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 .
Status of Claims
Claims 1-19 are cancelled. Claims 20-38 are pending. Claims 20-38 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 20-38 have an effective filing date of 01/09/2020, corresponding to EP20305011.7.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/08/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Rejections Maintained
Claims 20-38 are rejected under 35 U.S.C. 103 as being unpatentable over Lantz et al. (WO2008087219, publication date: 07/24/2008, IDS), in view of Dahlen (Dahlen et al, Therapeutic Advances in Vaccines and Immunotherapy, 2018, 6(1) 3-17).
Rejections Withdrawn
Claims 27 is 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.
Response to Remarks filed 09/03/2025
Applicant arguments regarding the 35 USC 112a rejection of claim 27 have been fully considered and are persuasive. The amendment to the claim overcomes the rejection. Therefore, the rejection is withdrawn.
Applicant’s arguments regarding the 35 USC 103 rejection of claims 20-38 have been fully considered and are not persuasive.
Initially Applicant argues: “the technical objective of designing a bispecific antibody to redirect MAIT cells to tumor cells is not disclosed in the cited documents and Applicants submit that, absent the teachings of this application, one skilled in the art would not have been motivated to make a bispecific antibody in which one aspect of the antibody redirected MAIT cells to tumor cells. Importantly, none of the cited documents taken alone or in combination teach or suggest the claimed antibody (an anti-MAIT anti-TAA bispecific antibody), let alone an antibody binding to the Va7.2 chain of s MAIT TCR. Lantz et al. merely relates to the design of an anti-Va7.2 antibody, and does not suggest bispecific antibodies, let alone bispecific antibodies able to bind to a MAIT cell and a tumor cell. This document does not contain any information about redirection of MAIT cells to kill tumor cells and/or the advantages of such redirection. Importantly, this document does not show any data on the activation of MAIT cells after binding to the anti-Va7.2 antibody. The experimental section of the document merely demonstrates the specificity of the antibody and does not provide any evidence to support its potential use in cancer therapy, let alone in a bispecific antibody. Dahlen et al. is a review about classical bispecific antibodies that redirect T cells, which target the TCR/CD3 complex. While Dahlen et al. highlight the disadvantages of existing T-cell redirection strategies, it remains silent on any alternative approach involving MAIT cells. Dahlen et al. state that "antigen-independent activation of T cells leads to rapid and powerful activation of a large T-cell pool, which may explain the toxicity seen by such compounds. The toxicities observed with T-cell redirecting compounds prompt further mechanistic studies of T-cell activation and dosing regimens to support the development of treatments with an improved safety profile." Thus, Dahlen et al. do mention the issue of unwanted toxicities, but do not suggest to targeting another TCR than CD3 nor alternative types of T cells, such as MAIT cells.”
However, Lantz teaches the antibody 3C10, which binds Va7.2-Ja33 (Lantz et al, pg. 32, paragraph 00119) comprising reference SEQ ID NO: 2 (comprises 100% of instant SEQ ID NO: 4, 5, and 6) and reference SEQ ID NO: 4 (comprises SSS and 100% of instant SEQ ID NO: 7 and 8). Dahlen et al teaches bispecific antibodies against TCRs and tumor associated antigens including CD19, CD20, EGFR, HER2, CEA, PSMA, EpCAM, and PD-L1 (Dahlen et al, pg. 6, Table 1). The ability of the resulting antibody of the combined invention to bind to the TCR of MAIT cells is an inherent quality as the antibody of Lantz et al is the same antibody of the instant application. Additionally Dahlen et al teach that bispecific antibodies can be used in the treatment of cancer, as discussed in detail below. Lantz et al. state that “[t]he invention further provides a method of modulating MAIT cell activity in a patient in need thereof, comprising the step of administering to said patient a composition according to the invention. In one embodiment, the MAIT cell activity is enhanced, wherein the patient has a disease or disorder wherein such enhancement may promote, enhance, and/or induce a therapeutic effect (or promotes, enhances, and/or induces such an effect in at least a substantial proportion of patients with the disease or disorder and substantially similar characteristics as the patient, as may determined by, e.g., clinical trials). In one embodiment, the composition induces proliferation of MAIT cells; in another embodiment, the composition induces the production of cytokines, for example IL-2 and/or IL-10. In another embodiment, the MAIT cell activity is inhibited, wherein the patient has a disease or disorder wherein such inhibition may promote, enhance, and/or induce a therapeutic effect (or promotes, enhances, and/or