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 15 August 2025 has been entered in full.
Claims 27-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species and invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04 March 2025.
Claims 1-26 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02 September 2025, 07 August 2025, and 02 July 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. It is noted that on the IDS of 02 September 2025, citation “WO 20180137234” (Baker et al., published 17 May 2018) has been crossed out because the WO document number does not match the information provided on the IDS. The Examiner was unable to independently search and find a WO document with that number. Applicant has also not provided a legible copy of the WO document.
Drawings
1. The replacement drawings were received on 15 August 2025. These drawings are unacceptable.
The Examiner acknowledges that the replacement drawings correct the issues set forth at page 3 of the previous Office Action of 25 March 2025 for Figures 1A-1F, 4A-4K, 5B, 5C, 6A-6C, 7A-7F, and 8A-8D. However, the replacement drawings are objected to because Figures 2A-2E do not comply with 37 C.F.R. § 1.84(U)(1), which states that partial views of a drawing which are intended to form one complete view, whether contained on one or several sheets, must be identified by the same number followed by a capital letter. Figure 2 of the instant application, for example, is now presented on 2 separate pages (with “continued” at the bottom of the second page). Both sheets have A-E across the top, lending to confusion. Please note that this issue could be overcome, for example, by relabeling the two pages for Figure 2 as “Figure 2A, 2B” and relabeling the A-E subparts within the Figures with roman numerals or numbers.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Applicant is reminded that once the drawings are changed to meet the separate numbering requirement of 37 C.F.R. 1 1.84(U)(1), Applicant is required to file an amendment to change the Brief Description of the Drawings and the rest of the specification accordingly.
Withdrawn Objections and/or Rejections
2. The Sequence Listing Requirement deficiency set forth at pages 4-6 of the previous Office Action of 25 March 2025 are withdrawn in view of Applicant’s amendment to the instant specification (15 August 2025).
3. The objections to the specification as set forth at page 6 of the previous Office Action of 25 March 2025 are withdrawn in view of the amended specification (15 August 2025).
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.
4. Claims 1-16 and 26 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 in detail at pages 6-13 of the previous Office Action of 25 March 2025 and is summarized herein below for convenience.
Claim 1 of the instant application is directed to an Antibody Cage (AbC) nanoparticle, comprising:
(a) a plurality of antibodies, each antibody comprising at least two fragment crystallizable (Fc) domains, and
(b) a plurality of cyclic oligomers, each cyclic oligomer comprising a polypeptide comprising:
(i) an Fc-binding domain,
(ii) a monomer domain to position the Fc-binding domains to promote assembly of the nanoparticle, and
(iii) an oligomer domain to assemble the polypeptides to form the cyclic oligomer,
wherein the Fc domains of the plurality of antibodies non-covalently interact with Fc-binding domains of the plurality of cyclic oligomers to form the nanoparticle.
Claim 4 recites that the monomer domain comprises a helical domain.
Claims 5-16 recite that the oligomer and monomer domains comprise polypeptide sequences at least 90% identical to specific residues of SEQ ID NOs: 1-9.
Briefly, the instant specification does not teach a specific definition for an Fc-binding domain, a monomer domain (that also comprises a helical domain), or an oligomer domain, other than the specific sequences recited in Table 1. Therefore, in view of the lack of guidance in the instant specification, the “Fc-binding domain”, “monomer domain”, “oligomer domain”, and “90% identical” limitations recited in the claims are broadly interpreted by the Examiner has reading upon any possible Fc-binding domain, monomer domain, and oligomer domain, as well as any fragment/variant/derivative that shares 90% sequence identity over specific residues of SEQ ID NOs: 1-9. However, the specification does not teach any Fc-binding domain, monomer domain, or oligomer domain other than the specific sequence residues listed in Table 1.
