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 .
Status of Application, Amendments and/or Claims
The amendment of 30 October 2025 has been entered in full. Claims 1, 7, 9, 10, and 12 are amended. Claims 2 and 4-6 are cancelled. Claims 17-21 are added.
Claims 13, 15, and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09 June 2025.
Claims 1, 3, 7-12, 14, and 17-21 are under consideration.
Drawings
The replacement drawings were received on 30 October 2025. These drawings are acceptable.
Withdrawn Objections and/or Rejections
1. The objections to the drawings as set forth at pages 3-4 of the previous Office Action of 31 July 2025 are withdrawn in view of the submission of replacement drawings (30 October 2025).
2. The Sequence Listing Requirement deficiencies set forth at pages 5-10 of the previous Office Action of 31 July 2025 are withdrawn in view of the amended specification and Applicant’s statements at pages 8-9, under section B (30 October 2025).
3. The objections to claims 1, 10, and 11 as set forth at page 10 of the previous Office Action of 31 July 2025 are withdrawn in view of the amended claims (30 October 2025).
4. The rejections of claims 1-12 and 14 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph as set forth at pages 10-15 of the previous Office Action of 31 July 2025 are withdrawn in view of the amended and cancelled claims (30 October 2025).
5. The rejection of claims 1-12 and 14 under 35 U.S.C. 102(a)(1) as being anticipated by Foster et al. (WO 2018/226750) as set forth at pages 15-29 of the previous Office Action of 31 July 2025 is withdrawn in view of the amended and cancelled claims and Applicant’s persuasive arguments at page 11 of the Response of 30 October 2025. Specifically, Foster et al. discloses polypeptides comprising at least three TNF homology domains that are covalently linked by a linker peptide, e.g. ALVRSSSRTPSDK in SEQ ID NO: 34 and 35, which is longer than 10 amino acids and has a different sequence compared to Xa of the instant claimed polypeptides.
6. The rejection of claims 1-12 and 14 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent 12,065,472 as set forth at pages 25-28 of the previous Office Action of 31 July 2025 is withdrawn in view of the amended and cancelled claims (30 October 2025). Specifically, the TNFR binding protein complex of the ‘472 patent comprising 12 or more protein ligands that comprise a TNF homology domain of SEQ ID NO: 43 or 80 encompassed by the claims of the ‘472 patent (see for instance, claims 2 and 11) has a different sequence compared to the instant claimed polypeptides. For example, if the ‘472 patent polypeptide complex comprises a TNF homology domain of SEQ ID NO: 43 or 80 and the linker L1 is absent, the resulting sequence of the C-terminus of one homology domain and N-terminus of another homology domain would be: …VYFGIIAL//SSRTPSDKPVAHV (wherein the // denotes the end of one domain and the start of another). This sequence comprises an extra serine (SSRTPSDK) and thus, is different from the Xa of the instant claimed polypeptides (see claim 1, XN selection; claim 7(i)).
Claim Objections
7. Claims 1, 7, 17, 18, and 21 are objected to because of the following informalities:
7a. In claim 1, line 17, after the phrase “G-G-G”, the word “and” or “or” is missing and should be inserted.
7b. In claim 1, line 20, after the phrase “(SEQ ID NO: 8),”, the word “and” or “or” is missing and should be inserted.
7c. In claim 1, line 22, after the phrase “TNF alpha”, the word “with” should be replaced with “of”.
7d. In claim 7, subpart (iii), after the phrase “(SEQ ID NO: 8),”, the word “and” is missing and should be inserted.
7e. In claim 17, line 3, after the phrase “15 amino acids;”, the word “or” is missing and should be inserted.
7f. In claim 18, line 1, the “(b)” should be deleted.
7g. In claim 21, line 3, after the phrase “IgG2m4,”, the word “and” or “or” is missing and should be inserted.
Appropriate correction is required.
Maintained 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.
