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 12 February 2026 has been entered in full. Claims 1, 4-6, 13, 16, 25, and 29 are amended. Claims 7, 9, 14, 15, 17-23, 26-28, 30-44, 46, 47, and 49-51 are cancelled.
Claims 1-6, 8, 10-13, 16, 24, 25, 29, 45, and 48 are under consideration in the instant application.
Drawings
The replacement drawings were received on 12 February 2026. These drawings are acceptable.
Withdrawn Objections and/or Rejections
1. The objection to the drawings as set forth at page 3 of the previous Office Acton of 13 November 2025 is withdrawn in view of the submission of replacement drawings (12 February 2026).
2. The Sequence Listing Requirement deficiency set forth at pages 4-5 of the previous Office Action of 13 November 2025 is withdrawn in view of Applicant’s amendment to the instant specification (12 February 2026).
3. The objections to the specification as set forth at pages 5-6 of the previous Office Action of 13 November 2025 are withdrawn in view of Applicant’s amendments to the instant specification (12 February 2026).
4. The objections to claims 13, 25, and 49 as set forth at page 6 of the previous Office Action of 13 November 2025 are withdrawn in view of the amended and cancelled claims (12 February 2026).
5. The rejections of claims 1-6, 8, 10-13, 16, 24, 25, 29, 45, 48, and 49 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph as set forth at pages 6-8 of the previous Office Action of 13 November 2025 are withdrawn in view of the amended and cancelled claims and Applicant’s persuasive arguments (12 February 2026).
6. The rejection of claim 49 under 35 U.S.C. 101 as set forth at pages 8-9 of the previous Office Action of 13 November 2025 is withdrawn in view of the cancelled claim (12 February 2026).
Information Disclosure Statement
In view of Applicant’s comments in the Response of 12 February 2026 indicating that on the IDS of 02 September 2025, reference 20180137234 is a USPGPB (and not a WO), the Examiner has considered US2018/0137234 and attached the re-signed IDS for Applicant’s records. The two other references have been lined through because they were previously considered by the Examiner.
New 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.
7. Claims 1-6, 8, 10-13, 16, 24, 25, 29, 45, and 48 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.
7a. Claims 1-6, 8, 10-13, 16, 24, 25, 29, 45, and 48 are rejected as being indefinite because claims 1, 13, 25, and 29 recite the phrase “wherein optional residues are absent”. There is insufficient antecedent basis for this limitation in the claims. Claims 1, 13, 25, and 29 do not recite any optional residues. It is not clear what residues are optional and thus, one of ordinary skill in the art would not be apprised of the scope of the invention.
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.
8. Claims 1-6, 8, 10-13, 16, 24, 25, 29, 45, and 48 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 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. The basis for this rejection is set forth at pages 9-17 of the previous Office Action of 13 November 2025 and is reiterated herein below for convenience.
Claim 1 of the instant application, for example, is directed to a polypeptide comprising an amino acid sequence at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 1-9, wherein optional residues are absent, wherein the polypeptide is capable of (a) assembling into a polymer, including but not limited to a homo-polymer, and (b) binding to a constant region of an IgG antibody.
The specification of the instant application teaches designed proteins that drive the assembly of arbitrary antibodies symmetric assemblies with well-defined structures (page 27, lines 20-21). The specification continues to disclose that to design a homo-oligomer terminating with an Fc-binding interface that has the correct geometry to hold the IgGs in the correct relative orientation for the desired architecture, three protein building blocks are fused together: Fc-binders, monomers, and homo-oligomers (page 27, lines 30-33). The specification indicates that the Fc-binder forms the first nanocage interface between the antibody and the nanocage-forming design; the homo-oligomer forms the second nanocage interface between designed protein chains, and the monomer links the two interfaces together in the correct orientation to generate the desired nanomaterial (page 27, lines 33-34; page 28, lines 1-2). The specification teaches that protein A interface residues are grafted onto a designed helical repeat protein (page 28, lines 3-5). Additionally, in order to create designs predicted to form antibody nanocages, a library was used that consists of 2 Fc-binding proteins, 42 de novo designed helical repeat protein monomers, and between 1-3 homo-oligomers (page 28, lines 5-8). In particular, Table 1 at pages 8-9 of the specification lists sequences and original building blocks for the designs.
