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 without traverse of Group I in the reply filed on 10/03/2025 is acknowledged. Claims 9-13 and 22 are withdrawn from examination as directed to a non-elected invention.
Alternative Names
OX40 is also commonly known as CD134, TNFRSF4 (see p. 1, line 28 of the specification) and ACT35.
Information Disclosure Statement
In the IDS filed 10/07/2025 does not comply with 37 CDR 1.98(a)(2) and (3), which require a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed, and (i) A concise explanation of the relevance, as it is presently understood by the individual designated in § 1.56(c) most knowledgeable about the content of the information, of each patent, publication, or other information listed that is not in the English language. The concise explanation may be either separate from applicant’s specification or incorporated therein; (ii) A copy of the translation if a written English-language translation of a non-English-language document, or portion thereof, is within the possession, custody, or control of, or is readily available to any individual designated in § 1.56(c). See MPEP § 609.05(a).
Applicant did not provide with the IDS a copy of CN110003338 and concise explanation or an English-language translation (n.b., it appears CN1112223338 was submitted instead) or concise explanation or translation of CN 113045655. “Where the information listed is not in the English language, but was cited in a search report or other action by a foreign patent office in a counterpart foreign application, the requirement for a concise explanation of relevance can be satisfied by submitting an English-language version of the search report or action which indicates the degree of relevance found by the foreign office. This may be an explanation of which portion of the reference is particularly relevant, to which claims it applies, or merely an "X", "Y", or "A" indication on a search report. The requirement for a concise explanation of non-English language information would not be satisfied by a statement that a reference was cited in the prosecution of a United States application which is not relied on under 35 U.S.C. 120.” MPEP 609.04(a)(III)
Claim Interpretation
The specification uses the words “identity” and “homology” interchangeably in conjunction with “percentage” (%) and as defined on p. 14, lines 17-27.
Specification
The disclosure is objected to because of the following informalities: On p. 78, line 26 (first paragraph of Ex. 10), it is stated that Table 1 shows the CDR, VH.VL and HC/LC of HFB3010011; however, Table 1 is temperature analysis data.
Appropriate correction is required.
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: ANTI-OX40 ANTIBODY AND
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.
Claims 2-4, 8, 18 and 24 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 2-4 recite the broad recitation at least 80% homology, and the claims also recites 100%, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. 100% homology includes all lower percentages of homology. For example, a sequence which shares 100% homology with another, also shares at least 80% homology with it.
Regarding claims 3, 8, 18 and 24, the phrase “preferably” renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Also, for claim 24, if the kit does not comprise more than the antibody or antigen-binding fragment thereof according to claim 1, then there is nothing to distinguish it from the product of claim 1, which would result effectively in a gap between elements, making the claim indefinite on that basis.
Claim 8 is indefinite because it is drawn to an antibody-drug conjugate, but it is unclear if the drug is the recited additional therapeutic agent. If the additional therapeutic agent is not conjugated to the antibody, it is unclear what the physical relationship of the additional agent is to the antibody. In a preferred embodiment in the claim the agent is linked to the anti-OX40 antibody or antigen-biding fragment thereof via a linker, but such linkage is not required and it is not stated that the agent is the “drug” or is conjugated.
Regarding claim 18, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). An unambiguous alternative is “including”, if appropriate, e.g., ‘squamous cell carcinoma, including epithelial squamous cell carcinoma,….’
Claim 18 is also indefinite because of the parenthetical phrases beginning with “comprising” followed by an inclusive list of cancers, i.e., not expressed in the alternative but separated by “and”. There are two reasons: I) It is unclear if, for example, the lung cancer (lines 2-3) comprises/has all the listed types of lung cancers, i.e., both small and non-small cell lung cancer, adenocarcinoma of the lung and squamous cell carcinoma of the lung, or if was intended that the lung cancer is one of those listed. If the latter is the case, then using “or” instead of “and” would help clarify. II) It is unclear if the types of cancers in the parentheses are limiting, that is, for example, is the lung cancer required to comprise one of the four listed subtypes or are those merely exemplary. If they are exemplary, then deleting the parentheses and using “including” instead of “comprising” would express this. If they are limiting, then using phrasing such as ‘wherein the lung cancer is ….’ would express that.
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.
