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 .
Application Status
The Response to the non-final Office Action filed April 19, 2026 is acknowledged. Claims 1, 4, 9-10, 12-13, 16-19, 24-26, 28-29, 33-35, 38, and 41 are pending. Claims 1, 9-10, 12-13, 18-19, 25-26, 28-29, and 41 are amended. Claims 33-35 and 38 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1, 4, 9-10, 12-13, 16-19, 24-26, 28-29, and 41 are under examination herein.
WITHDRAWN OBJECTIONS AND REJECTIONS
The objection to the specification is withdrawn in view of Applicant's amendments to ¶ 095 and 0110.
The prior grounds of rejection of claims 9, 26, and 29 under 35 U.S.C. § 112(b) are withdrawn in view of Applicant's amendments to said claims.
The rejection of claims 1, 4, 9-10, 12-13, 16-19, 24-26, and 41 under 35 U.S.C. § 112(a) is withdrawn in view of Applicant's amendments to claim 1.
The rejection of claim 29 under 35 U.S.C. § 101 is withdrawn in view of Applicant's amendments to said claim.
The rejection of claims 1, 4, 10, 18-19, 24-26, and 41 under 35 U.S.C. § 102 as being anticipated by Sennhenn (WO 2020/083909 A1; cited in IDS) is withdrawn in view of Applicant's amendments to claim 1 to recite “specifically decreasing” EPHB2 function in a cancer cell.
MAINTAINED AND NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
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.
Claim 29 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a new rejection necessitated by claim amendment.
Claim 29 recites the kit of claim 28, wherein the kit further comprises a label stating “said antibody or the pharmaceutical composition comprising said antibody is for use with said immunotherapy” in part (a). There is insufficient antecedent basis for this limitation in the claim. Prior claim 28 recites that the kit comprises both an anti-EPHB2 antibody (or a pharmaceutical composition comprising the same) and a pharmaceutical composition comprising an anti-PD-1/PD-L1 antibody. As drafted the claim language does not make sufficiently clear whether “said antibody” or “the pharmaceutical composition comprising said antibody” refers to the anti-EPHB2 antibody or to the anti-PD-1/PD-L1 antibody.
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.
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.
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.
(1)
Claims 1, 4, 9-10, 12-13, 16-19, 24-26, 28-29, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Mao (US 2008/0254024 A1) in view of Garcia-Aranda (International Journal of Molecular Sciences (2019) 20(9): 2296; cited in IDS). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
Mao discloses anti-EphB2 antibodies and immunoconjugates, compositions thereof, and methods of using the same for therapeutic and diagnostic applications (e.g., Abstract; ¶ 0010-0067). Relevant to claims 1, 4, 10, 12-13, 16-17, and 41, Mao discloses exemplary anti-EphB2 antibodies and immunoconjugates which reduce, inhibit, or block EphB2 activity in vitro or in vivo, such as by reducing or blocking EphB2 ligand binding to EphB2 (e.g., ¶ 0037; Examples 3-5 at ¶ 0424-0428). Mao provides use of an antibody of the invention for treating a cancer (e.g., a colorectal cancer, melanoma, renal carcinoma, and others) or killing a cancer cell by administering an anti-EphB2 antibody of the invention (e.g., ¶ 0037-0038, 0047-0062; Example 1). Mao illustrates that EphB2 mRNA is overexpressed in human cancer tissue relative to healthy tissue (e.g., Figures 2-4; Example 1 at ¶ 0419-0421). Mao further provides that antibodies of the invention may be used in combination with other compositions in a therapy, e.g., another antibody that also inhibits tumor growth, either separately or in the same formulation (e.g., ¶ 0365-0368). By administering the anti-EphB2 antibody to a subject in need thereof, the method would necessarily comprise or consist of contacting an EPHB2-expressing cancer cell in the subject and decreasing the function of EPHB2 in the EPHB2-expressing cancer cell.
Relevant to claims 28-29, Mao provides kits comprising a composition having one or more anti-EphB2 antibodies of the invention for use in the preparation of a therapeutic treatment for cancer, which further comprises instructions for administering the composition to a subject in need thereof (e.g., ¶ 0046-0052).
However, Mao does not expressly teach administering an immunotherapy (e.g., an anti-PD-1 antibody) in combination with an anti-EphB2 antibody of the invention.