The instant specification teaches that the disclosure provides polypeptide comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the polypeptide is capable of (a) assembling into a polymer, including but not limited to a homo-polymer, and (b) binding to a constant region of an IgG antibody (page 1, lines 25-31). At page 10, Table 2, the specification lists predicted interface residues at the oligomeric interface in each SEQ ID NO that would be conserved. Table 3 at pages 10-11 of the specification lists amino acid residues present at an Fc binding interface in each SEQ ID NO that would be conserved. The specification teaches that amino acid substitutions relative to the reference sequence may comprise substitutions at polar residues in the reference peptide and that polar residues on the surface of the polypeptide that are not at the Fc or oligomeric interfaces may be substituted with other polar residues while maintaining folding and assembly property of the designs (page 11; lines 2-8). Lastly, the specification teaches that amino acid changes from the reference polypeptide are conservative amino acid substitutions (page 12, lines 2-10; page 13, lines 1-4).
Therefore, in view of the teachings of the instant specification, the percent identity limitations recited in the claims are broadly interpreted by the Examiner has reading upon any polypeptide fragment/variant/derivative that shares at least 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9. However, the specification does not teach any polypeptide fragment/variant/derivative sequences other than the specific amino acid sequences of SEQ ID NOs: 1-9 listed in Table 1.
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof. In the instant case, the factors present in the claims are (1) an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9 and (2) functional characteristics of assembling into a polymer, including but not limited to a homo-polymer, and binding to a constant region of an IgG antibody. There is no identification of any particular sequence or structure of the polypeptide that must be conserved in order to provide the required functions of assembling into a polymer and binding to a constant region of an IgG antibody. Thus, the claims are drawn to a genus of polypeptides that shares 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of polypeptides that shares at least 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9 and the functions of assembling into a polymer and binding to a constant region of an IgG antibody. In other words, the specification does not teach the structure which results in a polypeptide fragment/variant/derivative with the claimed required characteristics. The description of the specific polypeptide amino acid sequences of SEQ ID NOs: 1-9 set forth in Table 1 of the specification, is not adequate written description of an entire genus of polypeptides that share at least 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9 (that assemble into a polymer and bind to a constant region of an IgG antibody).
Regarding the de novo designed helical repeat monomers of the instant specification (page 28, line 7), relevant literature teaches that approaches to computational de novo protein design use (i) physics-based approaches and atomistic representations, grounded in structural biological principles and rules derived from naturally occurring protein structures and (ii) AI-based strategies (Kortemme, T., Cell 187: 526-544, 2014; page 529, column 1, 1st full paragraph). However, de novo protein design and functional protein generation are not without challenges. Kortemme teaches that a key challenge is that the space of potential new sequences and structures is vast, sparsely populated with folded and functional proteins, and poorly mapped (page 529, column 1, last paragraph). Kortemme continues to state:
“For example, for a small protein of 100 residues, there are 20100 = ~10130 sequence possibilities when considering the 20 naturally occurring amino acid types. Since the number of possibilities is larger than the estimated number of atoms in the universe (~1080), trying (termed sampling) all these sequences and their possible structures is impossible. Instead, efficient search algorithms are needed to navigate the enormous space of possibilities. At the same time, there are in principle vast numbers of de novo proteins with new sequences, structures, and functions that could be found” (page 529, bottom of column 1 through the top of column 2).
