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/Restriction
Applicant’s election without traverse of Invention VIII, in the reply filed on 24JUL2025 is acknowledged.
Upon further consideration, the invention of group I (i.e., claim(s) 1, 43, and 140) as set forth in the restriction requirement mailed 24JUL2025 has been rejoined to group VIII (i.e., claims 36, 73, 75, 103, and 105). In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 2, 11, 30, 131-133, 138-139, 141, 148, and 152 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 24JUL2025.
Claim Status
Claims 2, 11, 30, 36, 43, 73, 75, 103, 105, 131, 133, 138-141, 148, and 152 remain amended.
Claims 3-10, 12-29, 31-35, 37-34, 44-72, 74, 76-102, 104, 106-130, 134-137, 142-147, 149-151, and 153-162 have been cancelled.
Claims 1-2, 11, 30, 36, 43, 73, 75, 103, 105, 131-133, 138-141, 148, and 152 are pending in the instant application.
Claims 1, 36, 43, 73, 75, 103, 105, and 140 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2020/046005, filed 12AUG2020, which claims the benefit of:
US Provisional Patent Application No. 62/885751, filed 12AUG2019;
US Provisional Patent Application No. 62/902318, filed 18SEP2019;
US Provisional Patent Application No. 62/911010, filed 04OCT2019; and
US Provisional Patent Application No. 63/056115, filed 24JUL2020. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 22NOV2022 and 24JUL2025 is/are acknowledged and the references cited therein have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 43, and 140 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, recites the phrase "optionally," which 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(h)(II). Claims 43 and 140 are also rejected since they depend from claim 1, but do not remedy this deficiency.
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.
Enablement
Claims 1, 43, and 140 are 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.
In the instance of claim 1, the nature of the invention is drawn to a 4-1BB x OX40 bispecific antibody comprising a polypeptide comprising a first and second scFv, a linker, which is optionally a hinge region and a immunoglobulin constant region is not fully enabled. This is because i) the breadth of scFv structures for each binding moiety (i.e., currently characterized by binding to a specific antigen without defining six nondegenerate CDRs for each scFv and the undue experimentation required for screening of structures); ii) the breadth of immunoglobulin constant region (i.e., the specification discloses that the constant region comprises immunoglobulin CH2 and CH3 domains of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, or IgD, wherein the constant region is mutated, ¶0056-0057); iii) the unclear nature of how the polypeptides do not dimerize (i.e., constant regions mutated to prevent Fc-mediated binding, CDC activity, or ADCC; however, there is no information regarding mutations for reducing dimerization, ¶0057 and in working examples an IgG hinge region is used which would play a role in polypeptide dimerization); and iv) the lack of working examples wherein the linkers are not an IgG hinge region between the end of the first scFv and the immunoglobulin constant region and an additional linker (i.e., SEQ ID NO: 118) between the end of the immunoglobulin constant region and the scFv (i.e., as evidenced by SEQ ID NOs: 78-100 and 144).
Furthermore, with regard to single-chain Fv binding structures, it should be pointed out that it is well established in the art that these fusion proteins are comprised of the variable heavy (VH) and variable light (VL) chains, which are joined together by a flexible peptide linker (i.e., affects folding, stability, and target affinity). Similar to antibody structures the VH and VL chains of an scFv each consist of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Ahmad, et al., Clin Dev Immunol, 2012, 980250, 1-15, see entire document, specifically Figure 1). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an scFv (Winkler, et al., J Immunol, 2000, 165, 4505-4515, see entire document, specifically see abstract and Herold, et al., Sci Rep, 2017, 7, 1-17, see p 8, ¶1). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves. Therefore, in the instance of a bispecific antibody, comprising a first scFv that binds 4-1BB and a second scFv that binds OX40, the art supports that six clearly defined CDRs for each scFv is required, and a single amino acid change in the CDR can significantly impact the binding of the scFv to its antigen. Therefore, the implementation of the invention would require undue experimentation for one of ordinary skill in the art to make and/or use the invention. Claims 43 and 140 are also rejected since they depend from claim 1, but do not remedy this deficiency. Although claim 43 is further limited by the VH/VL pairs for the 4-1BB binding moiety comprising amino acid sequences of SEQ ID NOs: 17/18, 19/20, 21/22, 23/24, 32/18, or 143/20, there is no further definition of the OX40 binding moiety or the immunoglobulin constant domain and therefore is not fully enabled as currently claimed.
