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 .
Response to Amendment
All rejections of claim 3 are moot in view of the cancelation of the claim.
The rejection of claims 2 and 4 under 35 USC 112(b) is withdrawn in view of the amendment to the claims to recite “at least 80% with SEQ ID NO:…”
The rejection of claim 8 under 35 USC 112(b) is withdrawn in view of the amendment to the claim specifying the additional therapeutic agent is linked to the antibody or antigen-binding fragment thereof.
The rejection of claim 18 under 35 USC 112(b) is withdrawn in view of the amendment removing “for example” and the parenthetical phrases beginning with “comprising”.
The rejection of claim 7 under 35 USCS 112(a) is withdrawn in view of the amendment removing “sdAb”.
Alternative Names
OX40 is also commonly known as CD134, TNFRSF4 (see p. 1, line 28 of the specification) and ACT35.
New
Specification
The amendment filed 4/21/2026, the substitute specification, is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: The substitute specification on p. 83, second full paragraph, now refers to Table B (sequence listing at the end of the specification) as showing the CDR, VH/VL and HC/LC sequences of anti-OX40 antibody HFB301001. Both the table at the end of the specification (now labeled “Table B”) and the Sequence Listing filed 9/26/2022, list the sequences as being of HFB10-1E1hG1. However, now as amended the specification contradicts this by saying the sequences in the end table (Table B) are of HFB301001, which is new matter because there is nowhere in the specification indicating that these two antibodies are identical, having the same sequences.
Applicant is required to cancel the new matter in the reply to this Office Action.
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 17, 18 and 25 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating cancer in a subject with a cancer by administering a therapeutically effective amount of the OX40 antibody or antigen-binding fragment thereof according to claim 1 or antibody-drug conjugate according to claim 8, wherein the antibody or antigen-binding fragment has a heavy chain Fc region able to bind and crosslink Fc receptor(s) (FcR) or the conjugated drug is cytotoxic, does not reasonably provide enablement for wherein the antibody or antigen-binding fragment or antibody-drug conjugate does not cross-link FcR or wherein the conjugate is not cytotoxic. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims for the reasons set forth in the previous Office action and for the following reasons addressing the amendment to the claims and specification: Claims 17 and 25 have been amended to specify the subject being treated has cancer and, therefore, prevention or prophylaxis is no longer encompassed. The rejection has been recast to remover the portion directed thereto.
The claims are drawn to methods of treating cancer in a subject with cancer by administering the antibody or antigen-binding fragment thereof of claim 1 (claims 17-18) or the antibody-conjugate of claim 8 (claim 25). The issue of enablement relates to the agent being used for the treatment, either the anti-OX40 antibody or antigen-binding fragment thereof or the antibody-drug conjugate.
The structure of the OX40 antibody determines its function. The only OX40 antibody of the invention shown to have antitumor activity is HFB10-1E1hG1 (Example 5). This is a full-length agonistic antibody that “is anti-human IgG cross-linking dependent” (p. 66, line 1) that includes an IgG1 Fc region (Example 3.2). Note that OX40 antibody HFB301001 is disclosed as having antitumor activity, but no structural information about the antibody is provided (Example 14). Although, Raue et al. (AACR Virt. Meet. E-poster #2285, 2020, cited in the IDS filed 2/13/23), identifies HFB301001 as being an IgG1 isotype antibody in Fig. 4. As discussed in instant Example 3.1, entitled “Agonistic activity of HFB10-1E1hG1 in Jurkat report cells” (first paragraph):
Anti-OX40 antibodies can be divided into two categories according to their different ways of activating, the first class of OX40 agonistic activity is independent of the Fc receptor cross-linking; the other class requires Fc receptor cross-linking for OX40 agonistic activity. Tumor tissue and surrounding draining lymph nodes have more tumor-associated inflammatory cells. The Fc receptor FeyR2b is more likely to be clustered around tumor cells. Therefore, “cross-linked antibody” agonists have higher tissue selectivity. Only in the tumor microenvironment can the antibody have a significant agonistic effect, while in the normal tissue parts of the body, the effect will remain at a low level. This can improve the safety window for treatment.