In the instant case, the factors present in the antibody cage nanoparticle claims are (1) structural characteristics of an Fc-binding domain, a monomer domain, an oligomer domain, and 90% identity over specific residues of SEQ ID NOs: 1-9 and (2) functional characteristics of forming a cyclic oligomer and assembling/forming a nanoparticle. There is no identification of any particular sequence or structure of the Fc-binding domain, monomer domain, or oligomer domain that must be conserved in order to provide the required functions of forming a cyclic oligomer and assembling/forming a nanoparticle. Thus, the claims are drawn to a genus of Fc-binding domains, monomer domains, oligomer domains, and any fragment/variant/derivative that shares 90% sequence identity over specific residues 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 Fc-binding domains, monomer domains, oligomer domains, and fragments/variants/derivatives that share 90% sequence identity over specific residues of SEQ ID NOs: 1-9 and the functions of forming a cyclic oligomer and assembling/forming a nanoparticle. In other words, the specification does not teach the structure which results in an Fc-binding domain, monomer domain, oligomer domain, and sequence fragment/variant/derivative with the claimed required characteristics. The description of the specific Fc-binding domain sequences, monomer domain sequences, and oligomer domain sequences set forth in Table 1 at pages 8-9 of the specification, is not adequate written description of an entire genus of Fc-binding domains, monomer domains, oligomer domains, and fragments/variants/derivatives that share 90% sequence identity over specific residues of SEQ ID NOs: 1-9.
Therefore, only an antibody cage nanoparticle comprising (a) a plurality of antibodies, each antibody comprising at least two crystallizable Fc domains; and (b) a plurality of cyclic oligomers, each cyclic oligomer comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, 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).
Applicant’s Arguments
(i) At the top of page 3 of the Response of 15 August 2025, Applicant argues that the state of the art had significantly advanced past the literature cited by the Examiner. Applicant indicates that submitted herewith is a declaration of Dr. David Baker which describes the advances in de novo protein design made by his research group and the field prior to and including the present invention. Applicant states that given the advanced state of the art at the time of the invention, the exemplary polypeptide sequences provided in the specification demonstrate that the inventors were in possession of the necessary common attributes or features possessed by the members of the genus.
(ii) Furthermore, at page 2 of the declaration, Dr. Baker points out the literature cited by the Examiner does not reflect the state of the field of protein design or the level of sophistication of researchers in this field at the time of the invention. Dr. Baker states that a critical distinction from the literature cited by the Examiner is that the present invention lies in the field of design of structural proteins, and therefore, the ease (or difficulty) of predicting consequences of individual amino acid changes is irrelevant. Dr. Baker argues that what matters here is the ability to design polypeptide sequences that serve the desired structural function of forming the antibody cage nanoparticle. Dr. Baker reviews the state of the art of de novo protein design and cites Huang et al. (Nature 537: 320-327, 2016); Koga et al. (Nature 491: 222-227, 2012); Brunette et al. (Nature 528: 580-584, 2015); Fleishman et al. (PLoS One 6(6): e20161, 2011); Silva et al. (Methods Mol Biol 1414: 285-304, 2016); Vulovic et al. (Biochem 118(23): e2015027118, 2021); Hsia et al. (Nature Comm 12: 2294, 2021); Divine et al. (Science 372: 47, 2021); Jansson et al. (FEMS Immunol Med Microbiol 20(1): 69-78, 1998); King et al. (Nature 510: 103-108, 2014); Fallas et al. (Nature Chem 9(4): 353-360, 2017). Dr. Baker indicates that another significant source in the field is the Protein Data Bank, from which numerous protein structures can be drawn as building blocks. At page 2 of the declaration, Dr. Baker also asserts that the instant specification explains how to arrive at any number of antibody cages using the general computational method for antibody cage design (see US2023/0330033, [0150-1053], for example). Dr. Baker submits that the application amply demonstrates possession of the invention as claimed and provides everything needed for one to make and use the claimed invention, when the specification is read in light of the state of the art described in these and other publications.
Examiner’s Response
Applicant’s arguments and the declaration under 37 CFR 1.132 filed 15 August 2025 have been fully considered but are insufficient to overcome the rejection of claims 1-16 and 26 based upon insufficiency of disclosure under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph (written description) as set forth in the last Office action.