Garcia-Aranda reviews the role of protein kinases that are most frequently altered in tumor cells and their potential utility to enhance response to existing immunotherapeutic treatments. Garcia-Aranda teaches that immunotherapies based on the use of anti-PD-1/anti-PD-L1 blocking antibodies have shown great promise in the treatment of many cancers including melanoma, renal cell carcinoma (RCC), and others by preserving the anti-tumor capacity of T cells, but that use of immunotherapy as a mono-therapy rarely has a response rate exceeding 40% (Abstract; Section 1). Accordingly, Garcia-Aranda contends that new treatment strategies are needed to improve the efficacy of PD-1/PD-L1 inhibitors (Section 1).
Garcia-Aranda notes that the presence of altered receptor kinases, including Eph receptors, is a common phenotype in tumor cells (e.g., Section 2; Table 2). Garcia-Aranda teaches that the effectiveness of the combination of kinase inhibitors and anti-PD-1/anti-PD-L1 therapy (e.g., the anti-PD-1 antibody nivolumab) has been explored in several studies and shown to improve median overall survival (e.g., Section 2; Table 4), relevant to claims 1, 18-19, 24-26, and 41.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the combination cancer treatment method disclosed by Mao to include administering an immunotherapy (e.g., an anti-PD-1 antibody) based on the further teachings of Garcia-Aranda, and to generate a kit comprising both therapies for the purpose of treating cancer in a subject in need thereof. The skilled artisan would have been motivated to administer an anti-EPHB2 blocking antibody because Mao and Garcia-Aranda both teach that EPHB2 is overexpressed in many cancer tumors, and would further have been motivated to administer an anti-PD-1 or anti-PD-L1 blocking antibody because Garcia-Aranda teaches that anti-PD-1/anti-PD-L1 inhibiting antibodies have demonstrated promise in cancer treatment through their ability to restore T cells’ anti-tumor capacity and overcome tumor cell immune escape mechanisms. Further, Garcia-Aranda provides that the combination of an inhibitor of a protein kinase such as EPHB2 in combination with PD-1/PD-L1 blocking therapies has the capacity to enhance treatment response relative to anti-PD-1/anti-PD-L1 monotherapy. There would have been a reasonable expectation of success because each of these therapeutic options individually have been disclosed to be useful for the same purpose (i.e., treating a cancer), and “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. See MPEP § 2144.06(I).
Further regarding claim 9, while Mao and Garcia-Aranda do not appear to expressly discuss whether a combination treatment of the disclosure may be practiced as a first line or second line treatment, it would have been obvious to treat a subject in need thereof in either case, as the subject has a clear need to be treated. Furthermore, since Garcia-Aranda teaches that co-administering a protein kinase inhibitor enhances the efficacy of anti-PD-1/anti-PD-L1 blocking therapies, one would be motivated to either use the combination treatment method in a subject naïve to immunotherapy (to produce an enhanced effect relative to anti-PD-1/anti-PD-L1 mono-therapy) or to enhance the efficacy of a previously administered anti-PD-1/anti-PD-L1 mono-therapy.
(2)
Claims 1, 4, 9-10, 12-13, 16-19, 24-26, 28-29, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Sennhenn (WO 2020/083909 A1; supra) in view of Mao (US 2008/0254024 A1; supra) and Barquilla (Annual Review of Pharmacology and Toxicology (2015) 55: 465-487; cited in IDS). This is a maintained rejection which has been updated to reflect Applicant's claim amendments.
Sennhenn discloses protein kinase inhibitors that are structurally similar to but functionally distinct from dasatinib, and pharmaceutical compositions thereof, as well as methods of using said inhibitors and/or compositions in the treatment of proliferative disorders (e.g., leukemia or solid tumors) alone or in combination with immune checkpoint inhibitors (e.g., Abstract; ¶ 1-35, 243; claims 1-6, 14-16, 19-22). Sennhenn discloses an exemplary protein kinase inhibitor “B3” which, like dasatinib (“A8”), inhibits the activity of EPHB2 to less than about 25% of residual activity (e.g., ¶ 13, 39; Figure 3; Examples 1-3). Sennhenn teaches a method of treating a proliferative disorder (e.g., a solid tumor, melanoma, colorectal cancer) by administering to a subject in need thereof a compound as illustrated in claim 1 (which inhibits the activity/expression of EPHB2) as well as an additional therapeutic agent (e.g., an anti-PD-1 antibody such as nivolumab), wherein the treatment comprises inhibiting EPHB2 and enhancing tumor response to anti-PD-1 immunotherapy (e.g., claims 1-6, 14-16, 19-22), anticipating claims 1, 4, 10, 18-19, 24-26, and 41.
