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 and species of claim 1 which is (b) and (q) in the reply filed on 07/06/2026 is acknowledged.
Information Disclosure Statement
The information disclosure statement filed 02/27/2024 lists reference #A6, CN 110627906 A, which fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information and is not in the English language. It has been lined-through and not been considered.
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 1-4, 7-8, 11 and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 13-14 of copending Application No. 19/070,406 (‘406) in view of US 2021/0253724 A1.
Instant claim 1(d), (b) and (q), respectively, are drawn to a single domain antibody (sdAb) or polypeptide comprising said single domain antibody, wherein the single domain antibody specifically binds human 4-1BB and comprises respectively. CDR1-3 of SEQ ID NO:18, 25 and 32, SEQ ID NO:18, 59 and 38, or SEQ ID NO: 23, 30 and 38. Claims 2-3 recite the antibody sequence comprises one of SEQ ID NO:40-48 and 60-62. Claims 4 is drawn only to the species of 1(b). Claim 5 limits the amino acid to any one of SEQ ID NO:49-57, while claim 6 limits the amino acid sequence to any one of SEQ ID NO:1, 3-16. Claim 7 is drawn to the polypeptide of claim 1 which is a chimeric antigen receptor (CAR) or a bispecific antibody, with claim 8 drawn only to a bispecific antibody. Claim 11 is drawn to a composition comprising the antibody or polypeptide of claim 1 and a pharmaceutically acceptable carrier. Claim 12 are drawn to a method of treating cancer in a patient comprising administering to the patient an effective amount of the antibody or polypeptide of claim 1.
‘406 claims a bispecific antibody comprising a CEACAM5 binding region and a single domain anti-4-1BB sdAb (VHH) comprising the CDR1-3 of SEQ ID NO:21, 24, 23 (claims 1 and 2, corresponding to instant claim 1(d), SEQ ID NO:18, 25 and 32), SEQ ID NO:21, 25, 26 (claim 1, corresponding to instant claim 1(b), SEQ ID NO:18, 59, 38) or SEQ ID NO:27, 28, 26 (claim 1, corresponding to instant claim 1(q), SEQ ID NO:23, 30, 38) and an anti-CEACAM5 antibody or antigen-binding fragment thereof (claim 1). Claim 3 specifies the VHH is selected from the group consisting of: SEQ ID NO:2-10 or 37-38, which corresponds to instant SEQ ID NO:40-48 and 60-61. Claim 4 is drawn to the antibody comprising the sequence of SEQ ID NO:37, which comprises instant CDR1-3 SEQ ID NO:18, 25, 32 and is the same as instant SEQ ID NO:60. Claims 5-6 specify the bispecific antibody comprises an IgG Fc and the Fc fragment is N-terminal to the two sdAbs. Claim 13 is drawn to a composition comprising the bispecific antibody of claim 1 and a pharmaceutically acceptable carrier. Claim 14 is drawn to a method of treating cancer by administering the bispecific antibody of claim 1.
US 2021/0253724 teaches a bispecific antibody with bivalent binding to 4-1BB, also known as CD137, and monovalent binding to CEA “Carcinoembryonic antigen (CEA)’, also known as Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) ([0004], [0137] and Tables 8 and 10, and Figs. 1A-1D). In Fig. 1C, the IgG Fc is N-terminal to two anti-4-1BB sdAb. 4-1BB signaling stimulates IFNy secretion, proliferation of NK and T cells, and promotes dendritic cell (DC) activation ([0005]). Also, agonistic 4-1BB antibodies have shown potent antitumor activity in murine tumor models ([0005]). It is taught anti-4-1BB x anti-CEACAM5 antigen binding domain-containing constructs, e.g. anti-4-1BB (20H4.9)xCEA (MFE23 or A5B7 or A5SH1EL1D) hulgG1 P329GLALA 2+1 H2H, bind efficiently to human CEACAM5-expressing cells (FIGS. 12B, 12C and 12D) ([0106)). Antibody 20H4.9 has been shown to be effective in treating melanoma, ovarian and renal cell carcinoma in human patients (0007]). It is reported that tumors of epithelial origin and their metastases contain CEA. Further, while CEA is expressed by normal cells, its expression increases in cancerous cells with expression over the entire surface ([(0137] middle). High expression was detected in 95% of colorectal carcinomas, 90% of pancreatic cancers, 80% of gastric cancers, 60% of non-small cell lung cancers, and 40% of breast cancers (end of [0137]).
The species of 4-1BB sdAb that is part of the bispecific antibody claimed in ‘406 anticipates the corresponding sdAb of the instant application, as well as the instantly claimed bispecific antibody binding 4-1BB and an antigen different than 4-1BB (e.g., CEACAM5). In view of the claims of the patent and teaching of a bispecific 4-1BB- x CEACAM5-binding antibody of US 2021/0253724 and method of treating a cancer therewith, a method of treating cancer with a bispecific antibody comprising the instant 4-1BB antibody would have been obvious. Further, a CAR would have been obvious, particularly a bispecific 4-1BB- x CEACAM5-binding CAR for the treatment of cancer.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 7-8, 11 and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 12-13 of U.S. Patent No. 12,247,081 B2 (‘081) in view of US 2021/0253724 A1.