induces such an effect in at least a substantial proportion of patients with the disease or disorder and substantially similar characteristics as the patient, as may determined by, e.g., clinical trials). Such treatment methods can be used for a number of mucosal immune disorders, including, but not limited to, cancer, infection (e.g. viral infection), irritable bowel syndrome, Crohn's disease, ulcerative colitis, and Celiac disease (emphasis added).” Lantz et al. also state that “[a]ccording to another embodiment, the antibody compositions of this invention may further comprise another therapeutic agent, including agents normally utilized for the particular therapeutic purpose for which the antibody is being administered. The additional therapeutic agent will normally be present in the composition in amounts typically used for that agent in a monotherapy for the particular disease or condition being treated. Such therapeutic agents include, but are not limited to, therapeutic agents used in the treatment of cancers (emphasis added)…” Based upon these teachings, one of ordinary skill in the art would be particularly motivated to combine the teachings of Lantz et al. and Dahlen et al., because the resultant invention would combine the administration of multiple medicaments that could be used to treat cancer. Furthermore Lantz et al. suggest the use of antibodies of the invention in combination with an additional therapeutic agent thus providing additional motivation to combine the cited references to arrive at the claimed invention. Finally, the resultant bispecific antibody would be expected to place therapeutic T cells in the tumor microenvironment by virtue of the TAA-binding moiety.
Applicant further argues: “In addition, none of the cited documents would provide one of ordinary skill in the art with a reasonable expectation of success in arriving at the claimed invention (the claimed bispecific antibody in redirecting MAIT cells and killing tumor cells, as exemplified in the patent application). In this regard, the examples of the application show that a bispecific antibody targeting the Va7.2 TCR alpha chain of a MAIT cell and a TAA is able to:
(i) specifically activate MAIT cells (while minimally activating total CD8+ T cells). See Example 3; and
(ii) promote in vitro cytotoxicity of MAIT cells against various tumor cell lines, such as CD 19+, HER2 or EGFR tumor cell lines (see in particular Example 4, Example 11 or Example 13). It was also shown that the bispecific antibody of the invention is very efficient in reducing tumor growth in vivo. See Example 14 :"the tumor showed a slower growth before regressing at day 17 post tumor implantation. At day 17, the large majority of the animals treated with the bispecific antibodies showed weak or no bioluminescence signal." Thus, the present inventors are the first to demonstrate that a bispecific antibody targeting Va7.2 TCR alpha chain of a MAIT cell and a TAA can both (1) redirect MAIT cells and (2) efficiently promote MAIT cell cytotoxic activity against tumor cells, in vivo. One of ordinary skill in the art would not have been able to predict or expect such an activity for MAIT cells in the presence of such a bispecific antibody. Indeed, one could have reasonably expected that a bispecific antibody binding to the TCR, and especially to the Va7.2 chain, might interfere with TCR signaling, negatively impact MAIT cell function, or fail to result in productive cell activation.”
However, one of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Lantz et al with those of Dahlen et al to arrive at a multispecific molecule capable of simultaneous binding to a Mucosal Associated Invariant T (MAIT) cell and a tumor cell, said multispecific molecule comprising at least one domain that specifically binds a Va7.2 T cell receptor (TCR) and at least one domain that specifically binds a tumor associated antigen (TAA). One of ordinary skill in the art would have been motivated to do so, because Lantz et al teach an antibody against Va7.2Ja33 antibody, 3C10, a polypeptide comprising the heavy chain of 3C10, a polynucleotide encoding the polypeptide, and a host cell transfected with an expression vector comprising the polynucleotide. Lantz et al further teaches the use of the antibody in a subject with cancer. Furthermore, based on the teachings of Dahlen et al, one of ordinary skill in the art would have been motivated to treat solid or hematological malignancies with a bispecific antibody against a TCR and a tumor associated antigen. As such one of ordinary skill in the art would have been motivated to modify the invention of Lantz et al, which teaches an antibody against Va7.2Ja33 that can be used to treat cancer, to further include an antibody arm against a tumor associated antigen, because there would have been a reasonable expectation, that the resultant invention, which comprises a bispecific antibody against Va7.2Ja33 and a tumor associated antigen, is effective in treating hematological malignancies and solid tumors.
