DETAILED ACTION
Disposition of Claims
Claims 1-3, 8-13, 15-23, and 25-26 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250032604A1, Published 01/30/2025.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/11/2026 and 12/09/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of implied phraseology (e.g. “This disclosure provides…”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See ¶[0250] “www.nature.com/articles/nature17978”; ¶[0465] “https://doi.org/10.1016/j.apsb.2016.02.001” .
Claim Rejections - 35 USC § 112(b); Second Paragraph
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.
Claim 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 repeatedly recites a “first sequence” and a “second sequence” in describing alternative arrangements within the open reading frame, and also provides a list (a)-(h) of items which may be within the open reading frame (ORF). From the wording of the claim, it is unclear if the repeatedly recited “first sequence” and “second sequence” throughout the claimed open reading frame should be the same or different (e.g. the “first sequence” in (a) is “SARS-CoV-2 S protein” but the “first protein” in part (b) is “Influenza A virus HA protein”). Next, it is unclear if (a)-(h) are meant to be elements all within the circular polyribonucleotide, or if (a)-(h) are a Markush grouping where only one of (a)-(h) is meant to be selected or if any combination of (a)-(h) may be present. Due to these issues, the scope of the claim is uncertain because a person of ordinary skill in the art would not be reasonably apprised whether the claim requires repeated copies of identical immunogen-encoding and multimerization-domain-encoding sequence combinations, or permits different combinations in other positions, or if only one of (a)-(h) should be present in the construct.
For at least these reasons, claim 2 is rejected on the grounds of being indefinite.
Claim 3 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites the limitation "each multimerization domain" in line 2. There is insufficient antecedent basis for this limitation in the claim, as claim 1 only recites a singular multimerization domain.
Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 8 recites the “circular polyribonucleotide of claim 1, wherein the open reading frame comprises, arranged in the following 5'-to-3' order:
(a) a first sequence encoding an immunogen and second sequence encoding a T4 foldon domain;
(b) a first sequence encoding an immunogen and second sequence encoding a ferritin domain;
(c) a first sequence encoding an immunogen and second sequence encoding a p-annulus peptide;
(d) a first sequence encoding an immunogen and second sequence encoding an AaLS peptide;
(e) a first sequence encoding an immunogen, a second sequence encoding a T4 foldon domain, and a third sequence encoding an immunogen;
(f) a first sequence encoding an immunogen, a second sequence encoding a T4 foldon domain, and a third sequence encoding a ferritin domain; or
(g) a first sequence encoding an immunogen, a second sequence encoding a ferritin domain, and a third sequence encoding a T4 foldon domain.“
From the wording of the claim, it is unclear if the repeatedly recited “first sequence” and “second sequence” throughout the claimed open reading frame should be the same or different (e.g. the “first sequence” in (a) is “SARS-CoV-2 S protein” but the “first protein” in part (b) is “Influenza A virus HA protein”). Next, it is unclear if (a)-(g) are meant to be elements all within the circular polyribonucleotide, or if (a)-(g) are a Markush grouping where only one of (a)-(g) is meant to be selected or if any combination of (a)-(g) may be present. Due to these issues, the scope of the claim is uncertain because a person of ordinary skill in the art would not be reasonably apprised whether the claim requires repeated copies of identical immunogen-encoding and multimerization-domain-encoding sequences or permits different combinations in other positions or if only one of (a)-(g) should be present in the construct.
For at least these reasons, claim 8 is rejected on the grounds of being indefinite.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 recites the limitation "each immunogen" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim, as claim 1 only recites a single immunogen. One suggestion is to have claim 9 depend upon claim 8, which recites multiple immunogens.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a circular polyribonucleotide comprising an open reading frame (ORF) comprising a sequence encoding an immunogen and a sequence encoding a multimerization domain.
Further limitations on the circular polyribonucleotide of claim 1 are wherein the open reading frame comprises, arranged in the following 5'-to-3' order:(a) a first sequence encoding an immunogen and second sequence encoding a multimerization domain;(b) a first sequence encoding an immunogen, a second sequence encoding a multimerization domain, and a third sequence encoding an immunogen;(c) a first sequence encoding an immunogen, a second sequence encoding a multimerization domain, a third sequence encoding an immunogen, and a fourth sequence encoding a multimerization domain;(d) a first sequence encoding an immunogen, a second sequence encoding a multimerization domain, and a third sequence encoding a multimerization domain;(e) a first sequence encoding a multimerization domain and second sequence encoding an immunogen;(f) a first sequence encoding a multimerization domain, a second sequence encoding an immunogen, and a third sequence encoding a multimerization domain;(g) a first sequence encoding a multimerization domain, a second sequence encoding an immunogen, a third sequence encoding a multimerization domain, and a fourth sequence encoding an immunogen; or (h) a first sequence encoding a multimerization domain, a second sequence encoding a multimerization domain, and a third sequence encoding an immunogen (claim 2); wherein the multimerization domain comprises;(a) a T4 foldon domain;(b) a ferritin domain;(c) a beta-annulus peptide;(d) an AaLS peptide; or (e) a lumazine synthase domain (claim 3); wherein the open reading frame comprises, arranged in the following 5'-to-3' order:(a) a first sequence encoding an immunogen and second sequence encoding a T4 foldon domain;(b) a first sequence encoding an immunogen and second sequence encoding a ferritin domain;(c) a first sequence encoding an immunogen and second sequence encoding a p-annulus peptide;(d) a first sequence encoding an immunogen and second sequence encoding an AaLS peptide;(e) a first sequence encoding an immunogen, a second sequence encoding a T4 foldon domain, and a third sequence encoding an immunogen;(f) a first sequence encoding an immunogen, a second sequence encoding a T4 foldon domain, and a third sequence encoding a ferritin domain; or (g) a first sequence encoding an immunogen, a second sequence encoding a ferritin domain, and a third sequence encoding a T4 foldon domain (claim 8); wherein the immunogen is operably linked to a secretion signal sequence (claim 9); wherein the open reading frame is operably linked to an IRES (claim 10); wherein the circular polyribonucleotide further comprises a second open reading frame encoding a second polypeptide operably linked to a second IRES (claim 11), wherein the second polypeptide is a polypeptide immunogen (claim 12), wherein the second polypeptide is a polypeptide adjuvant (claim 13); wherein the circular polyribonucleotide further comprises a non-coding ribonucleic acid sequence that is an innate immune system stimulator (claim 15), and wherein the innate immune system stimulator is selected from a GU-rich motif, an AU-rich motif, a structured region comprising dsRNA, or an aptamer (claim 16).
Claim 17 is drawn to an immunogenic composition comprising the circular polyribonucleotide of claim 1 and a pharmaceutically acceptable excipient.