Therefore, while the specification is enabled for a bispecific antibody comprising a homodimer of two identical polypeptides, each comprising six defined CDRs consisting of SEQ ID NOs: 5-10 and 11-16 for binding 4-1BB and OX40, respectively, an immunoglobulin hinge region linking the first binding domain to the defined immunoglobulin constant region and a second linker (i.e., SEQ ID NO: 118) linking the C-terminus of the constant region to a second binding domain; does not reasonably provide enablement for more.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 140 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2018/0118841 A1 (Ellmark, et. al, 03MAY2018, included in IDS), herein referred to as “’841.”
‘841 teaches bispecific polypeptides comprising a first and second target selected from OX40 and CD137 (i.e., 4-1BB), wherein the structures are selected from the (scFv-Fc-scFv)2 bispecific antibodies, such as ADAPTIRTM bispecific antibodies (i.e., (scFv-hinge-Fc-scFv)2) (see abstract, ¶0034-0046, and Fig 19). ‘841 further teaches a pharmaceutical composition comprising the bispecific antibody and a pharmaceutically acceptable excipient (¶0116).
Therefore, the prior art anticipates the invention as presently claimed.
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.
Provisional Non-Statutory Double Patenting
Claims 1 and 140 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 4-6, 8-10, 13-14, 16-19, 21, 26-27, 29, 31, 34-36, 38-40, 42-49, 53-54, 57-59, 61-62, 67-68, 72, 74-77, 80-82, 84-87, 89-91, 93-101, 106-117, 119, 124-126, 130-132, 137, 144, 147-157 of co-pending Application No. 17/802920; herein referred to as the “reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the composition of the multispecific protein of the reference application anticipates the bispecific antibody and the pharmaceutical composition thereof of the instant application. Specifically, both the multispecific and bispecific antibody of the reference and instant application, respectively comprise a polypeptide which comprises in order from amino- to carboxy-terminus i) a first binding domain, ii) a hinge region, iii) an immunoglobulin constant region, and iv) a second binding domain. The reference application is generic; whereas the binding domains of the instant application are specific to 4-1BB and OX40.
The co-pending claims of the reference application recite: A composition comprising a multispecific protein, a buffer, an excipient, and a surfactant, wherein (a) the multispecific protein is a dimer of two identical peptides, wherein each polypeptide comprises in order from amino- to carboxy-terminus i) a first binding domain, ii) a hinge region, iii) an immunoglobulin constant region, and iv) a second binding domain; and (b) the buffer comprises or consists of succinate or a pharmaceutically acceptable salt or acid thereof (i.e., claim 1). The composition of claim 1, wherein the immunoglobulin constant region comprises the immunoglobulin CH2 and CH3 domains of IgG1, etc. (i.e., claim 17); or wherein the first binding domain binding domain is a 4-1BB binding domain and the second binding domain is an OX40 binding domain or vice versa (i.e., claim 29). The composition of claim 29, wherein the 4-1BB binding domain is an scFv and the OX40 binding domain is an scFv (i.e., claim 31).
In this instance, because the multispecific protein of the composition of claim 1 of the reference application is generic to binding domains inclusive of antigen and structure (i.e., antibody, Fab, scFv, etc.), which are linked by a linker (i.e., hinge) and an immunoglobulin constant region and because the reference application composition includes the multispecific protein and pharmaceutically acceptable excipients, there is no clear difference in the scope between the products of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 36, 43, 73, 75, 103, 105, and 140 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6, 10, 16, 18-19, 21-25, 28-32, 48, and 55-56 of co-pending Application No. 18/546751; herein referred to as the “reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the bispecific antibody or antigen binding fragment that binds 4-1BB and OX40 of SEQ ID NO: 13 and the pharmaceutically acceptable excipients of the reference application anticipates the bispecific 4-1BB x OX40 and pharmaceutical compositions thereof of the instant application. Specifically, both bispecific antibodies comprise the same antigen binding domains and overall structures.
The co-pending claims of the reference application recite: A pharmaceutical composition comprising: (a) a bispecific antibody or antigen-binding fragment thereof that specifically binds 4-1BB and OX40; (b) about 5 mM to about 15 mM of a stability promoting buffer; (c) about 25 mM to about 50 mM of a stabilizing amino acid, etc. (i.e., claim 1). The pharmaceutical composition of claim 1 wherein the 4-1BB x OX40 bispecific antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 13 (i.e., claim 31).
In this instance, because the 4-1BB x OX40 bispecific antibody or antigen-binding fragment comprising SEQ ID NO: 13 of the reference application contains the HCDRs1-3/LCDRs1-3 combinations, VH/VL pairs, and scFvs of the 4-1BB and OX40 antigen binding domains, and the full binding construct of the instant application comprising scFv-hinge-immunoglobulin constant region-linker-scFv of the instant application (see OA.APPENDIX), and because a pharmaceutically acceptable excipient is used, there is no clear difference in the scope between the products of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641