Furthermore, the qualities of activating MAIT cells and providing cytotoxicity against cancer cells are expected results of the combined invention of Lantz et al and Dahlen et al.
Therefore, the 35 USC 103 rejection of claims 20-38 is maintained.
Maintained Rejections- Non-final rejection 06/04/2025
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 20-38 are rejected under 35 U.S.C. 103 as being unpatentable over Lantz et al. (WO2008087219, publication date: 07/24/2008, IDS), in view of Dahlen (Dahlen et al, Therapeutic Advances in Vaccines and Immunotherapy, 2018, 6(1) 3-17).
Lantz teaches the antibody 3C10, which binds Va7.2-Ja33 (Lantz et al, pg. 32, paragraph 00119) comprising reference SEQ ID NO: 2 (comprises 100% of instant SEQ ID NO: 4, 5, and 6) and reference SEQ ID NO: 4 (comprises SSS and 100% of instant SEQ ID NO: 7 and 8). Lantz further teaches an antibody fragment selected from Fab, Fab', Fab'-SH, F (ab') 2, Fv, diabodies, single-chain antibody fragment, or a multispecific antibody comprising multiple different antibody fragments (Lantz et al, pg. 56, claim 15). Lantz et al teaches an exemplary immunoglobulin (antibody) structural unit that comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one ''light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids that is primarily responsible for antigen recognition (Lantz et al , pg. 12, paragraph 0055). Lantz et al further teaches single chain polypeptides containing only one heavy chain variable region, or a fragment thereof containing the three CDRs of the heavy chain variable region, without an associated light chain moiety; and multispecific antibodies formed from antibody fragments (Lantz et al, pg. 28, paragraph 00109). Additionally, Lantz et al teaches the DNA of a hybridoma producing an antibody of this invention, preferably a 3C10-like antibody, may be modified so as to encode a fragment of this invention. The modified DNA is then inserted into an expression vector and used to transform or transfect an appropriate cell, which then expresses the desired fragment (Lantz et al, pg. 29, paragraph 00111). Lantz et al further teaches the antibody can be used in a subject having cancer (Lantz et al, pg. 5, paragraph 0019).
Therefore, Lantz et al teach an antibody against Va7.2Ja33 antibody, 3C10, a polypeptide comprising the heavy chain of 3C10, a polynucleotide encoding the polypeptide, and a host cell transfected with an expression vector comprising the polynucleotide. Lantz et al further teaches the use of the antibody in a subject with cancer. Lantz et al does not teach that the 3C10 antibody is bispecific for a tumor associated antigen for hematological malignancies or solid tumor cells. Furthermore Lantz et al does not teach a multispecific molecule comprising at least one multispecific antigen-binding fragment comprising at least two Fab fragments with different CHI and CL domains, wherein said Fab fragments are tandemly arranged in any order, the C-terminal end of the CHI domain of a first Fab fragment being linked to the N- terminal end of the VH domain of the following Fab fragment through a polypeptide linker, wherein at least one Fab fragment binds Va7.2, and at least another Fab fragment binds the TAA. Additionally, Lantz et al does not teach a multispecific molecule comprising two identical antigen-binding arms, each consisting of a multispecific antigen-binding fragment.