Further limitations on the immunogenic composition of claim 17 are wherein the composition further comprises a second circular polyribonucleotide (claim 18), wherein the second circular polyribonucleotide comprises an open reading frame encoding an immunogen (claim 19), wherein the second circular polyribonucleotide comprises an open reading frame encoding a polypeptide adjuvant (claim 20), and wherein the second circular polyribonucleotide comprises a non-coding ribonucleic acid sequence that is an innate immune system stimulator (claim 21).
Claim 22 is drawn to a method of inducing an immune response against an immunogen in a subject, the method comprising administering to the subject the circular polyribonucleotide of claim 1.
Further limitations on the method of claim 22 are wherein the method is further comprising administering an adjuvant to the subject (claim 25); and further comprising administering a polypeptide immunogen to the subject (claim 26).
Claim 23 is drawn to a method of treating or preventing a disease, condition, or disorder in a subject, the method comprising administering to the subject the circular polyribonucleotide of claim 1.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 2, 15-19, 22, and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature, namely a naturally occurring virus, and methods of natural infection, without significantly more.
Product claims: The claims recite a circular polyribonucleotide comprising an open reading frame (ORF) comprising a sequence encoding an immunogen and a sequence encoding a multimerization domain (claim 1). Claim 2 further recites alternative arrangements of the sequence encoding the immunogen and the sequence encoding the multimerization domain. Claim 17 recites an immunogenic composition comprising the circular polyribonucleotide of claim 1 and a pharmaceutically acceptable excipient.
This judicial exception is not integrated into a practical application because, under broadest reasonable interpretation, claims 1 and 2 encompass a naturally occurring hepatitis delta virus (HDV) circular RNA genome. The instant specification defines an “immunogen” as any molecule or molecular structure that includes one or more epitopes recognized, targeted, or bound by an antibody or T-cell receptor and that induces an immune response in a subject (¶[0045]). The claims do not require that the circular polyribonucleotide be synthetic or engineered or otherwise structurally different from a naturally occurring viral RNA. The claims also do not require that the immunogen sequence and the multimerization domain sequence encode separate proteins or originate from different sources.
Cornillez-Ty et. al. (Cornillez-Ty CT, et. al. J Virol. 2003 Oct;77(19):10314-26.) explains that HDV possesses a naturally occurring, approximately 1.7-kb, minus-sense closed circular RNA genome. The HDV genome comprises an open reading frame encoding the small and large hepatitis delta antigens. Cornillez-Ty further explains that both delta antigens contain a common amino-terminal multimerization domain and that the delta antigens assemble in vivo as antiparallel coiled-coil dimers and can assume an octameric quaternary structure. The article therefore establishes that naturally occurring HDV includes a circular polyribonucleodtide comprising an open reading frame having a sequence encoding an immunogen, i.e. HDV antigen, and a sequence encoding a multimerization domain.
The HDV antigen falls within Applicant’s definition of an immunogen because it is an antigen containing epitopes recognized by the immune system. The reference expressly identifies the encoded proteins as the small and large “delta antigens”, and explains that the single antigenomic open reading frame encodes the epitopes of both delta-antigen polypeptides. The common amino-terminal region of those same proteins functions as a multimerization domain. Accordingly, the naturally occurring HDV circular RNA satisfies the limitations of claim 1. Claim 2 does not distinguish the claimed circular polyribonucleotide from naturally occurring HDV. At least alternative (a) encompasses an open reading frame (ORF) having, in a 5’ to 3’ direction, a sequence encoding an immunogenic portion of the delta antigen followed by a sequence encoding another portion of the same protein that functions as a multimerization domain, or vice versa, depending on how the functional sequence boundaries are assigned. The claim does not require that the recited sequences be separate genes, separated by a linker, or heterologous in nature. Claim 15 requires that the circular polyribonucleotide further comprises a non-coding ribonucleic acid sequence that is an innate immune system stimulator, which is inherently present in HDV as during replication, intracellular host pattern recognition receptors (PRRs) detect specific structural features of HDV viral RNA (Dandri M, et. al. Semin Immunopathol. 2021 Aug;43(4):535-548. Epub 2021 May 21.) Claim 16 notes that this innate immune response is triggered by such things as dsRNA intermediates in the HDV genome (Zhang Z, et. al. Viruses. 2020 Nov 20;12(11):1334.) Claim 17 only adds that the circular polypeptide is present in an “immunogenic composition” (¶0453]), which includes phosphate-buffered saline (PBS) and water (¶[0037][0417]), which do not markedly change the nature of the HDV, while claims 18-19 and 21 only requires a second circular polyribonucleotide in the composition; there is no requirement that said second circular polyribonucleotide differs from the first, including that the encoded immunogen is different. As a result, claims 2, 15-19, and 21 continue to encompass the naturally occurring HDV circular RNA.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception according to the stepwise analysis.
Step 2A, Prong One. Claims 1-2 and 15-16 recite a nature-based product that is naturally-occurring. A naturally occurring product necessarily lacks markedly different characteristics from itself in its natural state. The claims do not recite any structural, functional, or other characteristic that distinguishes the claimed circular polyribonucleotide from the naturally-occurring HDV circular RNA. Claims 1-2 and 15-16 therefore recite a product-of-nature exception.
Step 2A, Prong Two. Claims 1-2 and 15-16 do not include any additional element beyond the naturally occurring circular polyribonucleotide itself. The claims therefore do not integrate the product-of-nature exception into a practical application. Claim 17 only adds that the circular polyribonucleotide is present in an “immunogenic composition” with a pharmaceutically acceptable excipient, while claims 18-19 and 21 requires the presence of a second circular polyribonucleotide. As set forth supra, the specification defines such excipients as PBS and water, which do not impose a meaningful limit on the product-of-nature exception as they do not impart any markedly different structural or functional characteristic on the circular polyribonucleotide, and the second circular polyribonucleotide does not need to be different from the first. Claims 17-19 and 21 therefore do not integrate the natural product into a practical application.
Step 2B. Claims 1-2 and 15-16 contain no additional products beyond the product-of-nature exception. Claim 17 recites the addition of a pharmaceutically acceptable carrier, but such carrier does not alter the structure or function of the natural product, while claims 18-19 and 21 does not require the second circular polyribonucleotide to be different from the first. Claims 1-2, 15-19, and 21 are therefore lacking an inventive concept to transform the exception into patent-eligible subject matter.