Kortemme discloses that the fundamental and generally unsolved problem is the design of function (page 529, column 2, 2nd full paragraph). For computational design, the precise description of the requirements for a designed protein’s function, such as specific conformational dynamics or electrostatics in an active site, may be lacking (page 529, column 2, 2nd full paragraph). There are also multiple requirements for function, including protein stability, the ability to adopt several conformations in a catalytic cycle, rates of interconversion, and recognition of desired interaction partners (and avoidance of others) (page 529, column 2, last paragraph). Kortemme teaches that the mechanism by which resulting functional proteins operate may not always be clear (page 530, column 1). Huang et al. also acknowledge similar challenges (Nature 537: 320-327, 2016; cited on the IDS of 03 September 2025; page 326, column 1, 2nd full paragraph).
Furthermore, idealized de novo designed “backbone” sequences lack the structural irregularities that are hallmarks of functional motifs in natural proteins such as surface cavities, kinked secondary structure elements and desolvated polar groups (Listov et al., Nature Rev Mol Cell Biol 25: 639-653, 2024; page 647, column 1, 1st full paragraph). Listov et al. continue to disclose that because of their regularity, many designed proteins exhibit high stability, but methods for designing sophisticated activities in de novo proteins are limited (page 647, column 1, 1st full paragraph). For instance, one of the functional design challenges is that natural proteins are much larger and topologically more complex than those that have been the subject of design studies (Listov et al., page 647, column 1, 1st full paragraph). Moreover, function in natural proteins often depends on large and structured loop regions, and such regions continue to pose a severe challenge to structure prediction and design methods (Listov et al., page 647, column 1, 1st full paragraph). For example, although the Rosetta software suite has been successful in the design of polyhedral protein assemblies, many designs do not aggregate or do not assemble into the intended architecture due to misfolding or suboptimal assembly conditions (Mallik et al. ChemBioChem 24: e202300117, 2023; page 4, column 2, last paragraph through page 5, top of column 1). Dawson et al. (Curr Opin Chem Biol 52: 102-111, 2019) indicate that significant challenges in this field remain, chief amongst them is the need to deliver functional de novo proteins (abstract). Listov et al. clearly state that the ultimate goal of protein design is developing general methods that can be reliably applied to generate desired functions without recourse to natural starting points (page 647, column 2, 3rd full paragraph). However, Listov et al. admits that this goal is far from being achieved (page 647, column 2, 3rd full paragraph). Dawson et al. also disclose that “the ability to design functional de novo proteins from scratch, or to embellish existing de novo scaffolds with new functions, is still in its infancy” (page 102, column 2, 1st full paragraph; page 107, column 2, last paragraph).
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, 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). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). 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). A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566). In the instant application, the skilled artisan cannot envision the detailed chemical structure of the polypeptide fragments/variants/derivatives that share 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9 of the encompassed claims, 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. The specific polypeptide sequence is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only a polypeptide comprising the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9 (and polymers and particles comprising such), but not the full breadth of the claims meets the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
(i) At the bottom of page 11 of the Response of 12 February 2026, Applicant states that for the sole purpose of accelerating prosecution, claim 1 has been amended to recite a polypeptide comprising an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 1-9, wherein the polypeptide is capable of assembling into a polymer and binding to a constant region of an IgG antibody. Applicant argues that at a 90% sequence identity combined with the identification of interface-binding residues, core residues, and loop residues, a person of ordinary skill in the art would readily recognize that such closely related variants retain structural and functional characteristics of the disclosed polypeptides without undue burden.
Applicant’s arguments have been fully considered but are not found to be persuasive. Contrary to Applicant’s arguments, there is no identification of any particular sequence or structure of the polypeptide that must be conserved in order to provide the required functions of assembling into a polymer and binding to a constant region of an IgG antibody. Thus, the claims are drawn to a genus of polypeptides that shares 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9.
Furthermore, the art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427;; all cited on the IDS of 03 September 2025). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009; cited on the IDS of 03 September 2025), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18).