However, Sennhenn does not teach administering an antagonistic anti-EPHB2 antibody as an EPHB2 inhibitor in the combination treatment methods of the invention, or that the anti-EPHB2 agent administered in said method is specific only for EPHB2.
The teachings of Mao, with respect to administering an anti-EPHB2 blocking antibody in combination with another antibody to treat cancers, are recited in the 35 U.S.C. § 103 rejection above.
Barquilla reviews the role of the Eph receptor tyrosine kinase family in disease states including cancer. Barquilla teaches that Eph inhibitory antibodies are among several types of molecules that can be used to interfere with Eph/Ephrin signaling (e.g., pages 475-478; Table 1). By contrast, Eph small-molecule antagonists target multiple Ephs and may target additional targets (e.g., Table 1). According to Barquilla, “Antibodies are particularly suitable for modulating the Eph/ephrin system, given their high binding affinity and specificity coupled with their long in vivo half-life” (page 477).
Based on the further teachings of Mao and Barquilla, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute an anti-EPHB2 blocking antibody in place of the EPHB2 inhibitor compound taught by Sennhenn in a combination treatment method for cancer. The skilled artisan would have been motivated to do so because, as taught by Barquilla, using an anti-EPHB2 antibody would be desirable because antibodies have higher binding affinity and specificity compared to small molecule antagonists, and furthermore, antibodies have a longer in vivo half-life. Mao provides a proof-of-concept that an anti-EPHB2 antibody may be administered in combination with another anti-tumor therapeutic antibody to effect a treatment for cancer. There would have been a reasonable expectation of success because the protein kinase inhibitor taught by Sennhenn and the anti-EPHB2 antibodies described by Mao and Barquilla have equivalent functions (inhibiting EPHB2 signaling) and may be used for the same desired purpose of treating cancer. Furthermore, as stated in MPEP § 2144.06(I), “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”.
Further regarding claim 9, while Sennhenn, Mao, and Barquilla do not appear to expressly discuss whether a combination treatment of their respective disclosures may be practiced as a first line or second line treatment, it would have been obvious to treat a subject in need thereof in either case, as the subject has a clear need to be treated. Furthermore, since Sennhenn teaches that co-administering a protein kinase inhibitor enhances the efficacy of an anti-PD-1 blocking therapy, one would be motivated to either use the combination treatment method in a subject naïve to immunotherapy (to produce an enhanced effect relative to anti-PD-1/anti-PD-L1 mono-therapy) or to enhance the efficacy of a previously administered anti-PD-1/anti-PD-L1 mono-therapy.
Response to Arguments (Combined)
Applicant's combined arguments filed April 19, 2026 have been fully considered but they are not persuasive.
Applicant argues that the cited references of Garcia-Aranda and Sennhenn do not particularly point to the combination of EPHB2 and PD-1/PD-L1 and teach many other kinases as potential therapeutic targets, many of which Applicant states have since been tested in combination with PD-1/PD-L1 blockade and do not achieve a synergistic effect. Remarks at pages 11-12. Applicant points to references testing the combination of a Bruton’s tyrosine kinase (BTK) inhibitor and an anti-PD-1 monoclonal antibody for the treatment of chronic lymphocytic leukemia (i.e., Gu (2018) Blood 132(Suppl. 1): 4416), platinum-resistant metastatic urothelial cancer (i.e., Zhang (2020) Cancer 126(20): 4485-4497), and head and neck squamous cell carcinoma (i.e., Taylor (2022) Clinical Cancer Research 28(5): 903-914) or the combination of a CSF1R inhibitor and an anti-PD-L1 antibody for the treatment of unresectable or metastatic sarcoma (i.e., Rosenbaum (2025) ESMO Open 10(8): 105522) to support the idea that “a skilled artisan cannot predict which of the kinases taught by Garcia-Aranda … will synergize with PD-1/PD-L1 blocking and that there is therefore no reason to expect that EPHB2 would synergize”. Remarks at pages 12-13.
