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 .
Election/Restrictions
Applicant’s election of the species II and (i) a first target antigen of which the first multispecific antigen binding molecule targets that is a tumor associated antigen (TAA) and is CD22 (ii) the format of the first multispecific antigen binding molecule is a bispecific antibody (i.e., targeting CD22 and CD28), and (iii) a second target antigen of which the second multispecific antigen binding molecule targets that is a TAA and is CD20 in the reply filed on 06/19/2026 is acknowledged. Because Applicant did not distinctly and specifically point out any errors in the restriction/election requirement, the election has been treated as an election without traverse (MPEP 818.03(a)).
Claim Status
Claims 2-3, 6, 10-17, 19, 21, 24-31, 33-36, 38, 40, 42-43, 45, 47, 49-51, 53, 55-56, and 58-112 have been cancelled; claims 39 and 44 have been amended; and claims 113-115 have been newly added, as requested in the amendment filed on 06/19/2026. Following the amendment, claims 1, 4-5, 7-9, 18, 20, 22-23, 32, 37, 39, 41, 44, 46, 48, 52, 54, 57, and 113-115 are pending in the instant application.
Claims 1, 4-5, 7-9, 18, 20, 22-23, 32, 37, 46, 48, 52, and 54 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of invention in the Response filed 06/19/2026, there being no allowable generic or linking claim.
Claims 39, 41, 44, 57, and 113-115 are under examination in the instant office action.
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 39, 41, 44, 57, and 113-115 have an effective filing date of April 11, 2022 corresponding to PRO 63/329,762.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/07/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because portions of Figures 1A and 1C, specifically the IHC staining portions of the figures, appear to comprise labels for the staining which are unclear and difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: there is an extra period at the end of Paragraph 0021 and the beginning of Paragraph 0022, there are extra spaces at the beginning of Paragraphs 0187-0188 and 0313-0314. Appropriate correction is required.
The disclosure is further objected to because it contains an embedded hyperlink and/or other form of browser-executable code at Paragraphs 0230 and 0270. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to for the use of the terms BiTE, DART, TandAb, nanobodies, small modular immunopharmaceuticals, SMIP, MicroProteins, BESTFIT, Blincyto, CountBright, FlowJo, V-PLEX, Filtermate, TopCount, AlphaLISA, Microbeta, MicroScint, GraphPad Prism, Cytoseal, U-Plex, Vybrant, CellTrace, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 41 is objected to because of the following informalities: the claim comprises references to Tables 2 and 5 of the specification. MPEP 2173.05(s) recites: “[w]here possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.’ Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 39, 41, 44, and 113-115 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 39 recites the limitation "the target antigen" in line 3. There is insufficient antecedent basis for this limitation in the claim because there is no earlier recitation of “a target antigen” in the claim. Furthermore, it is noted that there are, ultimately, two target antigens recited later in the claim, a first target antigen and a second target antigen, and as such it would be unclear as to which target antigen “the target antigen” would refer to. Thus, claim 39 is considered to be indefinite. For the purpose of examination, the recitation of "the target antigen" in claim 39 is being interpreted as referring to the first target antigen of the first multispecific antigen binding molecule.
Claims 41, 44, and 113-115 are included in this rejection as they all depend from and/or incorporate claim 39.
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 39, 41, 44, 57, and 113-115 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/132066 A1 (Foreign Patent Document Reference BA on 08/07/2023 IDS; herein after referred to as “Murphy”).
Murphy teaches methods comprising administering to a subject in need thereof a therapeutic composition comprising an anti-CD28 antibody or a bispecific antigen binding molecule that specifically binds CD28 and a target antigen (e.g., CD22), wherein the expression "a subject in need thereof" means a human or non-human animal that exhibits one or more symptoms or indicia of cancer (e.g., a subject expressing a tumor or suffering from any of the cancers mentioned herein below), or who otherwise would benefit from an inhibition or reduction in CD22 activity or a depletion of CD22+ cells (Paragraph 00155). The antibodies and bispecific antigen-binding molecules of the invention (and therapeutic compositions comprising the same) are useful, inter alia, for treating any disease or disorder in which stimulation, activation and/or targeting of an immune response would be beneficial; in particular, the anti-CD28/anti-CD22 bispecific antigen-binding molecules of the present invention may be used for the treatment, prevention and/or amelioration of any disease or disorder associated with or mediated by CD22 expression or activity or the proliferation of CD22+ cells, wherein the mechanism of action by which the therapeutic methods of the invention are achieved