8. Claims 1, 3, 7-10, 14, 17, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,173,046. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a polypeptide comprising three peptide TNF homology domains of TNF-ligand family members that specifically bind to TNF receptor 2 (TNFR2). The basis for this rejection is set forth for claims 1-10 and 14 at pages 21-23 of the previous Office Action of 31 July 2025.
Claim 1 of the instant application is directed to a polypeptide comprising a binding domain consisting of three peptide TNF homology domains of TNF-ligand family member proteins (THD) that specifically bind to the extracellular part of TNFR2, wherein the C-terminus of the first and second THD, respectively, which is in each case defined by the C-terminal sequence V-Y-F-G-I-I (SEQ ID NO: 3), is linked to the N-terminus of the second and third THD, respectively, which is in each case defined by the N-terminal sequence P-V-A-H-V (SEQ ID NO: 4) through a peptide Xa, which is in each case independently selected and has a length of 9 to 10 amino acids, wherein the peptide Xa consists of Xc-XL-XN wherein
Xc is A-L;
XL is absent or is selected from the group consisting of G, G-G, G-G-G-G, G-G-G-G (SEQ ID NO: 16);
XN is absent or selected from the group consisting of, P-S-D-K (SEQ ID NO: 6), T-P-S-D-K (SEQ ID NO: 7), R-T-P-S-D-K (SEQ ID NO: 8), S-R-T-P-S-D-K (SEQ ID NO: 9), and wherein the THD comprises a contiguous amino acid sequence consisting of amino acids 88 to 231 of full length human TNF alpha with SEQ ID NO: 5, but comprising the mutations D143N and A145R of the ectodomain of human TNF alpha corresponding to D219N and A221R, respectively, relative to SEQ ID NO: 5.
Meanwhile, claim 1 of the ‘046 patent recites a polypeptide comprising three peptide TNF homology domains of TNF-ligand family member proteins (THD) that specifically bind to TNFR2, wherein the C-terminus of the first and second THD, respectively, is directly linked to the N-terminus of the second and third THD, respectively, and wherein each of the THDs consist of amino acids 81 to 233 of SEQ ID NO: 5, but with mutations D219N and A221R relative to SEQ ID NO: 5. The claims of the ‘046 patent are species claims that anticipate the genus claims of the instant application.
It is noted that the amino acid sequence of SEQ ID NO: 5 of the ‘046 patent claims is 100% identical to the amino acid sequence of SEQ ID NO: 5 of the instant application. Furthermore, N-terminal amino acids 88-92 of SEQ ID NO: 5 of the ‘046 patent are “PVAHV” while the C-terminal amino acids of SEQ ID NO: 5 of the ‘046 patent are “VYFGII”, meeting the limitations of instant claims 1 and 3. There is an additional “AL” at the C-terminus of SEQ ID NO: 5 of the ‘046 patent, meeting the limitations of instant claim 1.
It is noted that N-terminal amino acids 81-92 of SEQ ID NO: 5 of the ‘046 patent are: SRTPSDKPVAHV. Meanwhile, the C-terminal amino acids 226-233 of SEQ ID NO: 5 of the ‘046 patent are: VYFGIIAL. The following is a visualization:
N-term C-term N-term C-term N-term C-term
SRTPSDKPVAHV… VYFGIIAL
SRTPSDKPVAHV… VYFGIIAL
SRTPSDKPVAHV… VYFGIIAL
Therefore, a polypeptide comprising three TNF domains directly linked to one another as recited in claim 1 of the ‘046 patent anticipates the polypeptide of instant claims 1 and 7, wherein Xc is A-L, XL is absent, and XN is S-R-T-P-S-D-K (SEQ ID NO: 9).
Claims 9, 10, and 18 of the instant application and claims 2 and 3 of the ‘046 patent recite a polypeptide multimer comprising two polypeptides of the polypeptide that are linked to a dimerization domain.
Claim 14 of the instant application and claims 4-5 of the ‘046 patent recite a pharmaceutical composition comprising the polypeptide.