Dawson et al. (Curr Opin Chem Biol 52: 102-111, 2019) also indicate that significant challenges in the field of de novo protein design remain, chief amongst them is the need to deliver functional de novo proteins (abstract; emphasis added by Examiner). Listov et al. (Nature Rev Mol Cell Biol 25: 639-653, 2024) clearly state that the ultimate goal of protein design is developing general methods that can be reliably applied to generate desired functions without recourse to natural starting points (page 647, column 2, 3rd full paragraph). However, Listov et al. admits that this goal is far from being achieved (page 647, column 2, 3rd full paragraph). Dawson et al. also disclose that “the ability to design functional de novo proteins from scratch, or to embellish existing de novo scaffolds with new functions, is still in its infancy” (page 102, column 2, 1st full paragraph; page 107, column 2, last paragraph). One of the functional design challenges is that natural proteins are much larger and topologically more complex than those that have been the subject of design studies (Listov et al., page 647, column 1, 1st full paragraph). Moreover, function in natural proteins often depends on large and structured loop regions, and such regions continue to pose a severe challenge to structure prediction and design methods (Listov et al., page 647, column 1, 1st full paragraph).
Thus, the state of the art recognized that it would be highly unpredictable that a polypeptide comprising an amino acid sequence at least 90% identical to the amino acid selected from the group consisting of SEQ ID NOs: 1-9 would maintain its required conformation, assemble into a polymer, and bind to a constant region of an IgG antibody. The amino acid sequences of SEQ ID NOs: 1-9 range in size from 314 amino acids to 422 amino acids. So, for example, 90% sequence identity over instant SEQ ID NO: 7, which is 422 amino acids in length, encompasses 42 amino acid alterations. If 42 of these positions are substituted using the standard 20 amino acids, the number of possible variations is approximately 8.06 x 10111.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)).
9. Claims 1-6, 8, 10-13, 16, 24, 25, 29, 45, and 48 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 a polypeptide comprising the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9 (and polymers and particles comprising such), does not reasonably provide enablement for a polypeptide comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein optional residues are absent, wherein the polypeptide is capable of (a) assembling into a polymer, including but not limited to a homo-polymer, and (b) binding to a constant region of an IgG antibody. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. The basis for this rejection is set forth at pages 18-23 of the previous Office Action of 13 November 2025 and is reiterated herein below for convenience.
Claim 1 of the instant application, for example, is directed to a polypeptide comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein optional residues are absent, wherein the polypeptide is capable of (a) assembling into a polymer, including but not limited to a homo-polymer, and (b) binding to a constant region of an IgG antibody.
The specification of the instant application teaches designed proteins that drive the assembly of arbitrary antibodies symmetric assemblies with well-defined structures (page 27, lines 20-21). The specification continues to disclose that to design a homo-oligomer terminating with an Fc-binding interface that has the correct geometry to hold the IgGs in the correct relative orientation for the desired architecture, three protein building blocks are fused together: Fc-binders, monomers, and homo-oligomers (page 27, lines 30-33). The specification indicates that the Fc-binder forms the first nanocage interface between the antibody and the nanocage-forming design; the homo-oligomer forms the second nanocage interface between designed protein chains, and the monomer links the two interfaces together in the correct orientation to generate the desired nanomaterial (page 27, lines 33-34; page 28, lines 1-2). The specification teaches that protein A interface residues are grafted onto a designed helical repeat protein (page 28, lines 3-5). Additionally, in order to create designs predicted to form antibody nanocages, a library was used that consists of 2 Fc-binding proteins, 42 de novo designed helical repeat protein monomers, and between 1-3 homo-oligomers (page 28, lines 5-8). In particular, Table 1 at pages 8-9 of the specification lists sequences and original building blocks for the designs.