Method claims: Claim 22 recites a method comprising administering to a subject the circular polyribonucleotide of claim 1, thereby inducing an immune response against the immunogen. As discussed above with claim 1, the claimed circular polyribonucleotide encompasses the naturally occurring RNA genome of HDV. Claim 22 does not require that the administered circular polyribonucleotide be synthetic, engineered, formulated as a vaccine, or structurally or functionally different from the naturally occurring HDV. The claim also does not require administration by a particular route or delivery of an effective amount, or induction of a protective, therapeutic, or otherwise clinically meaningful immune response. Therefore, under broadest reasonable interpretation, the administering step encompasses natural infection, as does the induction of an immune response.
Claim 22 does not recite an additional element, or combination of elements, that amounts to significantly more than the judicial exceptions. Generic administration of the naturally occurring viral RNA, followed by its inherent immunological effect, does not add an inventive concept that transforms the natural product and natural phenomenon into patent-eligible subject matter. Claim 26 further recites administration of a protein immunogen. The additional administration is recited generically and does not require a particular protein immunogen, dose, route, timing, or functional relationship with the circular polyribonucleotide. At this level of generality, the additional administration merely adds conventional immunization material to the same natural-product administration process and does not meaningfully limit the judicial exceptions or amount to significantly more.
Accordingly, claims 22 and 26 are directed to a naturally occurring circular polyribonucleotide and the natural immune response produced by natural exposure to that circular polyribonucleotide, without additional limitations that integrate the exceptions into a practical application or provide an inventive concept.
For these reasons, claims 1-2, 15-19, 21-22, and 26 are directed to products of nature and/or natural processes/correlations and are not patent eligible. One suggestion to overcome this rejection is to incorporate limitations from claims not included in this rejection into the rejected claims. Applicant is also free to argue that the claims are drawn to patent-eligible subject matter.
Claim Rejections - 35 USC § 112(a); First Paragraph
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.
Claims 1-3, 8-13, 15-23, and 25-26 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 isolated circular polyribonucleotides and compositions and methods of use thereof, does not reasonably provide enablement for any circular polyribonucleotides in any formulation, system, background, or method. 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/or use the invention commensurate in scope with these claims.
The claim is directed broadly to “a circular polyribonucleotide” without limitation as to form, environment, or method of use. As such, the claim encompasses the nucleic acid in a wide range of contexts, including incorporation into vectors, plasmids, artificial chromosomes (e.g. bacterial or yeast artificial chromosomes (BACs or YACs)), cosmids, prokaryotic and eukaryotic cells, and organismal systems (e.g. Bacteria and Archaea, Eukaryotes (including vertebrate and invertebrate animals, plants, and fungi), and viruses).
The specification does not provide guidance sufficient to enable the use of the claimed nucleic acid across this full scope, including in complex biological systems where expression, stability, and functionality may vary depending on the host environment and delivery method.
Accordingly, undue experimentation would be required to determine how to make and use the claimed nucleic acid across the full scope of the claim. It is suggested that the claim be amended to read upon “an isolated circular polyribonucleotides” [emphasis added] in order to overcome this rejection.
Claims 1-3, 8-13, 15-23, 25, 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 circular polyribonucleotides encoding a SARS-CoV-2 receptor-binding domain immunogen fused to a T4 foldon multimerization domain, including the tested LNP-formulated and adjuvanted compositions and the disclosed mouse and non-human-primate administration methods, does not reasonably provide enablement for circular polyribonucleotides encoding the full scope of immunogens and multimerization domains encompassed by the claims, the various multi-domain arrangements, additional immunogens or immunostimulatory agents, and the use of those constructs to induce an immune response or treat or prevent any claimed disease, condition, or disorder. The specification does not enable any person skilled in the art to make and use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to a circular polyribonucleotide having an open reading frame that encodes an immunogen and a multimerization domain, compositions comprising the circular polyribonucleotide, and methods of administering the circular polyribonucleotide to induce an immune response or treat or prevent a disease, condition, or disorder.
The specification describes the design and generation of circular RNAs encoding a SARS-CoV-2 RBD immunogen or an influenza hemagglutinin immunogen fused to selected multimerization domains. The disclosed construct designs include SARS-CoV-2 RBD fused to T4 foldon, β-annulus, or ferritin, as well as influenza HA fused to T4 foldon, β-annulus, or ferritin (Example 1 starting at ¶[0555-0558]). The specification demonstrates that a circular RNA encoding the SARS-CoV-2 RBD-T4 foldon construct of SEQ ID NOs: 84 and 85 expressed a trimeric product in transfected HEK293T cells (Example 2 ¶[0559-0562]). The same RBD-T4 foldon construct was evaluated for expression and immunogenicity in mice and non-human primates (Examples 3-7; ¶[0563-0585]).
However, claims 1-3, 8-13, 15-23, 25, and 26 are not limited to the disclosed RBD-T4 foldon embodiment. Claim 1 encompasses any circular polyribonucleotide having an open reading frame encoding any immunogen together with any multimerization domain. Claim 2 further encompasses several arrangements containing multiple immunogen-encoding or multimerization-domain-encoding sequences, while claim 3 encompasses T4 foldon, ferritin, β-annulus, AaLS, and lumazine synthase domains. Claim 8 includes combinations in which an immunogen is linked to both T4 foldon and ferritin. The specification further states that, when a construct includes multiple immunogens or multimerization domains, those components may be the same or different (¶[0208]).
Claims 11–13 and 15–21 add further breadth through a second open reading frame, a second immunogen, a polypeptide adjuvant, a noncoding innate-immune stimulator, or a second circular polyribonucleotide encoding such a component. Claims 22, 23, 25, and 26 encompass administration of the broadly claimed circular polyribonucleotide to induce an immune response or to treat or prevent a disease, condition, or disorder, with or without an additional adjuvant or protein immunogen. The claimed scope therefore extends well beyond the RBD-T4 foldon constructs for which expression and immunogenicity results are reported.
State of the prior art and predictability of the art. At the time the application was filed, it was known that SARS-CoV-2 antigens could be fused to several different protein scaffolds. Jerala et. al. (WO 2022/043449 A1) teaches that foldon directs trimerization of an antigen, while ferritin and lumazine synthase form substantially larger protein assemblies. Jerala also teaches β-annulus as a short peptide that forms nanoparticles and explains that the size, structure, and trafficking of a scaffolded antigen affect presentation to the immune system (pp. 5–8 and Examples 5-11.) Jerala further identifies a material problem with this approach: an immune response may be directed against the scaffolding protein itself, which may impair later immunizations or eliminate cells producing a scaffold-containing antigen. The reference did not treat all scaffolds as interchangeable. Instead, Jerala prepared and tested different RBD-scaffold constructs, measured their expression and antibody responses, and separately evaluated trafficking and neutralization. The reported RBD-β-annulus protein remained in lymph nodes longer than monomeric RBD, while the scaffolded constructs were tested individually to determine whether they produced the desired immune response (p. 6 and Examples 5-11.)