Applicant further submits that the combination of EPHB2 blockade and PD-1/PD-L1 blockade as claimed showed an unexpected synergistic effect which could not have been predicted from the cited prior art references. Applicant argues that the combination of EPHB2 blockade and PD-1 blockade produced a 44% increase in killing (caspase 3/7 positive events) over PD-1 blockade alone for melanoma, which “cannot be additive since EPHB2 blocking alone had no effect” (e.g., Figures 2A and 2C; Example 2). Applicant states that the synergistic effect “is broadly applicable in cancer and not restricted to a specific cancer type” based on “the same synergistic effect” shown in Figure 3, for colon carcinoma. Remarks at page 12. Applicant further highlights that PD-1 blockade increases expression of several ephrins which are ligands of EPHB2 and that “this effect is not universal to the many other kinases recited in Garcia-Aranda and Sennhenn” or even to all ephrin receptors (e.g., Example 3 and Figure 4). Remarks at page 13.
In response to Applicant's arguments against the references of Garcia-Aranda and Sennhenn individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). However, it is noted that at least Sennhenn clearly provides for a cancer treatment method bridging an agent that blocks EPHB2 function and the PD-1/PD-L1 signaling pathway. Furthermore, it was known from at least the teachings of Mao and Garcia-Aranda that EPHB2 is overexpressed in many cancer tumors, and from the teachings of Garcia-Aranda that the use of combination therapies to improve treatment efficacy for anti-PD-1/anti-PD-L1 is a known strategy in the relevant art. With respect to Applicant's arguments regarding the combination of a BTK inhibitor or CSF1R inhibitor with an anti-PD-1 or anti-PD-L1 antibody, respectively, these are not found convincing because it is recognized that BTK and CSF1R are distinct kinases that are not in the same family of receptor tyrosine kinases as EPHB2. As such, the kinases act through distinct biological pathways and are involved in distinct functions from the instantly claimed EPHB2.
Regarding Applicant's assertions regarding unexpected synergistic results, MPEP § 716.02(d) sets forth that whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). In the present case, the instant claims are significantly broader in scope and do not reflect the method used to obtain the alleged synergistic results. Example 2 of the disclosure states that melanoma cells were pre-incubated with the anti-EPHB2 antibody clone 2H9 while autologous tumor-infiltrating lymphocytes (TILs) were pre-incubated with the anti-PD-1 antibody nivolumab, and the pre-incubated TILs were subsequently added to the pre-incubated cancer cells (e.g., page 32 of specification). Example 2 states that “two experiments were run” on these mixed cells, one in which caspase 3/7 was measured and one in which 4-1BB positive events were measured (e.g., page 32; Figures 2A-2B). The disclosure and figures do not provide statistical information regarding any apparent differences between treatment groups and whether the same observations hold across multiple experimental replicates and/or in vivo. Example 2 also notes, “Importantly, in the absence of TILs, combined administration of anti-EPHB2 and anti-PD-1 had no effect on cell survival (Fig. 2D)” (page 32). It is not discernible from the data presented in the disclosure whether pre-incubation of melanoma cells with an anti-EPHB2 antibody followed by incubation with autologous TILs that have not been pre-incubated with an anti-PD-1 antibody also increases cell killing or how this effect compares to those pre-treated with nivolumab. With respect to the colon carcinoma findings, it is noted that the protocol differs in that the cancer cells were pre-incubated in the presence of anti-PD-1 antibody and anti-EPHB2 (or isotype control), followed by the addition of autologous TILs (not antigen-specific), unlike the antigen-specific TILs pre-incubated with nivolumab for treatment of melanoma (e.g., page 33). The disclosure and Figure 3 likewise do not provide any statistical comparisons between the tested groups for the colon carcinoma experiment, and comparative data with anti-EPHB2 monotherapy is not shown. With respect to the EPH ligands data (Example 3), it’s unclear from the data presented in Figure 4 that a 2% or 10% increase in expression represents a statistically meaningful increase in expression.
For these reasons, the rejections are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
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