Claim 7 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 7 is drawn to the anti-OX40 antibody or antigen-binding fragment thereof according to claim 1, wherein the antigen-binding fragment is a Fab, Fab’, F(ab’)2, Fv, scFv (single-chain Fv) or sdAb. Claim 1 requires the antibody or antigen-binding fragment thereof to comprise a heavy chain variable region (VH) and a light chain variable region (VL). sdAb stands for “single domain antibody” and has no VL. Therefore, the antigen-binding fragment cannot be a sdAb if it has a VL.
Further, the specification does not disclose any particular single-domain antibodies which bind OX40. One skilled in the art could envision a Fab, Fab’, F(ab)2, F(ab’)2, Fv or scFv given the knowledge of the full VH and VL of an antibody that bound OX40. However, single-domain antibody structures are distinct, with binding relying on a single variable set of CDRs, usually derived by immunization of camels (Yan et al., J. Transl. Med. 12:343, 2014). Yan et al. used a large library of 1.65 x 109 CFU/mL based on CDR-H3 domains and was able to isolate only 2 single antigen-binding single-domain antibodies (p. 7/12, col. 2, second paragraph, and p. 9/12, col. 2, last paragraph). Previously using an immune-based library they isolated only three antigen-binding antibodies. This supports the lack of expectation of a common structure of single-domain antibodies based on a CDR-H3 sequence or full variable domain to allow the skilled artisan to readily envision a representative number of species of the genus of OX40-binding sdAb encompassed by the claim.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). With the exception of an antibody fragment requiring the CDR1-3 of each of the VH and VL, the skilled artisan cannot envision or recognize the detailed chemical structure of the encompassed antigen-binding fragments, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Claims 17, 18 and 25 are 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 or reducing the severity or shortening the length of a cancer in a subject in need thereof 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 or wherein treatment is prophylactic or preventative. 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.
The claims are drawn to methods of treating cancer in a subject in need thereof by administering the antibody or antigen-binding fragment thereof of claim 1 (claims 17-18) or the antibody-conjugate of claim 8 (claim 25). There are two issues of enablement with the claims. One deals with enablement of treatment. The other with the agent being used for the treatment.
As defined in the specification (p. 40, lines 30-33), “The term “treatment” includes prophylaxis and/or therapeutic treatment. Treatment is considered prophylactic of preventative if administered prior to the clinical manifestation of the disease, disorder or condition. Therapeutic treatment includes, for example, reducing or reducing the severity or shortening the length of a disease,..” The specification provides no working examples of using the antibody, antigen-binding fragment thereof, or an antigen-drug conjugate in a prophylactic/preventative context. Nor is direction or guidance provided to allow prediction of when administration would need to begin in order for prophylaxis or prevention to be successful. In order to be able to prevent a disease or disorder such as cancer, one must first be able to anticipate its onset and second be able to maintain administration throughout the duration of susceptibility so it does not occur. The term “preventing” generally carries the meaning of keeping something from happening. There is no guidance for or working example of anticipating the cancers encompassed by the instant claims, nor how to maintain treatment for the necessary duration to prevent the eventual onset of the disease or disorder. Note the claims are written such that treatment is of cancer, comprising administration to a subject in need thereof, which includes prevention and prophylaxis because the subject does not need to have cancer when treated. This is different from treating cancer in a subject, i.e., a subject who has cancer. The use of the term a “therapeutically effective amount” does not resolve this enablement issue because the term simply means an amount sufficient to achieve the intended purpose (p. 40, lines 24-26).
Additionally, 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. 64, 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 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-filingreferences 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 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 26 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 inclusion of prophylaxis or prevention for treatment in the absence of working examples and direction or guidance in the specification or support in the prior art therefor, 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.
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 1-8, 14, 17, 18 and 23-25 are 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. 18572,719 (‘710, reference application). 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, scFv or sdAb. (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.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
Both the instant specification and Raue et al. (ACCR Virtual Annual Meeting, E-poster #2285, June 22-24, 2020) disclose anti-OX40 agonist antibody HFB301001. The poster shares inventors and applicant with the instant application. No sequence of this antibody is disclosed and there is insufficient disclosure of overlapping functional characteristics of HFB301001 with instant HFB10-1E1 to determine if they are the same or share the same VH and VL CDRs. While an epitope on OX40 to which HFB301001 binds is disclosed (Example 10), no epitope of HFB10-1E is.
US Patent 9,644,032 B2 teaches antibodies binding OX40, including as part of an antibody-drug conjugate (col. 83, lines 62-64). The sequence of the CDRs of the disclosed antibodies are different from the claimed antibody. The antibodies of the patent do not anticipate or render obvious the instant claims.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
December 18, 2025