Rauch et al. (WO2021156267A1) likewise teaches a broad set of nucleic-acid vaccine formats, including mRNA, self-replicating RNA, circular RNA, viral RNA, and replicon RNA. For coronavirus antigens, Rauch identifies foldon, ferritin, and lumazine synthase as different trimerization or antigen-clustering elements. The reference states that a circular RNA may encode a SARS-CoV-2 antigen, but it provides separate sequence-defined constructs for particular spike, RBD, foldon, ferritin, and lumazine-synthase combinations rather than a general rule showing that every immunogen-scaffold combination would express, assemble, and produce an immune response (See e.g. List 1 starting at p. 36). Rauch specifically identifies a truncated RBD-foldon construct, truncated RBD-ferritin construct, and truncated RBD-lumazine-synthase constructs having particular disclosed sequences. Rauch also explains that foldon promotes trimerization (p. 33, “Trimerization elements”), ferritin forms a 24 subunit particle (p. 32, ¶1), and lumazine synthase has particle-forming properties (p. 31, ¶4-6). These teachings confirm that the multimerization domains encompassed by claim 3 differ in size, structure, stoichiometry, and mechanism of assembly.
The prior art therefore shows that selecting a known immunogen and a known multimerization domain did not by itself establish that the resulting fusion would be properly expressed, remain soluble, retain relevant epitopes, form the intended multimeric structure, reach appropriate immune tissues, and induce a useful immune response. The art was not sufficiently predictable to support extrapolation from the disclosed SARS-CoV-2 RBD-T4 foldon construct to any immunogen fused to any claimed multimerization domain, much less to constructs containing multiple immunogens, two different multimerization domains, additional immune-stimulatory cargo, or a second circular polyribonucleotide.
Accordingly, the results obtained using SARS-CoV-2 RBD fused to T4 foldon would not have reasonably established that the broader claimed scope could be practiced without further experimentation.
Level of skill in the art. One skilled in the art would have been familiar with nucleic-acid design, in vitro transcription, RNA circularization, sequence optimization, mammalian-cell transfection, LNP formulation, protein-expression assays, native gel electrophoresis, ELISA, ELISpot, and animal immunization studies. One skilled in the art also could have prepared candidate fusion constructs and measured expression, multimerization, antibody binding, cellular responses, and neutralization.
However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further experimentation, which additional immunogen and multimerization-domain combinations would be expressed from circular RNA and would assemble into an immunogenic product. Nor would those methods identify in advance which multi-domain arrangements, secondary ORFs, adjuvant polypeptides, noncoding immune stimulators, or combined circRNA formulations would retain the claimed biological activity.
Working examples. The specification provides working data in Examples 2-6 directed to a circular RNA encoding the SARS-CoV-2 RBD immunogen fused to a T4 foldon multimerization domain. Example 2 reports expression and trimer formation in HEK293T cells. Examples 3 and 4 report expression and immune responses in mice, and Examples 5 and 6 report expression and antibody responses in non-human primates (¶[0559-0584]).
Example 1 identifies additional construct designs containing ferritin or β-annulus and an influenza HA immunogen, but it does not report that those additional constructs were evaluated throughout the expression, assembly, and immunogenicity studies performed for RBD-T4 foldon (¶[0555-0558]). Example 7 describes collection and testing of primate samples but does not report a result (¶[0585]). Examples 8-12 describe circular RNAs that “are designed,” “are administered,” or “will be expected” to produce a result, rather than reporting completed experiments (¶[0586-0597]).
The specification does not provide working examples directed to an AaLS construct, a lumazine-synthase construct, an immunogen fused to both foldon and ferritin, or the various repeated immunogen and multimerization-domain arrangements encompassed by claims 2 and 8. The specification also does not provide working examples establishing expression and immunogenicity for the claimed second ORFs, second circular polyribonucleotides, polypeptide adjuvants, noncoding innate-immune stimulators, or treatment of the unrestricted range of diseases encompassed by claim 23. The disclosed examples therefore do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides guidance regarding the preparation and purification of circular RNA, the use of IRES elements and secretion signals, LNP formulation, administration to mice or non-human primates, and assays for measuring expression and immune responses (¶[0555–0597]). The specification also identifies several immunogen and multimerization-domain sequences and provides tables showing possible orders of those components.
However, the specification does not provide sufficient guidance regarding how to select compatible immunogens and multimerization domains across the claimed scope. The disclosure does not explain how one skilled in the art could determine in advance whether a selected fusion would fold correctly, remain soluble, preserve the relevant antigenic conformation, assemble with the intended stoichiometry, avoid aggregation, or remain accessible to the immune system.
The specification also does not explain how the relative position or copy number of the immunogen and multimerization domains affects circular-RNA translation, secretion, assembly, or immunogenicity. This concern is more pronounced for claim 8, which encompasses constructs containing both foldon and ferritin, and for claims 11-21, which add separate coding or noncoding immune-stimulatory elements. The disclosure provides possible components, but it does not provide a selection rule that distinguishes workable combinations from combinations that would not produce the claimed result.
For the method claims, the specification does not identify which broadly encompassed immunogens and constructs would induce an immune response in a particular subject, nor does it establish that administration of those constructs would treat or prevent the full range of diseases, conditions, or disorders encompassed by claim 23. A showing that an RBD-T4 foldon construct produces SARS-CoV-2-specific antibodies does not establish that any claimed immunogen-multimerization construct would provide an effective composition for an unrelated infectious disease, tumor, allergy, toxin, or other condition.
Quantity of experimentation necessary. To practice the full scope of the claims, one skilled in the art would need to select an immunogen and one or more multimerization domains, determine an appropriate domain order and linker arrangement, prepare the encoding circular RNA, and evaluate translation and secretion. The resulting protein would then need to be tested for folding, solubility, multimerization, antigenic conformation, and biological stability. Constructs that passed those initial tests would still need to be formulated and evaluated to determine whether they induced the intended immune response and, for claim 23, whether they treated or prevented the selected disease, condition, or disorder. For constructs containing a second ORF, a second circular polyribonucleotide, or an immune-stimulatory component, one skilled in the art would additionally need to determine whether the components were expressed at compatible levels and whether the combination improved, reduced, or qualitatively changed the immune response. This would require more than confirming that each component could be produced separately. The combined construct or composition would need to be tested because one component could alter RNA stability, expression, protein assembly, reactogenicity, antigen presentation, or the response directed against another component.
Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test additional embodiments to determine whether they express an appropriately assembled immunogen and induce the claimed immune response or therapeutic result. Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays; instead, the relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, one skilled in the art would need to prepare and test additional circular RNAs, fusion proteins, multi-domain arrangements, formulations, and combination compositions to determine which embodiments satisfy the claimed function or result.
Amgen. The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610–13 (2023).
In the instantly claimed invention, the specification provides working data for a circular RNA encoding SARS-CoV-2 RBD fused to T4 foldon, including expression and immunogenicity in mice and non-human primates. The claims also encompass any immunogen, several structurally different multimerization domains, repeated or mixed-domain arrangements, additional coding and noncoding immune stimulators, combined circular-RNA compositions, and methods directed to an unrestricted range of diseases and immune responses. The specification does not identify a general quality or provide sufficient guidance that would allow one skilled in the art to practice that broader scope without preparing and testing additional constructs.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and use the full scope of the invention recited in claims 1-3, 8-13, 15-23, 25, and 26 without undue experimentation.
Claims 1-3, 8-13, 15-23, 25, and 26 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
The written description requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement, the specification must reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention as of the filing date. Possession may be shown by a description of the complete structure of the claimed invention, a representative number of species falling within the scope of a claimed genus, or relevant identifying characteristics sufficient to show that the inventor had possession of the claimed subject matter.
Claims 1-3 and 8-10 recite circular polyribonucleotides comprising an open reading frame having a sequence encoding an immunogen and a sequence encoding a multimerization domain. Claim 2 recites several possible arrangements of immunogen-encoding and multimerization-domain-encoding sequences. Claim 3 limits the multimerization domain to T4 foldon, ferritin, β-annulus, AaLS, or lumazine synthase, while claim 8 recites additional arrangements containing specified multimerization domains. Claims 9 and 10 further recite a secretion signal and an IRES, respectively.
The specification describes circular RNAs designed to encode a SARS-CoV-2 RBD immunogen or an influenza HA immunogen fused to T4 foldon, β-annulus, or ferritin (Example 1 at ¶[0555-0558]). The specification provides nucleotide and amino acid sequences for these particular constructs. The specification further describes a circular RNA encoding SARS-CoV-2 RBD fused to T4 foldon, identified by nucleic acid SEQ ID NO: 84 and amino acid SEQ ID NO: 85 (Example 2 at ¶[0559-0562]). Expression and trimer formation were demonstrated for this RBD-T4 foldon construct in HEK293T cells, and the same construct was administered to mice and non-human primates (¶[0559–0584]).
However, the scope of claims 1-3 and 8-10 is not limited to the embodiments described in the specification. Claim 1 broadly encompasses a circular polyribonucleotide encoding any immunogen and any multimerization domain, and the claim does not limit the immunogen by sequence, source, pathogen, disease, structure, epitope, or recognized class. It also does not require that the encoded immunogen preserve a particular conformation or induce a specified type or degree of immune response.
The specification defines an immunogen broadly as “any molecule or molecular structure that includes one or more epitopes recognized, targeted, or bound by an antibody or a T cell receptor.” (¶[0045]). The disclosure extends that term to immunogens from viruses, bacteria, fungi, parasites, tumors, allergens, toxins, venoms, and other sources. It further states that an immunogen “may be any proteinaceous molecule that can be produced.” (¶[0109-0149][0180]). These statements describe a desired category of cargo, but they do not identify structural features common to the full claimed genus of immunogens.
The specification does not describe a sufficient number of species representative of this scope. The working disclosure is centered on one SARS-CoV-2 RBD-T4 foldon construct. Influenza HA, RSV F, human metapneumovirus F, VZV antigens, and constructs containing other multimerization domains are identified or proposed, but the specification does not provide representative completed constructs across the many unrelated immunogen classes encompassed by claim 1. A SARS-CoV-2 receptor-binding domain is not structurally representative of every viral protein, bacterial antigen, fungal antigen, parasite protein, tumor antigen, allergen, toxin, or other molecule falling within the definition of “immunogen.”
The claimed immunogens are defined, at least in part, by the recited function of containing an epitope recognized by an antibody or T-cell receptor and inducing an immune response. However, the specification does not establish a correlation between the disclosed structural features and that function sufficient to identify the additional immunogens falling within the scope of the claims. The specification describes particular RBD and influenza HA sequences, but it does not identify structural features common to the broader genus which would allow one skilled in the art to recognize every additional immunogen encompassed by claim 1. The disclosure of the desired immunological function, together with a catalogue of possible antigen sources, does not demonstrate possession of the full claimed genus.
The same concern applies to the claimed multimerization domains. The specification defines a multimerization domain by the function of self-assembling to form dimers, trimers, tetramers, or other oligomers (¶[0055]). Claim 1 is not limited to the domains specifically described in the application. It therefore encompasses any known or later-identified polypeptide segment capable of producing any multimeric state when encoded with an immunogen.
The specification provides sequences for selected foldon, ferritin, β-annulus, AaLS, lumazine-synthase, and related domains (¶[0195-0208]). Those domains differ substantially in length, structure, assembly mechanism, and the size of the resulting complex. The specification does not identify structural features common to the broader functional genus of multimerization domains or explain how one skilled in the art could recognize additional members from structure alone. The statement that a domain self-assembles describes the result to be achieved, but it does not show possession of every structure capable of producing that result.
The specification describes the RBD-T4 foldon construct of SEQ ID NOs: 84 and 85 and proposed constructs containing selected immunogens and scaffolds. However, claims 1-3 and 8-10 are not limited to those constructs. The claims encompass constructs that differ in the identity and size of the immunogen, the type of multimerization domain, copy number, domain order, linker arrangement, secretion signal, and IRES. Claims 2 and 8 further encompass repeated or mixed arrangements containing more than one immunogen-encoding sequence or more than one multimerization-domain-encoding sequence. The specification provides schematic arrangements and states that multiple immunogens or multimerization domains may be the same or different (¶[0208]). However, it does not describe representative complete constructs across that scope. In particular, the specification does not describe an actual construct containing both T4 foldon and ferritin as recited in claim 8, nor does it describe representative constructs containing different immunogens or different multimerization domains repeated in the various claimed orders. The disclosure of possible component arrangements does not, by itself, demonstrate possession of the substantially broader group of completed circular polyribonucleotides encompassed by the claims.