Further, it was shown that the HFB10-1E1hG1 exhibited cooperative agonist effect with OX40L in the presence of crosslinking with anti-human IgG (p. 66, lines 8-9). The need for cross-linking of an agonistic OX40 antibody for antitumor efficacy is supported by post-filing references Carrascosa et al. (J. Immunother. Canc. 8:e000816, 13 pages, 2020) and Zhang et al. (Biomolecules 12:1209, 14 pages, Aug. 2022). Carrascosa et al. notes (p. 3/13, last paragraph), “OX40 is well known to require receptor trimerization for efficient signal transduction.” Experiments showed “OX40-mediated TIL [tumor infiltrating lymphocyte] expansion was dependent on efficient OX40 crosslinking.” (p. 4/13, col. 1, second paragraph) In line with this an OX40 IgG1 was more effective than one having an IgG2 Fc in in vitro tumor infiltrating lymphocytes (TIL) expansion (p. 4/13 paragraph bridging cols. 1-2). Zhang et al. examined 4 agonistic OX40 antibodies and found that in order to substantially activate the NF-kB pathway, all need crosslinking by an IgG Fc of the antibody to its receptors. They “demonstrated the critical role of cross-linking in amplifying the antibody-mediated downstream activation signal.” (p. 6/14, end of first paragraph) It was found that not only epitope binding but also IgG isotype was important for antibody activity (e.g., p. 2/14, second to last sentence of third paragraph). Claims 17, 18 and 25 are drawn to methods of treating cancer; however, none of the antibodies or antigen-binding domains thereof used in the method are required to have an Fc domain that binds an FcR and facilitates crosslinking by the antibody. A method of treatment requires more than mere binding or minimal activity of a receptor. The activity must be sufficiently robust as to be therapeutic. Therefore, it reasonably appears absent evidence to the contrary that the antibody requires an IgG Fc domain able to bind FcR and produce OX40 crosslinking.
The exception to this relates to the antibody-drug conjugate used in the method of claim 25. If the drug is cytotoxic, then as long as the antibody binds OX40 one skilled in the art might expect cytotoxicity directed to OX40-expressing Treg cells. The specification discusses that OX40 binding to OX40L reduces immunosuppression by regulatory T cells, which can promote an antitumor response. Though the instant specification has no working example of an OX40 antibody-drug conjugate, similar conjugates were in clinical use at the time of the invention (e.g., Herrera et al., Clin. Lymphoma Myeloma Leuk. 18(7):453-468, 2018). Strugill et al. (Am. J. Hematol. Oncol. 13(11):4-15, 2017, cited in the IDS filed 10/07/2025, paragraph bridging pp. 8-9) discusses that OX40 engagement on Tregs decreases their immunosuppression in the tumor microenvironment and that OX40 antibody agonists are promising antitumor agents. Again, however, this is dependent on OX40 engagement, which reasonably appears to require FcR binding by the antibody. Nevertheless, when OX40 engagement does not result from contact with an OX40 antibody, the introduction of a cytotoxic agent to the Treg and subsequent killing of the Treg would similarly be expected to produce an antitumor effect in the same tumor microenvironment.
Therefore, for the reasons discussed above and including the breadth of antibodies due to the absence of receptor-binding Fc region required and breadth of conjugated drug, the limited teachings in the specification, the prior art teaching supporting a much narrower scope of enabled antibodies for the methods, and the complexity inherent in immunotherapy, it would require undue experimentation to practice the method commensurate in scope with the claims.