include killing of the cells expressing CD22 in the presence of effector cells, for example, T cells. Cells expressing CD22 which can be inhibited or killed using the bispecific antigen-binding molecules of the invention include, for example, cancerous B cells (Paragraph 00156). Murphy further teaches that the anti-CD28/anti-CD22 antibodies of the invention may be used in conjunction with other bispecific antigen binding molecules, such as with an anti-CD20/anti-CD3 bispecific antibody (Paragraph 00159). In Example 8, Murphy teaches that CD22xCD28 enhancement of CD20xCD3 targeted killing was evaluated in a 96- hour cytotoxicity assay targeting Raji cells engineered to lack expression of CD80 and CD86 (Raji-80/86DKO), and results include: (i) REGN1979 (CD20xCD3) activated and directed human T cells to deplete Raji cells lacking CD80 and CD86 expression in a dose-dependent manner, and the addition of a fixed concentration of CD22xCD28 bispecific antibodies to REGN1979 enhanced the cytotoxic efficacy (EC50) of REGN1979 3.5-6.4-fold when compared to REGN1979 with 1-arm CD28 or isotype control antibodies (see Table 17); (ii) the observed target-cell lysis mediated by REGN1979 was associated with T cell activation and proliferation, as measured by CD25 upregulation on CD8+ cells or CellTrace violet dilution respectively, wherein the addition of a fixed concentration of CD22xCD28 bi specific antibodies to REGN1979 enhanced the potency of REGN1979 induced T cell activation and proliferation 2.1 to 2.6 fold and 7.4-8.4 fold respectively when compared to REGN1979 with 1-arm CD28 or isotype control antibodies (see Table 17); (iii) REGN1979 induced the release of human cytokines, wherein cytokine released observed with REGN1979 in combination with CD22xCD28 bispecific antibodies was enhanced in the presence of a fixed concentration of a CD22xCD28 costimulatory molecules with a fixed concentration of 1-arm CD28 or isotype control antibodies (see Table 18) (Paragraphs 00225-00228; Tables 17-18 at Pages 69-70). In summary, Murphy teaches that co-stimulation increased the potency of targeted cytotoxicity, T cell activation, and cytokine release when compared to what was observed with CD20xCD3 in combination with control antibodies (Paragraph 00229). Example 11 further evaluated anti-tumor efficacy of administration of REGN5837 (CD22xCD28) in the presence and absence of REGN1979 (CD3xCD20); REGN5837 is a human lgG4-based bispecific antibody (bsAb) designed to target B cell NHLs (e.g., DLBCL) by bridging CD22+ B cells with CD28+ T cells, wherein the "signal 2" provided by REGN5837, in combination with other agents providing "signal 1" (e.g., delivering a signal via primary T-cell stimulation via the TCR or CD3 clustering), such as the CD20xCD3 bispecific antibody (bsAb) REGN1979, may provide amplified T cell activation and T cell-mediated killing of B cell NHLs, deepening the response to CD20xCD3, and REGN5837 may provide increased efficacy in patients unresponsive to CD20xCD3 monotherapy (Paragraph 00275). The experimental design, including bispecific antibody combinations, doses, and dosing schedules, are provided in Table 25 at Page 87. In tumor-bearing mice (NALM-6-luc tumors; CD22+, CD20+), treatment with 0.04, 0.4, and 4 mg/kg REGN5837 in the presence of 0.04 mg/kg REGN1979 resulted in statistically significant suppression of tumor growth compared with non-bridging control bsAbs (non-TAAxCD28 and non-TAAxCD3 bsAbs) at day 23 post-implantation (p<0.05, p<0.01, and p<0.001, respectively) (Paragraph 00287; Figure 6). On day 20 post-implantation, significant suppression of tumor growth was observed for the 0.4 and 4 mg/kg groups (p<0.05 for both groups), whereas neither REGN5837 (4 mg/kg) nor REGN1979 (0.04 mg/kg) monotherapy significantly reduced tumor growth compared with non-bridging control bsAbs; no difference between any REGN5837 + REGN1979 combination dose and either bsAb monotherapy reached statistical significance and rapid tumor growth was observed upon dosing with non-bridging control bsAbs throughout the dosing period, and all mice were euthanized on day 23 (Id.). In Example 12, the anti-CD20xCD3 bispecific antibody REGN1979 was tested for its ability to induce naive human T cells to kill target cells expressing human CD20 and CD22 in combination with a costimulatory CD22xCD28 antibody or 1-arm CD28 or isotype control antibodies (Paragraph 00293). REGN1979 activated and directed human T cells to kill Nalm6 (Figure 7) or WSUDLCL2 (Figure 8) cells in a dose-dependent manner. The addition of a fixed concentration of CD22xCD28 bispecific antibodies to REGN1979 enhanced the cytotoxic efficacy (EC50) of REGN1979 against Nalm6 cells 4.7-5.2 fold when compared to REGN1979 with 1-arm CD28 or isotype control antibodies (Table 26) or 17.5 fold against WSU-DLCL2 cells when compared to REGN1979 alone (Table 27) (Paragraph 00294). The addition of a fixed concentration of CD22xCD28 bispecific antibodies to REGN1979 enhanced the potency of REGN1979 induced T cell activation and proliferation in the presence of Nalm6 cells 2.3-2.6 fold and 5.4-7.1 fold respectively when compared to REGN1979 with 1-arm CD28 or isotype control antibodies (Table 26), or 8.2 and 16.1 fold in the presence of WSU-DLCL2 cells when compared to REGN1979 alone (Table 27); in assays with human PBMC and WSU-DLCL2 cells, REGN1979 