Claim 3 does not cure the deficiency of claim 1. Although claim 3 limits the multimerization domain to five identified alternatives, it continues to encompass each listed domain fused to any immunogen within the broad functional genus of claim 1. Disclosure of selected SARS-CoV-2 RBD and influenza HA constructs does not reasonably convey possession of circular polyribonucleotides encoding every immunogen fused to T4 foldon, ferritin, β-annulus, AaLS, or lumazine synthase. Claims 11-13 and 15-16 add a second open reading frame, a second immunogen, a polypeptide adjuvant, or a noncoding RNA sequence that stimulates the innate immune system. The specification identifies possible adjuvant classes and innate immune system stimulators (¶[0382][0404]). It also provides schematic depictions of circular RNAs containing two expression sequences. However, the specification does not describe representative complete constructs across the claimed scope or identify characteristics common to the broad range of additional cargo that may be combined with any immunogen-multimerization-domain construct encompassed by claim 1.
Claim 13 broadly permits the second polypeptide to be a cytokine, chemokine, costimulatory molecule, innate immune system stimulator, signaling molecule, transcriptional activator, cytokine receptor, bacterial component, or component of the innate immune system. These are materially different classes of molecules with no common structure identified in the specification. The disclosure of these categories as possible second products does not reasonably convey possession of circular polyribonucleotides encoding every member of those classes in combination with the full genus incorporated from claim 1.
Claims 15 and 16 similarly define the additional noncoding RNA, at least in part, by the function of stimulating the innate immune system. The specification identifies examples such as GU-rich, AU-rich, double-stranded, or aptamer-containing sequences. However, it does not identify structural features sufficient to distinguish the full group of operative noncoding stimulators from other RNA sequences or describe representative circular polyribonucleotides containing such sequences across the claimed scope.
Claims 17-21 recite immunogenic compositions comprising the circular polyribonucleotide of claim 1 and, in claims 18-21, a second circular polyribonucleotide encoding another immunogen, a polypeptide adjuvant, or a noncoding innate immune system stimulator. The specification describes LNP-formulated and adjuvanted compositions containing the SARS-CoV-2 RBD-T4 foldon circular RNA (Figs. 11-13; ¶[0574–0584]). It also schematically describes compositions containing a first and second circular RNA.
However, claims 17-21 broadly encompass compositions containing any circular polyribonucleotide within claim 1, together with any pharmaceutically acceptable excipient and the broadly recited second circular RNA components. The specification does not describe representative compositions across that scope or identify characteristics sufficient to show possession of the broader group of combinations. Disclosure of LNP-formulated and AddaSO3-admixed RBD-T4 foldon circular RNA does not reasonably convey possession of compositions containing every claimed immunogen-multimerization construct, alone or with the substantially broader range of second circular RNAs encompassed by claims 18-21.
Claims 22, 25, and 26 recite methods of inducing an immune response against an immunogen by administering the circular polyribonucleotide of claim 1, with claims 25 and 26 further reciting administration of an adjuvant or protein immunogen, respectively. The specification describes administration of circular RNA encoding SARS-CoV-2 RBD or SARS-CoV-2 RBD-T4 foldon to mice and non-human primates. The reported results concern RBD-specific antibodies, T-cell responses, and SARS-CoV-2 neutralizing antibodies (Figs. 8-12; ¶[0568-0584]).
However, claims 22 and 25-26 are not limited to SARS-CoV-2 RBD, T4 foldon, the tested formulations, or the disclosed immune responses. These claims encompass administration of any circular polyribonucleotide within claim 1 to induce any immune response against any immunogen, optionally with any adjuvant or protein immunogen. The specification does not describe representative methods using unrelated immunogens and multimerization domains or otherwise demonstrate possession of methods spanning the entire claimed genus. The disclosed RBD-specific response does not reasonably convey possession of methods using every viral antigen, bacterial antigen, tumor antigen, allergen, toxin, or other claimed immunogen.
Claim 23 recites treating or preventing a disease, condition, or disorder by administering the circular polyribonucleotide of claim 1. The specification describes immune responses directed to SARS-CoV-2 RBD and proposes additional vaccine constructs. However, claim 23 does not require that the encoded immunogen be associated with the disease being treated or prevented. It does not limit the claimed disease, condition, or disorder by cause, pathology, affected tissue, subject population, or therapeutic mechanism.
The specification does not describe representative treatment methods across that unrestricted scope or otherwise reasonably convey possession of using the claimed circular polyribonucleotides to treat or prevent every disease, condition, or disorder. A demonstration that an RBD-T4 foldon circular RNA induces SARS-CoV-2-specific antibodies does not show possession of treating unrelated infections, cancers, allergies, toxin exposure, autoimmune conditions, metabolic disorders, or other states of suboptimal health encompassed by claim 23. General statements that the compositions “may be used to treat or prevent a disease, disorder, or condition” do not provide a description of the claimed therapeutic genus (¶[0002][0089][0443]).
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventors had possession of the full scope of the subject matter recited in claims 1-3, 8-13, 15-23, 25, and 26 at the time the application was filed. The dependent claims do not cure the deficiency discussed above because they continue to encompass circular polyribonucleotides encoding any immunogen within the unsupported genus of claim 1. The additional limitations concerning sequence arrangement, selected multimerization domains, secretion signals, IRES elements, additional coding or noncoding cargo, compositions, subject identity, and coadministration do not provide adequate written-description support for the broader subject matter incorporated from claim 1.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 8-13, 17-20, 22-23, and 25-26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rauch et. al. (WO2021156267A1; Pub. 08/12/2021; hereafter “Rauch”.)
The Prior Art
Rauch teaches nucleic acids useful in the treatment of COVID-19 disease, the disease associated with infection from severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)(entire document; see abstract.) Rauch teaches that said nucleic acids used in the treatment may be RNA (reference claims 48-56), and that said RNA is coding RNA (reference claim 49) and may be circular RNA or replicon RNA (reference claim 50). Rauch teaches that the nucleic acid would encode an immunogenic fragment of a peptide or protein derived from SARS-CoV-2 (reference claim 1), and that said peptide or protein may be attached to a trimerization element (reference claims 22-23), such as a ferritin element, a lumazine synthase element, a surface antigen of Hepatitis B virus (HBsAg), or encapsuling (reference claim 24) or a foldon element (reference claim 26). Rauch therefore teaches the limitations of instant claims 1 and 3.