Applicant argues (second half of p. 9 through end of p. 11 of REMARKS) that Example 3.1 of the specification teaches there are two kinds of anti-OX40 antibodies having agonistic activity: i) those with agonistic activity independent of Fc receptor cross-linking, and ii) those requiring Fc receptor cross-linking for agonistic activity. Therefore, cross-linking is not a universal requirement for all OX40 antibodies. References Carrocosa et al. (J. immunother. Canc. 2020) and Zhang et al. (Biomolec. 2022), which were cited on the PTO-892 mailed 1/22/2026, merely describe OX40 antibody cross-linking as a preferred but not required mechanism for activity. Further, these references have the limitation of their antibodies binding in the OX40L-binding region, which region when bound by OX40L promotes a therapeutically desirable immune response (pointing to the “Introduction” of Zhang et al.). Zhang et al. explains that because their antibodies blocked binding of OX40 to OX40L, which was through different epitopes of OX40, Fc receptor-binding was also required to facilitate the downstream signal transduction due to the blocking of the endogenous OX40 receptor-ligand binding, which dampens endogenous activation of CD4+ and CD8+ T cells by APC cells (middle of p. 10 of REMARKS). In contrast to antibodies discussed by Zhang et al., “the claimed antibody does not block OX40 binding to its ligand” (emphasis by Applicant). Instead of binding OX40 region CRD2, “the claimed antibody binds to the CRD1 domain and therefore does not block OX40/OX40L interaction.” (emphasis by Applicant). The epitope to which the claimed antibody binds is shown in instant Fig. 13. Example 11 shows OX40L binding is maintained when the antibody is bound to OX40. Therefore, “it is clear that it is not necessary for the claimed antibody to comprise an IgG Fc domain to be able to crosslinked by Fc receptors,…” (emphasis by Applicant, last paragraph of p. 11 of REMARKS) A person of skill in the art would readily understand that antibody crosslinking is not required to compensate for blocking activation of OX40 by OX40L, since the antibody does not block the receptor-ligand interaction. The argument has been fully considered but is not persuasive. Section 3.1 of the specification and the introduction of Zhang et al. merely discuss that Fc receptor (FcR) binding by an OX40 antibody may be needed. Zhang et al. explains (p. 11, last paragraph), “When considering different types and abundance of Fc receptors on the cell surface, the isotypes of antibodies, the presence of nature ligands, etc., it becomes even more challenging in predicting the activity from the binding epitopes.” While the epitope reasonably plays a role in the need of FcR crosslinking, it is not clear from either the prior art or the instant application that an anti-OX40 antibody that does not block OX40L-induced OX40 activity will also not require Fc-dependent crosslinking for sufficient agonist activity in a therapeutic context. More to the point, the specification states (p. 66, line 1, of original specification), “The agonistic activity of HFB10-1E1hG1 is anti-human IgG cross-linking dependent.” Further, as stated in the rejection (previous Office action, second paragraph of p. 8), “Raue et al. (AACR Virt. Meet. E-poster #2285, 2020, cited in the IDS filed 2/13/23), identifies HFB301001 as being an IgG1 isotype antibody in Fig. 4.“ Regardless of whether or not the antibodies binds the OX40L binding domain, it requires IgG cross-linking for agonist activity. That the instant antibody does not block the endogenous OX40-OX40L activity is an especially desirable feature (see p. 66, lines 29-31, original specification). Further, the specification explains (p. 65, lines 19-24) that Fc receptor FcγR2b is more likely to be clustered around tumor cells, so “cross-linked antibody” agonists have a higher tumor tissue selectivity. “Therefore, "cross-linked antibody" agonists have higher tissue selectivity. Only in the tumor microenvironment can the antibody have a significant agonistic effect, while in the normal tissue parts of the body, the effect will remain at a low level. This can improve the safety window for treatment.” (see previous Office action paragraph, top of p. 9) This means that there is a need for antibody crosslinking in order to promote tumor-selective agonistic activity. It reasonably appears that for agonistic activity of the disclosed antibody is “IgG cross-linking dependent” as stated by the specification. It is not agreed the skilled artisan would expect the claimed anti-OX40 antibody to be “sufficiently robust as to be therapeutic” without an IgG Fc domain as argued by Applicant (p. 11 last paragraph) for the reasons discussed above.