Instant claim 1(d), (b) and (q), respectively, are drawn to a single domain antibody (sdAb) or polypeptide comprising said single domain antibody, wherein the single domain antibody specifically binds human 4-1BB and comprises respectively. CDR1-3 of SEQ ID NO:18,25 and 32, SEQ ID NO:18, 59 and 38, or SEQ ID NO: 23, 30 and 38. Claims 2-3 recite the antibody sequence comprises one of SEQ ID NO:40-48 and 60-62. Claims 4 is drawn only to the species of 1(b). Claim 5 limits the amino acid to any one of SEQ ID NO:49-57, while claim 6 limits the amino acid sequence to any one of SEQ ID NO:1, 3-16. Claim 7 is drawn to the polypeptide of claim 1 which is a chimeric antigen receptor (CAR) or a bispecific antibody, with claim 8 drawn only to a bispecific antibody. Claim 11 is drawn to a composition comprising the antibody or polypeptide of claim 1 and a pharmaceutically acceptable carrier. Claim 12 is drawn to a method of treating cancer in a patient comprising administering to the patient an effective amount of the antibody or polypeptide of claim 1.
US Patent ‘081 claims a bispecific antibody comprising a CEACAM5 binding region and a single domain anti-4-1BB sdAb (VHH) comprising the CDR1-3 of SEQ ID NO:21, 24, 23 (claims 1 and 2, corresponding to instant claim 1(d), SEQ ID NO:18, 25 and 32), SEQ ID NO:21, 25, 26 (claim 1, corresponding to instant claim 1(b), SEQ ID NO:18, 59, 38) or SEQ ID NO:27, 28, 26 (claim 1, corresponding to instant claim 1(q), SEQ ID NO:23, 30, 38) and an anti-CEACAM5 antibody or antigen-binding fragment thereof (claim 1). Claim 3 specifies the VHH is selected from the group consisting of: SEQ ID NO:2-10, which corresponds to instant SEQ ID NO:40-48. Claim 4 is drawn to the antibody comprising the sequence of SEQ ID NO:37, which comprises instant CDR1-3 SEQ ID NO:18, 25, 32 and to SEQ ID NO:60. Claim 12 is drawn to a composition comprising the bispecific antibody of claim 1 and a pharmaceutically acceptable carrier. Claim 13 is drawn to a method of treating cancer by administering the bispecific antibody of claim 1.
US 2021/0253724 teaches a bispecific antibody with bivalent binding to 4-1BB, also known as CD137, and monovalent binding to CEA “Carcinoembryonic antigen (CEA)’, also known as Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) ([0004], [0137] and Tables 8 and 10, and Figs. 1A-1D). 4-1BB signaling stimulates IFNy secretion, proliferation of NK and T cells, and promotes dendritic cell (DC) activation ([0005]). Also, agonistic 4-1BB antibodies have shown potent antitumor activity in murine tumor models ([0005]). It is taught anti-4-1BB x anti-CEACAM5 antigen binding domain-containing constructs, e.g. anti-4-1BB (20H4.9)xCEA (MFE23 or A5B7 or A5SH1EL1D) hulgG1 P329GLALA 2+1 H2H, bind efficiently to human CEACAM5-expressing cells (FIGS. 12B, 12C and 12D) ([0106)). Antibody 20H4.9 has been shown to be effective in treating melanoma, ovarian and renal cell carcinoma in human patients (0007]). It is reported that tumors of epithelial origin and their metastases contain CEA. Further, while CEA is expressed by normal cells, its expression increases in cancerous cells with expression over the entire surface ([(0137] middle). High expression was detected in 95% of colorectal carcinomas, 90% of pancreatic cancers, 80% of gastric cancers, 60% of non-small cell lung cancers, and 40% of breast cancers (end of [0137]).
The species of 4-1BB single domain antibody that is part of the bispecific antibody claimed in ‘081 anticipates the corresponding sdAb of the instant application, as well as the claimed bispecific antibody binding 4-1BB and an antigen different than 4-1BB (e.g., CEACAM5). In view of the claims of the patent and teaching of a bispecific 4-1BB- x CEACAM5-binding antibody of US 2021/0253724 and method of treating a cancer therewith, a method of treating cancer with a bispecific antibody comprising the instant 4-1BB antibody would have been obvious. Further, a CAR would have been obvious, particularly a bispecific 4-1BB- x CEACAM5-binding CAR for the treatment of cancer.
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 12 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 12 is drawn to a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of the antibody or polypeptide of claim 1. There are two issues of enablement for the claim. The first is what types of treatments of cancer are enabled. The second deals with enablement of using the single domain antibody (sdAb) or a polypeptide comprising it in the method.