Rauch teaches that the full-length SARS-CoV-2 S protein may comprise a secretory signal peptide (p. 18, lines 30-35; instant claim 9). Rauch teaches that the nucleic acid may comprise at least two different antigenic peptides, and that said peptides may each be under the control of an IRES, as the IRES can separate the coding sequences in a bicistronic or multicistronic system (p. 55, ¶4; instant claims 10-12). Rauch teaches the nucleic acid system can encode polypeptide adjuvants (p. 30, ¶7; instant claim 13). Rauch teaches adjuvants used in the system may elicit innate immune responses (pp. 106-107, ¶ bridging pages), and that suitable immunologic adjuvant sequences are known in the art (p. 31, ¶1). Rauch teaches the nucleic acids may be in immunogenic compositions (p. 9, ¶4) that comprise pharmaceutically acceptable carriers or excipients (p. 80, ¶4; instant claim 17). Rauch teaches that there may be one or more nucleic acids in the composition (p. 114¶3; p. 93, ¶3; p. 151, ¶1; instant claims 18-20). Rauch teaches the nucleic acid compositions may be used to treat or prevent a disorder, wherein the method comprises applying or administering to a subject in need thereof the nucleic acid compositions (reference claim 170), wherein said disorder treated is an infection with SARS-CoV-2 (reference claim 171; instant claim 23). Rauch teaches a method of inducing an immune response in a subject, wherein the method comprises administering to the subject at least a first composition comprising the RNA nucleic acid (reference claim 193; instant claims 22, 26), wherein said method may comprise administering an adjuvant (“the term “adjuvant”; instant claim 25). Rauch teaches at least SEQ ID NO: 58, which is a fusion protein of SARS-CoV-2 S protein lacking a transmembrane (TM) domain fused to a lumazine synthase at its C terminus (instant claim 2), and also teaches SEQ ID NO: 67, which is a fusion protein of SARS-CoV-2 S protein lacking a transmembrane (TM) domain fused to a ferritin domain at its C terminus (instant claim 8).
For at least these reasons, Rauch teaches the limitations of instant claims 1-3, 8-13, 17-20, 22-23, and 25-26, and anticipates the instant invention encompassed by said claims.
Claims 1-3, 8-13, 15-23, and 25-26 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Kahvejian et. al. (US20230193311A1; Pub. 06/22/2023; Priority 05/20/2020; hereafter “Kahvejian”) as evidenced by Kanekiyo et. al. (Kanekiyo M, et. al. Nature. 2013 Jul 4;499(7456):102-6. Epub 2013 May 22.; hereafter “Kanekiyo”) and Yassine et. al. (Yassine HM, et. al. Nat Med. 2015 Sep;21(9):1065-70. Epub 2015 Aug 24.; hereafter “Yassine”.)
The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
The Prior Art
Kahvejian teaches a circular polyribonucleotide encoding one or more immunogenic polypeptides (entire document; see abstract), wherein said immunogen may be fused to a multimerization domain, such as a foldon domain (¶[0672][0677]; instant claims 1, 3). Kahvejian teaches the NIHGen6HASS-foldon construct, as taught by Yassine, wherein Kanekiyo provides the structure for the HA-foldon fusion protein in Fig. 1, showing that the foldon domain was fused to the C-terminus of HA (instant claims 2, 8). Kahvejian teaches the immunogen may be a secreted protein and have a secretion signal sequence (¶[0322]; instant claim 9). Kahvejian teaches the circular polyribonucleotide may include one or more immunogenic sequences (reference claim 19) and can also include one or more internal ribosome entry site (IRES) element(s) that are operably linked to the one or more immunogenic sequences (¶[0334]; reference claim 24; instant claims 10-12). Kahvejian teaches the immunogenic sequence may be a polypeptide adjuvant (¶[0017][0612-0614]; instant claim 13), such as an innate immune system stimulator, such as a GU-rich motif, an AU-rich motif, dsRNA, or an aptamer (¶[0017]; instant claims 15-16). Kahvejian teaches the circRNA composition may be a pharmaceutical composition with a pharmaceutically acceptable excipient (reference claim 40; instant claim 17), and may comprise an adjuvant (reference claim 41). Kahvejian teaches that the composition may comprise one or more circular polyribonucleotides (¶[0061][0065]; instant claims 18-19), and since Kahvejian teaches the circular polyribonucleotides may encode immunogens (¶[0154]) or adjuvants (¶[0138]), and that adjuvants may be immunogenic proteins derived from other systems, such as bacteria (¶[0614]), Kahvejian teaches that the adjuvants may be encoded by the circular polyribonucleotides (instant claims 13, 20-21). Kahvejian teaches a method of inducing an immune response against an immunogen in a subject comprising administering to the subject the circular polyribonucleotide encoding the immunogen (reference claim 48; instant claim 22). Kahvejian teaches a method of treating or preventing a disease, disorder, or condition in a subject, the method comprising administering to the subject the circular polyribonucleotide encoding the immunogen (reference claim 43; instant claim 23). Kahvejian teaches that the methods may comprise administering an adjuvant (reference claims 49-50; instant claim 25) and that a further polypeptide immunogen may be administered to the subject (reference claim 54; instant claim 26).
Kahvejian therefore teaches, as evidenced by Yassine and Kanekiyo, every aspect of instant claims 1-3, 8-13, 15-23, and 25-26, and anticipates the invention encompassed by said claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 15-16 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Rauch as applied to claims 1-3, 8-13, 17-20, 22-23, and 25-26, above, and further in view of Stewart et. al. (US20200306286A1; Pub. 10/01/2020; hereafter “Stewart”) and Bruno (Bruno JG. Pharmaceuticals (Basel). 2018 Jun 23;11(3):62.; hereafter “Bruno”.)
The Prior Art
The teachings of Rauch have been set forth supra. While Rauch teaches that circular RNAs and replicons can deliver the immunogen-multimeric domain fusion proteins of the instant claims, and Rauch teaches that the nucleic acid may encode immunogenic adjuvanting proteins, Rauch fails to teach the inclusion of certain RNA structures known to cause an innate immune response, such as dsRNA, and Rausch actually actively appears to teach how to mask the RNA from certain innate immune responses. However, the use of certain RNA elements may be beneficial to not only allow for self-regulation of the circRNA elements, but can also stimulate the innate immune response in an adjuvanting manner, such as with the use of aptamers, as taught by Stewart.
Stewart teaches pharmaceutical compositions and preparations of circular polyribonucleotides and uses thereof (entire document; see abstract.) Stewart teaches the circular polyribonucleotides may encode therapeutic proteins (¶[0152]). Stewart teaches the circular polyribonucleotide may include an aptamer sequence, such as an RNA aptamer binding lysozyme (¶[0235][0255-0258][0261]).
Bruno teaches that while aptamers are generally considered non-immunogenic, that they may act like pathogen-associated molecular patterns (PAMPs), but strategies are available to make them more or less immunogenic, depending on the system in which they are used and the desired immune response (entire document; see abstract.)