The instant specification teaches that the disclosure provides polypeptide comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the polypeptide is capable of (a) assembling into a polymer, including but not limited to a homo-polymer, and (b) binding to a constant region of an IgG antibody (page 1, lines 25-31). At page 10, Table 2, the specification lists predicted interface residues at the oligomeric interface in each SEQ ID NO that would be conserved. Table 3 at pages 10-11 of the specification lists amino acid residues present at an Fc binding interface in each SEQ ID NO that would be conserved. The specification teaches that amino acid substitutions relative to the reference sequence may comprise substitutions at polar residues in the reference peptide and that polar residues on the surface of the polypeptide that are not at the Fc or oligomeric interfaces may be substituted with other polar residues while maintaining folding and assembly property of the designs (page 11; lines 2-8). Lastly, the specification teaches that amino acid changes from the reference polypeptide are conservative amino acid substitutions (page 12, lines 2-10; page 13, lines 1-4).
Therefore, in view of the teachings of the instant specification, the percent identity limitations recited in the claims are broadly interpreted by the Examiner has reading upon any polypeptide fragment/variant/derivative that shares at least 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9. However, the specification does not teach any polypeptide fragment/variant/derivative sequences other than the specific amino acid sequences of SEQ ID NOs: 1-9 listed in Table 1.
A large quantity of experimentation would be required of the skilled artisan to generate and screen the encompassed polypeptides that share at least 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9 of the instant claims. One skilled in the art would also not be able to predict that all possible polypeptide fragments/variants/derivatives would have the desired functional activities of assembling into a polymer and binding to a constant region of an IgG antibody. The specification even teaches that “[w]hile there have been some efforts to oligomerize antibodies to enhance avidity and receptor clustering, there are no current methods to precisely form ordered and structurally homogenous antibody-bound nanoparticle structures” (page 1, lines 19-22). A person of skill in the art would not know which amino acid residues in the polypeptides are considered essential and which are non-essential. Without detailed direction as to which amino acids are essential to the functions of the polypeptides, the skilled artisan would not be able to determine without undue experimentation which polypeptide fragments/variants/derivatives encompassed by the instant claims would exhibit the desired and claimed functional characteristics of assembling into a polymer and binding to a constant region of an IgG antibody.
Relevant literature teaches that approaches to computational de novo protein design use (i) physics-based approaches and atomistic representations, grounded in structural biological principles and rules derived from naturally occurring protein structures and (ii) AI-based strategies (Kortemme, T., Cell 187: 526-544, 2014; page 529, column 1, 1st full paragraph). However, de novo protein design and functional protein generation are not without challenges. The problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex. A key challenge in de novo protein design is that the space of potential new sequences and structures is vast, sparsely populated with folded and functional proteins, and poorly mapped (Kortemme, page 529, column 1, last paragraph). Kortemme continues to state:
“For example, for a small protein of 100 residues, there are 20100 = ~10130 sequence possibilities when considering the 20 naturally occurring amino acid types. Since the number of possibilities is larger than the estimated number of atoms in the universe (~1080), trying (termed sampling) all these sequences and their possible structures is impossible. Instead, efficient search algorithms are needed to navigate the enormous space of possibilities. At the same time, there are in principle vast numbers of de novo proteins with new sequences, structures, and functions that could be found” (page 529, bottom of column 1 through the top of column 2).
Kortemme discloses that the fundamental and generally unsolved problem is the design of function (page 529, column 2, 2nd full paragraph). For computational design, the precise description of the requirements for a designed protein’s function, such as specific conformational dynamics or electrostatics in an active site, may be lacking (page 529, column 2, 2nd full paragraph). There are also multiple requirements for function, including protein stability, the ability to adopt several conformations in a catalytic cycle, rates of interconversion, and recognition of desired interaction partners (and avoidance of others) (page 529, column 2, last paragraph). Kortemme teaches that the mechanism by which resulting functional proteins operate may not always be clear (page 530, column 1). Huang et al. also acknowledge similar challenges (Nature 537: 320-327, 2016; cited on the IDS of 03 September 2025; page 326, column 1, 2nd full paragraph).