The terms “treat” or “treatment” are defined in the specification ([0027]) as referring to both therapeutic treatment and prophylactic or preventive measures. “Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.” Also, the specification states [0029], “[P]hrases such as "to a patient in need of treatment" or "a subject in need of treatment" includes subjects, such as mammalian subjects, that would benefit from administration of an antibody or composition of the present disclosure used, e.g., for detection, for a diagnostic procedure and/or for treatment.” Therefore, it reasonably appears the claim includes prevention or prophylaxis for a patient at risk of cancer, as well as therapeutic treatment for a cancer already present in the patient. However, in order to be able to prevent or delay 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 claim, nor how to maintain treatment for the necessary duration to prevent the eventual onset of the cancer.
Additionally, therapeutic treatment requires more than mere binding of the antibody to its antigen. It requires an effect that can in this case lead to costimulation of an active immune cell, thereby enhancing immune cell proliferation, survival and/or secretion of cytokines and cytolytic activity of CD8+ T cells, thereby enhancing immune response in order to eliminate tumors (]0003] of the specification). While the specification shows that the antibody of claim 1 can bind 4-1BB (e.g., Figs. 1A-1B), it cannot induce 4-1BB-mediated NFκB activity (measured by 4-1BB NFκB-reporter activity in Jurkat cells; [0091]) in the absence of Fc crosslinking (Example 4 and Figs. 3A-3B). Nevertheless, the method of claim 12 requires administration of only the single domain antibody or a polypeptide comprising the antibody. There is no limitation drawn to crosslinking, for example. As a result, one skilled in the art would not reasonably expect to be able to successfully practice the claimed method of treatment (assuming the treatment is only therapeutic for the reasons set forth in the immediately preceding paragraph). That is, one would not have reasonably expected the single domain antibody to bind and enhance immune cell activity on its own or in the context of being comprised by a random polypeptide. This is in agreement with post-filing reference Wang et al. (Acta. Pharm. Sinica B, 14(7):2854-2868, 2024, cited in the IDS filed 02/25/2026, Fig. 2 and p. 2857, last full paragraph), which teaches different strategies used to modify sdAbs for anti-tumor therapeutics: “sdAb-drug conjugates by fusion sdAb with toxins, peptides and chemicals; multispecific sdAbs having distinct antigen binding sites; sdAb-based delivery systems using nanocarriers, and sdAb-based cell therapy such as chimeric antigen receptor (CAR)-T cell therapy.” (See also Table 1 for sdAb-based drugs that have been approved or are in middle- or late-stage clinical trials for treatment of solid tumors.) Neither the instant specification nor the prior or post-filing art provide a reasonable expectation of successful treatment of cancer in a subject with the disclosed sdAb per se. The specification does not provide guidance or direction on how to accomplish treatment with the sdAb or polypeptide comprising it commensurate in scope with the claim, nor are any in vivo working examples provided. Cancer treatment with antibodies is complex and often empirical, with outcomes dependent on particular dosages, regimens, drug combinations, cancer-associated gene expression, etc. For the reasons discussed, the method of claim 12 is not enabled.
Allowable Subject Matter
Claims 5 and 6 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Claim 5 limits the amino acid sequence of the antibody or polypeptide of claim 4 to comprising one of SEQ ID NO:49-57 (Table 5). Claim 6 is limited to the antibody or polypeptide of claim 1 to comprising one of SEQ ID NO:1, 3-16. These sequences are free of the prior art and neither the copending application nor patent relied upon above in the rejection under non-statutory double patenting claim an antibody or polypeptide comprising one of those sequences, which are specific humanized variable heavy chain sequences of VV02-1SP(1)-73 or positive clones of unique antibodies (Table 1, each comprising one of claim 1(a)-(q)).
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
The prior art discloses a number of 4-1BB single domain antibodies; however, the sequence of the prior art antibodies are different than those disclosed and do not anticipate or render obvious those of the instant claims. Below are examples of prior art disclosures of 4-1BB single domain antibodies.
US Patent 12,692,318 issued from a continuation application of the instant application and claims a distinct 4-1BB single domain antibody than the instant claims.
US 2020/0362051 A1 (cited in the IDS filed 2/27/2024) teaches single domain anti-CD137 antibodies (see claims).
US 10,501,551 B2 (cited in the IDS filed 9/16/2025) teaches single domain 4-1BB-binding antibodies (e.g., Fig. 2A-B and Examples 1-2).
US Patent 12,077,595 B2 is drawn to single domain CD137-binding antibodies (see examples and claims).
WO 2022/242679 A1 (cited in the IDS filed 09/03/2024) teaches VHH CD137 antibodies (see examples and claims).
WO 2017/123650 A2 (cited in the IDS filed 09/16/2025) teaches 4-1BB sdAbs. (see examples and claims).
Conclusion
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.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice .
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
September 11, 2026
Prosecution Insights