The Examiner acknowledges that after review of the references cited by Dr. Baker, most of the references cited by the Examiner in the previous Office Action were directed to the issue of predicting the function of naturally occurring proteins from structure alone, rather than de novo proteins. However, de novo protein design and functional protein generation are not without challenges, much like naturally occurring proteins. Silva et al. (Methods Mol Biol 1414: 285-304, 2016; cited on the IDS of 07 August 2025) state that “designing a truly de novo protein—protein interface is a challenging problem that remains largely unsolved” (page 285). Silva et al. continue to disclose that “to date, no computational method has been developed that can predict with perfect accuracy which designs will be functional when challenged experimentally” (top of page 298). Silva et al. even indicate that de novo protein design may need to be subjected to human-guided optimization (page 299-300).
Similar to Silva et al., Kortemme (Cell 187: 526-544, 2014; page 529, column 1, 1st full paragraph) 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 07 August 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).
Although significant advances have been made in the field of de novo protein design and development, Applicant is reminded that Applicant’s broad brush discussion of computationally designing de novo building-block protein components, such as an Fc-binding domain, monomer domain, or oligomer domain, to ultimately design antibody cage nanoparticles does not constitute a disclosure of a representative number of Fc-binding domains, monomer domains, or oligomer domains as recited in the instant claims. Dr. Baker even states in point #10 of the Declaration of 15 August 2025 that nothing in the application suggests that the general computational methods are limited to particular sequences and rather, the application describes a general process involving Fc-building blocks. This assertion further lends to the instant issue that the skilled artisan cannot envision the detailed chemical structure of the Fc-binding domains, monomer domains, oligomer domains, and fragments/variants/derivatives that share 90% sequence identity over specific residues 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 designing and generating it. The specific Fc-binding domain, monomer domain, and oligomer domain is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. 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).
There is no identification of any particular sequence or structure of the Fc-binding domain, monomer domain, or oligomer domain that must be conserved in order to provide the required functions of forming a cyclic oligomer and assembling/forming a nanoparticle. The description of the specific Fc-binding domain sequences, monomer domain sequences, and oligomer domain sequences set forth in Table 1 at pages 8-9 of the specification, is not adequate written description of an entire genus of Fc-binding domains, monomer domains, oligomer domains, and fragments/variants/derivatives that share 90% sequence identity over specific residues of SEQ ID NOs: 1-9. Thus, the claims are drawn to a genus of Fc-binding domains, monomer domains, oligomer domains, and any fragment/variant/derivative that shares 90% sequence identity over specific residues of SEQ ID NOs: 1-9. 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). Applicant is reminded that "[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. Regarding Applicant’s argument that the ability to design polypeptide sequences that serve to form an antibody cage nanoparticle is of importance, 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.
Therefore, only an antibody cage nanoparticle comprising (a) a plurality of antibodies, each antibody comprising at least two crystallizable Fc domains; and (b) a plurality of cyclic oligomers, each cyclic oligomer comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, 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).
5. Claims 1-16 and 26 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 an antibody cage nanoparticle comprising (a) a plurality of antibodies, each antibody comprising at least two crystallizable Fc domains; and (b) a plurality of cyclic oligomers, each cyclic oligomer comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9, does not reasonably provide enablement for an antibody cage molecule comprising a plurality of cyclic oligomers that comprise any possible Fc-binding domain, monomer domain, and oligomer domain, as well as any fragment/variant/derivative that shares 90% sequence identity over specific residues of SEQ ID NOs: 1-9. 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 in detail at pages 14-19 of the previous Office Action of 25 March 2025.