Furthermore, idealized de novo designed “backbone” sequences lack the structural irregularities that are hallmarks of functional motifs in natural proteins such as surface cavities, kinked secondary structure elements and desolvated polar groups (Listov et al., Nature Rev Mol Cell Biol 25: 639-653, 2024; page 647, column 1, 1st full paragraph). Listov et al. continue to disclose that because of their regularity, many designed proteins exhibit high stability, but methods for designing sophisticated activities in de novo proteins are limited (page 647, column 1, 1st full paragraph). For instance, one of the functional design challenges is that natural proteins are much larger and topologically more complex than those that have been the subject of design studies (Listov et al., page 647, column 1, 1st full paragraph). Moreover, function in natural proteins often depends on large and structured loop regions, and such regions continue to pose a severe challenge to structure prediction and design methods (Listov et al., page 647, column 1, 1st full paragraph). For example, although the Rosetta software suite has been successful in the design of polyhedral protein assemblies, many designs do not aggregate or do not assemble into the intended architecture due to misfolding or suboptimal assembly conditions (Mallik et al. ChemBioChem 24: e202300117, 2023; page 4, column 2, last paragraph through page 5, top of column 1). Dawson et al. (Curr Opin Chem Biol 52: 102-111, 2019) indicate that significant challenges in this field remain, chief amongst them is the need to deliver functional de novo proteins (abstract). Listov et al. clearly state that the ultimate goal of protein design is developing general methods that can be reliably applied to generate desired functions without recourse to natural starting points (page 647, column 2, 3rd full paragraph). However, Listov et al. admits that this goal is far from being achieved (page 647, column 2, 3rd full paragraph). Dawson et al. also disclose that “the ability to design functional de novo proteins from scratch, or to embellish existing de novo scaffolds with new functions, is still in its infancy” (page 102, column 2, 1st full paragraph; page 107, column 2, last paragraph).
(i) At the bottom of page 11 of the Response of 12 February 2026, Applicant states that for the sole purpose of accelerating prosecution, claim 1 has been amended to recite a polypeptide comprising an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 1-9, wherein the polypeptide is capable of assembling into a polymer and binding to a constant region of an IgG antibody. Applicant argues that at a 90% sequence identity combined with the identification of interface-binding residues, core residues, and loop residues, a person of ordinary skill in the art would readily recognize that such closely related variants retain structural and functional characteristics of the disclosed polypeptides without undue burden.
Applicant’s arguments have been fully considered but are not found to be persuasive. Contrary to Applicant’s arguments, there is no identification of any particular sequence or structure of the polypeptide that must be conserved in order to provide the required functions of assembling into a polymer and binding to a constant region of an IgG antibody. Thus, the claims are drawn to a genus of polypeptides that shares 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9. The specification does not teach any variants/substitutions of the amino acid sequences of SEQ ID NOs: 1-9.
The art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427;; all cited on the IDS of 03 September 2025). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009; cited on the IDS of 03 September 2025), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Indeed, Tokuriki et al. conclude that “a more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation” (see page 602, left column, 2nd paragraph). Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020; cited on the IDS of 03 September 2025) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017; cited on the IDS of 03 September 2025) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability. For evidence thereof, see Guo et al. (PNAS USA 101(25):9205-10, 2004; cited on the IDS of 03 September 2025), who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2). Fenton et al. supra, also acknowledge this (see abstract).
