, and further in view of Kaufmann, and in further view of Yazaki et al. A series of anti-CEA/anti-DOTA bispecific antibody formats evaluated for pre-targeting: comparison of tumor uptake and blood clearance. Protein Engineering, Design & Selection (2013), 26:3, p.187-193 (herein referred to as Yazaki).
The combination of June and Kaufmann teaches a bispecific antibody wherein a humanized OKT3 antibody is linked to a TAA antibody through a linker, wherein the linker is covalently attached to cysteines within a hinge region of each antibody using the specific linker taught by Kaufman as applied to instant claims 54 and 58-59 above for the purpose of targeting tumor cells for therapeutic cancer treatment.
The combination of June and Kaufmann does not teach that the bispecific antibody comprises humanized M5A (instant claims 54-55); that the OKT3 and M5A antibodies each have Fc domains (instant claim 64); or, that the OKT3 antibody Fc and M5A antibody Fc regions are oriented in opposite directions for a 6-lobed bispecific antibody morphology (instant claims 57 and 60).
Yazaki teaches bispecific antibodies wherein the TAA antibody is M5A, which is a humanized monoclonal antibody that recognizes carcinoembryonic antigen (CEA; title; abstract). Yazaki teaches that M5A can be radioiodinated to determine tumor targeting, blood distribution and pharmacokinetic properties (abstract). Yazaki further teaches that the M5A (i.e., “anti-CEA humanized hT84.66-M5A”) antibody has demonstrated high tumor accumulation as a direct radiolabeled agent in preclinical studies (p.187, col.2, para. 3).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filling date of the claimed invention to further combine the teachings of June and Kaufman with the teachings of Yazaki by modifying a humanized anti-OKT3/CD3 bispecific antibody (as taught by both June and Kaufman) to comprise an anti-CEA/humanized hT84.66-M5A antibody (as taught by Yazaki) and to use the DBM-PEG4-azide linker (as taught by Kaufmann) that binds a cysteine within the hinge region of the OKT antibody and a cysteine within the hinge region of a second antibody (as taught by Kaufmann) in order to receive the expected benefit of M5A-mediated high tumor accumulation (as taught by Yazaki). One of ordinary skill in the art would have a reasonable expectation of success because June, Kaufmann, and Yazaki all teach bispecific antibodies for the purpose of T-cell mediated therapeutic targeting to tumor cells via TAA-binding antibodies. Regarding the morphology of the dual bispecific antibody wherein the Fc regions of each antibody are oriented in opposite directions and wherein the dual bispecific antibody has a 6-lobed morphology (instant claims 57, 60, 62): these claims describe inherent properties of the known dual bispecific antibody taught by the combination of June, Kaufman, and Yazaki that does not render the claim patentably new (see MPEP §2112). The instant dual bispecific antibody comprising two antibodies functionalized by DBCO and PEGn-azide necessarily possesses the same linker connection as the dual bispecific antibody comprising two antibodies (taught by June, Kaufman, and Yazaki) functionalized by DBCO and PEG4-azide click chemistry molecules forming the linker taught by Kaufman. As evidenced by the instant specification, a dual bispecific antibody formed by this linker would produce a main product wherein the Fc molecules are oriented in opposite directions and the molecule has a 6-lobed structure, wherein 4 lobes are formed by the Fabs of each of the first and second antibodies, 1 lobe each is formed by the Fc regions each antibody (see instant specification p.2, [0008] and Figs.1A-1B). Thus, the combination of June, Kaufman, and Yazaki also teaches instant claims 57, 60, and 62 based on inherent structure/function properties.
Response to Arguments
Regarding the rejection for claims 54 and 58-59 and the rejection for claim 56 under 35 U.S.C. 103 for obviousness: Applicant traverses the rejection in remarks submitted 09/15/2025 based on the following recitations from the Office Action submitted 06/20/2025 (see applicant remarks on p.6, lines 4-20 and p.9-10):
Page 12: “The combination of June and Kaufmann does not teach that the bispecific antibody specifically comprises M5A.”
Page 13: “The combination of June and Kaufman does not teach that the bispecific antibody specifically comprises CC49.”
The latter statement in reference to CC49 was incorrectly cited in 09/15/2025 Office Action as the combination of June and Kaufman does, in fact, teach a “bispecific antibody compound comprising an OKT3 antibody covalently bound to CC49 through a linker.” Thus, the previously cited prior art Russoniello reference is has been removed and applicant’s traversal regarding “hindsight analysis” in the original obviousness rejection is moot. See corrected rejection above, which is maintained in modified form.
Regarding the rejection for claim 55 under 35 U.S.C. 103 for obviousness: Applicant traverses the rejection in remarks submitted 09/15/2025 (p.6-9) stating that the combination of June and Kaufman does not teach a bispecific antibody that comprises the M5A antibody (p.7, para.1); and, that the rationale of the rejection of June, Kaufman, and Yazaki is based on hindsight analysis. Applicant arguments have been fully considered but they are not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Accordingly, the combination of June, Kaufman, and Yazaki does, in fact, teach a bispecific antibody wherein the OKT3 antibody is covalently bound to M5A. See corrected rejection above, which is maintained in modified form.
Regarding the rejection for claims 57 under 35 U.S.C. 103 for obviousness: Applicant traverses the rejection in remarks submitted 09/15/2025 (p.10-14) stating that the combinations of June/Kaufman and June/Kaufman/Kontermann do not teach a bispecific antibody that comprises an OKT3 antibody and a CC49 antibody or an M5A antibody, respectively (p.7, para.1). However, the combination of June and Kaufman does, in fact, teach a bispecific antibody comprising OKT3 and CC49 antibodies as stated above; and, the combination of June, Kaufman, and Yazaki does teach a bispecific antibody comprising OKT3 and M5A as stated above (see corrected rejections above). Additionally, applicant argues that Kontermann teaches “formats” rather than the “6-lobed morphology” for the bispecific antibody; and that none of the references previously provided by Office Action submitted 06/20/2025 provides motivation to produce a bispecific antibody with the 6-lobed morphology. Applicant arguments have been fully considered and are persuasive regarding Kontermann. While Konterman teaches a dual bispecific antibody with a 6-lobed morphology, the examiner removes the Kontermann reference as the bispecific antibody taught by Kontermann has a linker joining the Fc regions of each antibody rather than the hinge regions of each antibody as instantly claimed. However, the examiner finds that the prior art teaches the instantly claimed structure, and thus, the 6-lobed morphology. The examiner provides further reasoning for the obviousness rejections above. Thus, the rejections are maintained in modified form. Based on the above determination, newly added claims 60-64, which include the limitations regarding the 6-lobed morphology are also newly rejected under 35 U.S.C. 103 for obviousness (see rejections above).
Conclusion
The instant office action is made non-final due to new rejections not necessitated by amendment.
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647