induced the release of human cytokines. Cytokine released observed with REGN1979 was enhanced in the presence of a fixed concentration of a CD22xCD28 compared to cytokine release induced by REGN1979 alone (Table 28, Figure 9) (Paragraphs 00295-00296). In summary, Murphy teaches that co-stimulation increased the potency of targeted cytotoxicity, T cell activation, and cytokine release when compared to what was observed with CD20xCD3 in combination with control antibodies or alone (Paragraph 00297). In Example 15, both in vitro and in vivo studies were done to evaluate the anti-tumor efficacy of the human CD22xCD28 bsAb REGN5837, in the presence or absence of a sub-efficacious dose of a human CD20xCD3 bsAb (REGN1979), in NSG mice after implantation with human PBMC and WSU-DLCL2 cells (Paragraph 00310); the experimental design, including bispecific antibody combinations, doses, and dosing schedules, are provided in Table 31 at Page 99. In tumor-bearing mice, treatment with 1 mg/kg REGN5837 in the presence of either 0.4 or 4 mg/kg REGN1979 resulted in statistically significant suppression of tumor growth compared with non-bridging control bsAbs (non-TAAxCD28 and non-TAAxCD3 bsAbs) by day 28 (6 days following the final antibody dose (Figure 13A and 13B); the combination of 1 mg/kg REGN5837 and 0.4 mg/kg REGN1979 resulted in a significant reduction in tumor volume relative to REGN1979 monotherapy by day 46 (Paragraph 00339). Both 0.4 and 4 mg/kg REGN1979 monotherapy resulted in modest tumor suppression relative to non-bridging controls by day 28, whereas REGN5837 monotherapy had no effect; rapid tumor growth was observed upon dosing with non-bridging control bsAbs throughout the dosing period, and all mice were euthanized on day 125 (Paragraph 00340). Thus, Murphy teaches that the combination of two bispecific antibodies (i.e., multispecific binding molecules) wherein the first bispecific antibody is a CD22xCD28 bispecific antibody and the second is a CD20xCD3 bispecific antibody are useful in the treatment of cancer, and more specifically cancers expressing CD22. However, it is further noted that the experimental data presented in the above-listed examples also supports that the combination of non-TAAxCD28 bispecific antibodies with a CD20xCD3 antibody would still be reasonably expected to treat cancer/tumors, as demonstrated by data presented in Figures 6 and 13A-B (reproduced below).
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The data above indicates that while the combination of CD22xCD28 and CD20xCD3 is the best therapeutic option in CD22-expressing cancers, even non-TAAxCD28 and CD20xCD3 exhibits therapeutic effects, demonstrating that the bispecific antibody targeting CD28 need not target an antigen expressed by the tumor/cancer in order to exhibit therapeutic effects. However, non-TAAxCD3 bispecific antibodies, even in combination with CD22xCD28 bispecific antibody, do not demonstrate any therapeutic effect, and produced nearly identical results to the non-TAAxCD28 and non-TAAxCD3 combination. Thus, for the combination of bispecific antibodies to demonstrate therapeutic effect, the tumor/cancer must, at a minimum, express the TAA of the CD3 bispecific antibody (e.g., CD20 in the above examples) in order to observe anti-tumor effects in combination with a CD28 bispecific antibody.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to mediate killing of tumor cells, induce killing of tumor cells, or induce T cell activation against tumor cells in a tumor in a subject comprising administering a first multispecific antigen binding molecule (e.g., CD22xCD28; CD22 being the first target antigen) and a second multispecific antigen binding molecule (e.g., CD20xCD3; CD20 being the second target antigen) to subjects who do not express the first target antigen, as suggested by Murphy. One would have been motivated to treat such a population because Murphy specifically demonstrates the combination of a non-TAAxCD28 bispecifc antibody in combination with a bispecific CD20xCD3 antibody, specifically in cases wherein cancer/tumor cells express CD20, still exhibits therapeutic effects including killing tumor cells, promoting T cell infiltration, and ultimately reducing tumor size and improving survival relative to, for example, a combination comprising non-TAAxCD28/non-TAAxCD3 or TAAxCD28/non-TAAxCD3. One of ordinary skill in the art would have a reasonable expectation of success treating a population of subjects who do not express the first target antigen in the method(s) of Murphy because Murphy successfully demonstrates treating tumors with a combination of a non-TAAxCD28 bispecifc antibody and a bispecific CD20xCD3 antibody, specifically in cases wherein the cancer/tumor cells express the second target antigen (i.e., CD20), but not the first target antigen (i.e., CD22 in the above-specified examples) whereby the CD20xCD3 bispecific antibody activated T cells and whereby the CD28-targeting bispecific antibody further enhances efficacy and T cell activation.
Conclusion
Claims 1, 4-5, 7-9, 18, 20, 22-23, 32, 37, 39, 41, 44, 46, 48, 52, 54, 57, and 113-115 are pending. Claims 1, 4-5, 7-9, 18, 20, 22-23, 32, 37, 46, 48, 52, and 54 are withdrawn. Claims 39, 41, 44, 57, and 113-115 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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