As discussed above, Dawson et al. (Curr Opin Chem Biol 52: 102-111, 2019) also indicate that significant challenges in the field of de novo protein design remain, chief amongst them is the need to deliver functional de novo proteins (abstract; emphasis added by Examiner). Listov et al. (Nature Rev Mol Cell Biol 25: 639-653, 2024) clearly state that the ultimate goal of protein design is developing general methods that can be reliably applied to generate desired functions without recourse to natural starting points (page 647, column 2, 3rd full paragraph). However, Listov et al. admits that this goal is far from being achieved (page 647, column 2, 3rd full paragraph). Dawson et al. also disclose that “the ability to design functional de novo proteins from scratch, or to embellish existing de novo scaffolds with new functions, is still in its infancy” (page 102, column 2, 1st full paragraph; page 107, column 2, last paragraph). One of the functional design challenges is that natural proteins are much larger and topologically more complex than those that have been the subject of design studies (Listov et al., page 647, column 1, 1st full paragraph). Moreover, function in natural proteins often depends on large and structured loop regions, and such regions continue to pose a severe challenge to structure prediction and design methods (Listov et al., page 647, column 1, 1st full paragraph).
The instant specification even teaches that “[w]hile there have been some efforts to oligomerize antibodies to enhance avidity and receptor clustering, there are no current methods to precisely form ordered and structurally homogenous antibody-bound nanoparticle structures” (page 1, lines 19-22). A large quantity of experimentation would be required of the skilled artisan to generate and screen the encompassed polypeptides that share at least 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9 of the instant claims. One skilled in the art would also not be able to predict that all possible polypeptide fragments/variants/derivatives would have the desired functional activities of assembling into a polymer and binding to a constant region of an IgG antibody. The amino acid sequences of SEQ ID NOs: 1-9 range in size from 314 amino acids to 422 amino acids. So, for example, 90% sequence identity over instant SEQ ID NO: 7, which is 422 amino acids in length, encompasses 42 amino acid alterations. If 42 of these positions are substituted using the standard 20 amino acids, the number of possible variations is approximately 8.06 x 10111. A person of skill in the art would not know which amino acid residues in the polypeptides are considered essential and which are non-essential. Without detailed direction as to which amino acids are essential to the functions of the polypeptides, the skilled artisan would not be able to determine without undue experimentation which polypeptide fragments/variants/derivatives encompassed by the instant claims would exhibit the desired and claimed functional characteristics of assembling into a polymer and binding to a constant region of an IgG antibody.
Proper analysis of the Wands factors was provided in the previous Office Action. Due to the large quantity of experimentation necessary to generate all possible polypeptide fragments/variants/derivatives that share 90% sequence identity with the amino acid sequences of SEQ ID NOs: 1-9 and screen such for the desired functional activities of assembling into a polymer and binding to a constant region of an IgG antibody; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; the state of the art which establishes the unpredictability of de novo protein structure and function (see Kortemme, Huang et al., Listov et al., Mallik et al., Dawson et al.); and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
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.
10. Claims 1-6, 8, 10-13, 16, 24, 25, 29, 45, and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 11, 16, 17, 19, 21, 24, 26, 32, 49, 50, 58 of copending Application No. 18/000,004. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite a particle comprising a plurality of polymers, wherein the monomer in each polymer comprises (i) an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, and (ii) a plurality of antibodies comprising Fc domains. The basis for this rejection is set forth at pages 24-25 of the previous Office Action of 13 November 2025.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
11. Claims 1, 10-13, 16, 24, 25, 29, 45, and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 18/912,238. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite a particle comprising (i) a plurality of antibodies, each antibody comprising at least two Fc domains and (ii) a plurality of polypeptide domains, each domain comprising the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the Fc domains of the plurality of antibodies non-covalently interact with the Fc-binding domain within the polypeptide domain to form the nanoparticle. The basis for this rejection is set forth at pages 25-26 of the previous Office Action of 13 November 2025.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(i) At page 12 , Applicant states that for the sole purpose of accelerating prosecution, Applicant has filed electronic terminal disclosures over the ‘004 and ‘238 applications.
Applicant’s response has been considered. However, no terminal disclaimers have been received in the instant application. Therefore, the provisional rejections are maintained.
Conclusion
Claims 1-6, 8, 10-13, 16, 24, 25, 29, 45, and 48 are rejected.
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
08 May 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
Prosecution Insights