Applicant argues (p. 12) the therapeutic use of the antibody-drug conjugate (ADC) in claim 25 is by “the mechanism of using antibody-drug conjugate to kill cells, such as using anti-OX40 antibody-drug conjugate to kill Tregs,” as opposed to using the ADC to engage OX40 to decrease Treg immunosuppression.(emphasis by Applicant) It is argued that the field of ADCs in which therapeutic ADCs are internalized with their surface receptors through endocytosis, relies on the ADC to exert its cytotoxicity in the cell to kill it. The Fc region of an antibody is not required for endocytosis. There are many examples of ADCs without Fcs, such as scFv antibodies. “The specification has clearly demonstrated that the claimed antibody binds to OX40, and the Examiner has acknowledged that "[i]f the drug is cytotoxic, then as long as the antibody binds OX40 one skilled in the art might expect cytotoxicity directed to OX40-expressing Treg cells".” The argument has been fully considered but is not persuasive. The issue is that claim 25 depends on the ADC of claim 8, which merely says the drug is “an additional therapeutic agent” not that it is a cytotoxic agent or an antitumor agent (emphasis added). A therapeutic agent could, for example, be an antibiotic or antihistamine, which would not reasonably be expected to kill the OX40-expressing tumor cell. These examples are consistent with the broadest reasonable interpretation of the additional therapeutic agent for claim 8. As a result, if the antibody itself does not have anti-tumor activity by IgG Fc-dependent cross-linking, the additional therapeutic agent, i.e., the “drug” of the antibody-drug conjugate, must be able to kill the tumor cell. As the claims are currently written, the drug does not and, therefore, the method of treating cancer in a subject with cancer is not enabled for its full scope.
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, 2, 4-8, 14, 17, 18 and 23-25 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 13, 15-20, 27, 29, 30, 32 and 35 of copending Application No. 18/572,710 (‘710, reference application) for the reasons set forth in the previous Office action with the exception of deletion of reference to a sdAb. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Both applications claim the same anti-OX40 antibody or antigen-binding fragment thereof comprising a VH comprising CDR1-3 of SEQ ID NO:1-3 and a VL comprising CDR1-3 of SEQ ID NO:9-11 (claim 1 of each). The VH and VL have the sequence of SEQ ID NO:4 and 12, respectively (instant claim 2 and claim 13 of ‘710), and heavy chain and light chain (HC and LC) constant regions respectively comprise SEQ ID NO:5 and 13 (instant claim 3 and claim 15 of ‘710). HC and LC signal sequences of SEQ ID NO:6 and 14, respectively, are claimed in instant claim 4 and claims 16-17 of ‘710. Both applications claim wherein the antibody is a monoclonal, an IgG, or fragment is a Fab, Fab’, F(ab’)2, Fv or scFv. (instant claims 5-7 and claims 1, 18 and 19 of ‘710). Both claim a pharmaceutical composition and kit comprising the antibody or antigen-binding fragment thereof (instant claims 14, 23 and 24 and claims 27 and 35 of ‘710). Instant claims 17-18 and claims 30 and 32 of ‘710 are drawn to a method of treating cancer with the antibody. An antibody-drug conjugate is claimed in instant claim 8 and claim 20 of ‘710. Instant claim 25 is drawn to a method of treating cancer by administering the antibody-drug conjugate, and this would have been obvious in view of the method of treatment with the antibody and the antibody-drug conjugate.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant requests (p. 13 of REMARKS) the rejection under provisional nonstatutory double patenting be held in abeyance until other rejections have been overcome and allowable subject matter has been indicated. The request has been fully considered, but the rejection cannot be held in abeyance and is maintained for the reasons of record.
It is noted there was an obvious typographical error in the rejection preamble listing the copending application number as “18572,719 (‘710, reference application).” It should have appeared as “18/572,710 (‘710 reference application).”
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
June 18, 2026
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