9. Claims 11 and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,173,046 as applied to claims 1, 3, 7-10, 14, 17, and 18 above, in view of Sambrook et al. (Molecular Cloning A Laboratory Manual, 2nd edition, Cold Spring Harbor, N.Y., 1989, pages 2.43-2.84), Bachman, J. (Meth Enzymol 530: 67-74, 2013), Jaye et al. (Nucl Acids Res 11(8): 2325-2355, 1983), Kloti, A. (U.S. Patent 6,399,857), Lewin, B. (Genes IV, Oxford: Oxford University Press, 1990; pages 118-120), and Murray, E.J. (“Cloning Genes in Mammalian Cell-lines” in Molecular Biology and Biotechnology. Great Britain: The Royal Society of Chemistry, 2000, pages 177-201). The basis for this rejection is set forth at pages 23-25 of the previous Office Action of 31 July 2025 and is reiterated below for convenience.
The claim limitations of the ‘046 patent are set forth directly above.
The claims of the ‘046 patent do not recite a nucleic acid encoding the claimed polypeptide that comprises three peptide THD that specifically binds to TNFR2 (claim 11) or a vector comprising the nucleic acid (claim 12).
Although the claims of the ‘046 patent are directed to a fusion polypeptide (and instant claim 11 is directed to nucleic acids encoding such), the nucleic acid sequences that encode the patented fusion polypeptide amino acid sequence can be determined and isolated by conventional methodologies known to one of skill in the art in view of the methods taught by Sambrook et al., Bachman, and Jaye et al. One skilled in the art can also use commercially available computer software to translate the polypeptide sequences of the '046 patent to nucleic acid sequences (see for example, U.S. Patent 6,399,857; column 6, lines 50-57). There are sets of three nucleotides that make up a codon, many amino acids are specified by more than one codon (degeneracy of the code), and 61 of the 64 possible combinations of three bases are used to code for specific amino acids (the other three code for stop signals) (see Lewin, B. Genes IV, Oxford: Oxford University Press, 1990; pages 118-120, Figure 7.7).
Additionally, Murray teaches that the use of vectors allows considerable flexibility in regulating expression of cloned genes (page 189, 2nd paragraph). Murray discloses that vectors can be classified into either viral- or plasmid-based, and each class may be sub-divided into general-purpose cloning vehicles or expression vectors (page 189, 2nd paragraph). Murray teaches plasmids, viral vectors, and retroviral vectors (pages 189-193).
Thus, it would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the fusion polypeptide of the ‘046 patent claims by isolating the nucleic acids encoding such and expressing/producing the polypeptide using recombinant expression vectors, as taught by Sambrook, Bachman, Jaye et al., Kloti et al., Lewin, and Murray et al. The person of ordinary skill in the art would have been motivated to make those modifications because the fusion polypeptide of the ‘046 patent is a selective TNFR2 agonist that can be administered to treat hyperproliferative disorders, inflammatory disorders, neurodegenerative disorders, metabolic disorders, and cancer (see ‘406 claims). The person of ordinary skill in the art reasonably would have expected success because the generation and isolation of nucleic acids via reverse transcription/translation, as taught by Sambrook, Bachman, and Jaye et al., was already being performed at the time the invention was made. Additionally, the person of ordinary skill in the art reasonably would have expected success because utilization of different vectors and host cells for polypeptide expression was routine at the time the invention was made. There are a limited number of methods to do such and thus, the person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely not the product of innovation but of ordinary skill and common sense (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
(i) At page 11 of the Response of 30 October 2025, Applicant indicates consideration of filing a terminal disclaimer once the claims are found otherwise allowable.
The rejections are maintained and held in abeyance until all other issues are resolved. However, Applicant is encouraged to submit a terminal disclaimer at Applicant's earliest convenience.
New Double Patenting
10. Claims 19 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,173,046 as applied to claims 1, 3, 7-10, 14, 17, and 18 above, in view of Sahin et al. (WO 2016/113395; published 21 July 2016; cited on the IDS of 19 December 2023).
The claim limitations of the ‘046 patent are set forth directly above.