Claim 1 of the instant application is directed to an Antibody Cage (AbC) nanoparticle, comprising:
(a) a plurality of antibodies, each antibody comprising at least two fragment crystallizable (Fc) domains, and
(b) a plurality of cyclic oligomers, each cyclic oligomer comprising a polypeptide comprising:
(i) an Fc-binding domain,
(ii) a monomer domain to position the Fc-binding domains to promote assembly of the nanoparticle, and
(iii) an oligomer domain to assemble the polypeptides to form the cyclic oligomer,
wherein the Fc domains of the plurality of antibodies non-covalently interact with Fc-binding domains of the plurality of cyclic oligomers to form the nanoparticle.
Claim 4 recites that the monomer domain comprises a helical domain.
Claims 5-16 recite that the oligomer and monomer domains comprise polypeptide sequences at least 90% identical to specific residues of SEQ ID NOs: 1-9.
Applicant’s Arguments
(i) At the bottom of page 3 of the Response of 15 August 2025, Applicant argues that as described in the Baker Declaration, the field of de novo protein design had advanced dramatically at the time of the invention, impacting each of the Wands factors. Applicant submits that, in view of this change in the state of the art, the experimentation required to explore the full scope of the claim would not be undue experimentation under Wands.
(ii) Furthermore, at page 2 of the declaration, Dr. Baker points out the literature cited by the Examiner does not reflect the state of the field of protein design or the level of sophistication of researchers in this field at the time of the invention. Dr. Baker states that a critical distinction from the literature cited by the Examiner is that the present invention lies in the field of design of structural proteins, and therefore, the ease (or difficulty) of predicting consequences of individual amino acid changes is irrelevant. Dr. Baker argues that what matters here is the ability to design polypeptide sequences that serve the desired structural function of forming the antibody cage nanoparticle. Dr. Baker reviews the state of the art of de novo protein design and cites Huang et al. (Nature 537: 320-327, 2016); Koga et al. (Nature 491: 222-227, 2012); Brunette et al. (Nature 528: 580-584, 2015); Fleishman et al. (PLoS One 6(6): e20161, 2011); Silva et al. (Methods Mol Biol 1414: 285-304, 2016); Vulovic et al. (Biochem 118(23): e2015027118, 2021); Hsia et al. (Nature Comm 12: 2294, 2021); Divine et al. (Science 372: 47, 2021); Jansson et al. (FEMS Immunol Med Microbiol 20(1): 69-78, 1998); King et al. (Nature 510: 103-108, 2014); Fallas et al. (Nature Chem 9(4): 353-360, 2017). Dr. Baker indicates that another significant source in the field is the Protein Data Bank, from which numerous protein structures can be drawn as building blocks. At page 2 of the declaration, Dr. Baker also asserts that the instant specification explains how to arrive at any number of antibody cages using the general computational method for antibody cage design (see US2023/0330033, [0150-1053], for example). Dr. Baker submits that the application amply demonstrates possession of the invention as claimed and provides everything needed for one to make and use the claimed invention, when the specification is read in light of the state of the art described in these and other publications.
Examiner’s Response
Applicant’s arguments and the declaration under 37 CFR 1.132 filed 15 August 2025 have been fully considered but are insufficient to overcome the rejection of claims 1-16 and 26 based upon insufficiency of disclosure under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph (scope of enablement) as set forth in the last Office action.
The Examiner acknowledges that after review of the references cited by Dr. Baker, most of the references cited by the Examiner in the previous Office Action were directed to the issue of predicting the function of naturally occurring proteins from structure alone, rather than de novo proteins. However, de novo protein design and functional protein generation are not without challenges, much like naturally occurring proteins. Silva et al. (Methods Mol Biol 1414: 285-304, 2016; cited on the IDS of 07 August 2025) state that “designing a truly de novo protein—protein interface is a challenging problem that remains largely unsolved” (page 285). Silva et al. continue to disclose that “to date, no computational method has been developed that can predict with perfect accuracy which designs will be functional when challenged experimentally” (top of page 298). Silva et al. even indicate that de novo protein design may need to be subjected to human-guided optimization (page 299-300).
Similar to Silva et al., Kortemme (Cell 187: 526-544, 2014; page 529, column 1, 1st full paragraph) 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 07 August 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).