Dahlen et al teaches bispecific antibodies against TCRs and tumor associated antigens including CD19, CD20, EGFR, HER2, CEA, PSMA, EpCAM, and PD-L1 (Dahlen et al, pg. 6, Table 1). Dahlen et al further teaches that bispecific antibodies can be used against tumors such as melanoma, Hodgkin’s lymphoma, Merkel cell carcinoma, non-small cell lung, head and neck, renal, bladder, colorectal, liver, gastric, and esophageal cancer.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Lantz et al with those of Dahlen et al to arrive at a multispecific molecule capable of simultaneous binding to a Mucosal Associated Invariant T (MAIT) cell and a tumor cell, said multispecific molecule comprising at least one domain that specifically binds a Va7.2 T cell receptor (TCR) and at least one domain that specifically binds a tumor associated antigen (TAA). One of ordinary skill in the art would have been motivated to do so, because Lantz et al teach an antibody against Va7.2Ja33 antibody, 3C10, a polypeptide comprising the heavy chain of 3C10, a polynucleotide encoding the polypeptide, and a host cell transfected with an expression vector comprising the polynucleotide. Lantz et al further teaches the use of the antibody in a subject with cancer. Furthermore, based on the teachings of Dahlen et al, one of ordinary skill in the art would have been motivated to treat solid or hematological malignancies with a bispecific antibody against a TCR and a tumor associated antigen. As such one of ordinary skill in the art would have been motivated to modify the invention of Lantz et al, which teaches an antibody against Va7.2Ja33 that can be used to treat cancer, to further include an antibody arm against a tumor associated antigen, because there would have been a reasonable expectation, that the resultant invention, which comprises a bispecific antibody against Va7.2Ja33 and a tumor associated antigen, is effective in treating hematological malignancies and solid tumors. The invention of Lantz et al and Dahlen et al meets the limitations of claims 20, 21, 25, and 26.
Regarding claims 21, 25, 26, and 27 Lantz teaches the antibody 3C10, which binds Va7.2-Ja33 (Lantz et al, pg. 32, paragraph 00119) comprising reference SEQ ID NO: 2 (comprises 100% of instant SEQ ID NO: 4, 5, and 6) and reference SEQ ID NO: 4 (comprises SSS and 100% of instant SEQ ID NO: 7 and 8).
Regarding claims 22 and 23 Lantz further teaches the antibody of any one of the above claims, wherein said antibody is an antibody fragment selected from Fab, Fab', Fab'-SH, F (ab') 2, Fv, diabodies, single-chain antibody fragment, or a multispecific antibody comprising multiple different antibody fragments (Lantz et al, pg. 56, claim 15). Lantz et al teaches an exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one ''light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids that is primarily responsible for antigen recognition (Lantz et al, pg. 12, paragraph 0055). It is noted that the CH and CL domains of an antibody are inherent parts of a full antibody and do not further limit the claims. It is further noted that polypeptide linkers that connect antibody domains is routine in the art and therefore, obvious.
Regarding claim 24 Lantz et al teaches an exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one ''light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids that is primarily responsible for antigen recognition (Lantz et al , pg. 12, paragraph 0055).
Regarding claims 28-32, Dahlen et al teaches bispecific antibodies against TCRs and tumor associated antigens including CD19, CD20, EGFR, HER2, CEA, PSMA, EpCAM, and PD-L1, which can be expressed on hematologic malignancies or solid tumors (Dahlen et al, pg. 6, Table 1).
Regarding claim 33, Lantz et al teaches single chain polypeptides containing only one heavy chain variable region, or a fragment thereof containing the three CDRs of the heavy chain variable region, without an associated light chain moiety; and multispecific antibodies formed from antibody fragments (Lantz et al, pg. 28, paragraph 00109).
Regarding claims 34-36 Lantz et al teaches the DNA of a hybridoma producing an antibody of this invention, preferably a 3C10-like antibody, may be modified so as to encode a fragment of this invention. The modified DNA is then inserted into an expression vector and used to transform or transfect an appropriate cell, which then expresses the desired fragment (Lantz et al, pg. 29, paragraph 00111). Regarding claim 36, it is noted that the method of culturing the cell and isolating the antibody from the culture is a common method in the art and therefore would be obvious to perform on the invention disclosed in Lantz et al as one would be motivated with a reasonable expectation of success to culture the hybridomas of Lantz et al and isolate antibodies from those cultures using cell culture assays routine in the art. Lantz et al teach one such method (Lantz et al, pg. 18-20, paragraphs 0079-0087).
Regarding claims 37 and 38, Dahlen et al teaches that bispecific antibodies can be used against tumors such as melanoma, Hodgkin’s lymphoma, Merkel cell carcinoma, non-small cell lung, head and neck, renal, bladder, colorectal, liver, gastric, and esophageal cancer, which includes solid tumors.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention, as evidenced by the references cited.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
No claims are allowed.
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/J.K.D./Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642