Although claims 2 and 3 of the ‘046 patent recites that the polypeptide multimer comprises two polypeptides linked to a dimerization domain, the claims of ‘046 do not recite a specific dimerization domain. The claims of the ‘046 patent do not recite that the polypeptide multimer is a linked to trimerization domain (or a specific trimerization domain).
Sahin et al. teach cytokine fusion proteins comprising three extracellular domains of a first ligand of the TNF superfamily forming a first homotrimer and three extracellular domains of a second ligand of the TNF superfamily forming a second homotrimer (page 2, lines 1-11). Sahin et al. disclose that the fusion protein comprises a dimerization domain selected from the group consisting of EHD2, MHD2, GHD3, AHD2, DHD3, EHD4, MHD4, and an Fc domain, meeting the limitations of instant claim 19 (page 2, lines 23-32; page 3, lines 25-34; page 4, lines 1-5; page 28, lines 3-15). Sahin et al. indicate that the cytokine fusion protein is also present as a trimeric complex, wherein three extracellular domains of the first ligand form a first homotrimer, and three extracellular domains of the second ligand form a second homotrimer (page 4, lines 24-30). Sahin et al. teach that suitable trimerization domains include a tenascin trimerization motif, a collectin trimerization motif, and streptavidin, meeting the limitations of instant claim 20 (page 28, lines 1-3).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the fusion polypeptide multimer of the ‘046 patent claims by linking the polypeptides comprising the TNF homology domains with a dimerization or trimerization domain (such as IgG1, IgG2, or IgG4 Fc lacking effector function; EHD2; MHD2; and tenascin, respectively), as taught by Sahin et al. The person of ordinary skill in the art would have been motivated to make those modifications because dimerization and trimerization of the fusion polypeptide of the ‘046 patent would enhance its receptor activation and stability (see Sahin et al., pages 48-49, Example 10; page 59, Example 18). The person of ordinary skill in the art reasonably would have expected success because the generation of polypeptide multimers with dimerization and trimerization domains was already routine and being successfully performed at the time the invention was made. There are a limited number of methods to do such and thus, the person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely not the product of innovation but of ordinary skill and common sense (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
11. Claims 19 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 12,173,046 as applied to claims 1, 3, 7-10, 14, 17, and 18 above, in view of Foster et al. (WO 2018/226750; published 13 December 2018; cited on the IDS of 07 December 2021).
The claim limitations of the ‘046 patent are set forth directly above.
Although claims 2 and 3 of the ‘046 patent recites that the polypeptide multimer comprises two polypeptides linked to a dimerization domain, the claims of ‘046 do not recite a specific dimerization domain.
Foster et al. teach a scTNFR2 fusion protein comprising a dimerization domain, three TNF homology domains (THDs) each comprising D143N/A145R mutations to confer selectivity for TNFR2, and a linker between each of the THDs (page 24, [086]). Foster et al. disclose multimerization of the fusion protein via a dimerization domain (page 14, [065]; page 17, [072]; page 20, [077-078]; SEQ ID NOs: 101-112 and 120). Foster et al. teach that the dimerization domain is selected from IgG1, IgG2, or IgG4 Fc lacking effector function; EHD2; and MHD2, meeting the limitations of instant claims 19 and 21 (page 24, [087]; page 50).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the fusion polypeptide multimer of the ‘046 patent claims by linking the polypeptides comprising the TNF homology domains with a dimerization domain, such as IgG1, IgG2, or IgG4 Fc lacking effector function; EHD2; and MHD2, as taught by Foster et al. The person of ordinary skill in the art would have been motivated to make those modifications because dimerization of the fusion polypeptide of the ‘046 patent would enhance its signaling and improve half-life (see Foster et al., page 17, [072]). The person of ordinary skill in the art reasonably would have expected success because the generation of polypeptide multimers with dimerization domains, such as IgG1, IgG2, or IgG4 Fc lacking effector function; EHD2; and MHD2 was already routine and being successfully performed at the time the invention was made. There are a limited number of methods to do such and thus, the person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely not the product of innovation but of ordinary skill and common sense (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
Conclusion
No claims are allowable.
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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BEB
Art Unit 1647
19 February 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647