Although significant advances have been made in the field of de novo protein design and development, Applicant is reminded that Applicant’s broad brush discussion of computationally designing de novo building-block protein components, such as an Fc-binding domain, monomer domain, or oligomer domain, to ultimately design antibody cage nanoparticles does not constitute adequate guidance, but rather, constitutes an invitation to experiment by trial and error. Dr. Baker even states in point #10 of the Declaration of 15 August 2025 that nothing in the application suggests that the general computational methods are limited to particular sequences and rather, the application describes a general process involving Fc-building blocks. This assertion further lends to the instant issue that the skilled artisan would not be able to predict that all possible Fc-binding domains, monomer domains, oligomer domains, and sequence fragments/variants/derivatives that share 90% sequence identity over specific residues of SEQ ID NOs: 1-9 of the encompassed claims would have the desired functional activities of forming a cyclic oligomer and assembling/forming a nanoparticle.
The instant specification does not teach a specific definition for an Fc-binding domain, a monomer domain (that also comprises a helical domain), or an oligomer domain, other than the specific sequences recited in Table 1. Therefore, a person of skill in the art would not know which amino acid residues in the domains are considered essential and which are non-essential. Without detailed direction as to which amino acids are essential to the functions of the Fc-binding domain, monomer domain, and oligomer domain for antibody cage nanoparticle formation, the skilled artisan would not be able to determine without undue experimentation which Fc-binding domains, monomer domains, and oligomer domains encompassed by the instant claims would exhibit the desired and claimed functional characteristics of forming a cyclic oligomer and assembling/forming a nanoparticle.
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 Fc-binding domains, monomer domains, oligomer domains, and fragments/variants/derivatives that share 90% sequence identity over specific residues of SEQ ID NOs: 1-9 and screen such for the desired functional activities of forming a cyclic oligomer and assembling/forming a nanoparticle; 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; 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.
6. Claims 1-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 13, 16, 24, 25, 29, 45, 48, and 49 of copending Application No. 17/907,372. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite a nanoparticle 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 provisional rejection is set forth at pages 20-21 of the previous Office Action of 25 March 2025 and reiterated herein below.
Claim 26 of the instant application and claim 48 of the ‘372 application recite pharmaceutical compositions comprising the nanoparticle.
It is also noted that the amino acid sequences of SEQ ID NOs: 1-9, as recited in the claims of the ‘372 application are 100% identical to the amino acid sequences of SEQ ID NOs: 1-9 recited in the claims of the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
7. Claims 1-26 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 nanoparticle 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 provisional rejection is set forth at pages 21-22 of the previous Office Action of 25 March 2025 and reiterated herein below.
Claim 26 of the instant application and claim 24 of the ‘004 application recite pharmaceutical compositions comprising the nanoparticle.
It is also noted that the amino acid sequences of SEQ ID NOs: 1-9, as recited in the claims of the ‘004 application are 100% identical to the amino acid sequences of SEQ ID NOs: 1-9 recited in the claims of the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(i) At page 4 of the Response of 15 August 2025, Applicant states that the provisional rejections will be addressed when the currently pending claims are in condition for allowance.
Applicant’s statement has been fully considered but is not found to be persuasive. The provisional double patenting rejections of instant claims 1-26 as set forth in detail above and in the previous Office Action of 25 March 2025 are maintained. Applicant does not present any arguments pointing out the specific distinctions that render the instant claims patentable over the ‘372 and ‘004 application claims. Applicant is reminded that only objections or requirements as to form not necessary to further consideration of the claims may be held in abeyance until allowable subject matter is indicated (see 37 CFR 1.11(b)). Applicant is encouraged to submit terminal disclaimers at Applicant’s earliest convenience.
Conclusion
No claims are allowable.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIDGET E BUNNER whose telephone number is (571)272-0881. The examiner can normally be reached Monday-Friday 9:00 am-6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
BEB
Art Unit 1647
06 November 2025
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647