Given the teachings of Rausch, one of skill in the art would be inclined to include adjuvanting materials in the circRNA structures. Given the teachings of Stewart, one of skill in the art would be motivated to use aptamers as regulatory elements in circular polyribonucleotides. While the art generally recognizes these aptamers as non-immunogenic, under certain conditions, as taught by Bruno, said sequences may stimulate the innate immune response through acting like pathogen-associated molecular patterns (PAMPs), but strategies are available to curtail the type and strength of immune response to these elements, as taught by Bruno. Therefore, given the teachings of Rausch, Stewart, and Bruno, it would be obvious to try and use aptamers in the circular RNA systems of Rausch to regulate expression of the immunogenic proteins from the circRNA and possibly elicit a beneficial adjuvanting immune response to the expressed heterologous proteins, thus making the limitations of instant claims 15-16 and 21 obvious to a skilled artisan.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Rauch in order to include elements such as aptamers in the circRNA, thereby allowing for self-regulation and possibly adjuvanting the system as well. One would have been motivated to do so, given the suggestion by Stewart that aptamers could be used in circRNA systems to help regulate expression of the therapeutic proteins from said systems. There would have been a reasonable expectation of success, given the knowledge that the aptamers could be adjusted, as necessary, to elicit or quell any immune response, as taught by Bruno. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 8-13, 15-23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8-9, 12-13, 15, 17, 19-20, 22, 27, 29-30, and 34-36 of copending Application No. 18/712,359 (reference application) in view of Ciaramella (US20200069793A1). Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming circular polyribonucleotides encoding immunogenic proteins, wherein said immunogens have multimerization domains and signal sequences. Both claim the presence of additional immunogenic peptides. Both claim the presence of additional adjuvants, and the presence of the circRNA in an immunogenic composition. Both claim the use of the circRNA in methods of inducing an immune response in a subject or of preventing or treating a disorder using said circRNA. The main difference is that the reference ‘359 claims are drawn to the immunogen being from varicella zoster virus (VZV), with specific glycoproteins and mutants thereof being the immunogens. However, VZV vaccines, and immunogenic proteins thereof, were well-known in the art at the time of filing, as evidenced by the teachings of Ciaramella, which teach VZV RNA compositions, sequences for said VZV glycoproteins, with specific mutations such as Y582G mutations, and immunogenic compositions thereof. Therefore, the ‘359 claims are an obvious species of the instant claims, especially given the teachings of Ciaramella.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 8-13, 15-23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-9, 16, 18, 20-22, 24, 30-32, and 35-36 of copending Application No. 18/712,356 (reference application) in view of Rauch (supra) and Stewart-Jones (US20230346914A1; Priority 02/07/2020; hereafter “Stewart-Jones”.) Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming circular polyribonucleotides encoding immunogenic proteins, wherein said immunogens have multimerization domains and signal sequences. Both claim the presence of additional immunogenic peptides. Both claim the presence of additional adjuvants, and the presence of the circRNA in an immunogenic composition. Both claim the use of the circRNA in methods of inducing an immune response in a subject or of preventing or treating a disorder using said circRNA. The main difference is that the reference ‘356 claims are drawn to the immunogens being from coronavirus (CoV) and influenza virus, with specific glycoproteins and mutants thereof being the immunogens. However, CoV and influenza vaccines, and immunogenic proteins thereof, were well-known in the art at the time of filing, as evidenced by the teachings of Stewart-Jones and Rauch. The teachings of Rauch have been detailed supra. Stewart-Jones which teaches CoV and influenza RNA compositions, sequences for glycoproteins and antigenic proteins from both respiratory viruses, with specific mutations to stabilize the spike protein of CoV, and immunogenic compositions thereof. Therefore, the ‘356 claims are an obvious species of the instant claims, especially given the teachings of Rauch and Stewart-Jones.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 8-13, 15-23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 11, 13, 16, 35, 45, 47, 51, 59-69 of copending Application No. 18/024,542 (reference application) in view of Rauch (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming circular polyribonucleotides encoding immunogenic proteins. Both claim the presence of additional immunogenic peptides, the use of IRES elements, and the expression of innate immune stimulators. Both claim the presence of additional adjuvants, and the presence of the circRNA in an immunogenic composition. Both claim the use of the circRNA in methods of inducing an immune response in a subject or of preventing or treating a disorder using said circRNA. The main difference is that the instant claims require that the immunogen be fused to a multimerization domain, but such a limitation would be obvious, given the teachings of Rauch (detailed supra). Therefore, the ‘542 claims are an obvious variation of the instant claims, given what was known in the art at the time of filing, as evidenced by Rauch.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 8-13, 15-23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 73-82 of copending Application No. 17/926,254 (reference application) in view of John et. al. (US20200129615A1). Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming circular polyribonucleotides encoding multiple immunogenic proteins and the use of IRES elements. Both claim the presence of adjuvants, and the presence of the circRNA in an immunogenic composition. Both claim the use of the circRNA in methods of inducing an immune response in a subject or of preventing or treating a disorder using said circRNA. The main difference is that the reference ‘254 claims are drawn to the immunogens being from herpes simplex virus (HSV), and the instant claims require the presence of multimerization domains on the proteins. However, HSV vaccines, and immunogenic proteins thereof, were well-known in the art at the time of filing, as evidenced by the teachings of John, which teach HSV RNA compositions, sequences for HSV immunogens and glycoproteins, the use of multimerization domains (such as foldon domains) attached to the immunogens, and immunogenic compositions thereof. Therefore, the ‘254 claims are an obvious species of the instant claims, especially given the teachings of John.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 8-13, 15-23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-9, 11, 15-18, and 21 of copending Application No. 17/925,920 (reference application) in view of Rauch (supra) and Stewart-Jones (US20230346914A1; Priority 02/07/2020; hereafter “Stewart-Jones”.) Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming circular polyribonucleotides encoding multiple immunogenic proteins. Both claim the presence of the circRNA in an immunogenic composition. Both claim the use of the circRNA in methods of inducing an immune response in a subject or of preventing or treating a disorder using said circRNA. The main difference is that the reference ‘920 claims are drawn to the immunogens being from coronavirus (CoV) and influenza virus, with specific glycoproteins and mutants thereof being the immunogens, and the instant claims require the presence of multimerization domains fused to the immunogens. However, CoV and influenza vaccines, and immunogenic proteins thereof, as well as the use of multimerization domains for surface glycoproteins of viral antigens, were well-known in the art at the time of filing, as evidenced by the teachings of Stewart-Jones and Rauch. The teachings of Rauch have been detailed supra. Stewart-Jones which teaches CoV and influenza RNA compositions, sequences for glycoproteins and antigenic proteins from both respiratory viruses, with specific mutations to stabilize the spike protein of CoV, and immunogenic compositions thereof. Therefore, the ‘920 claims are an obvious species of the instant claims, especially given the teachings of Rauch and Stewart-Jones.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 8-13, 15-23, and 25-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 19, 24-26, 28-29, 40-41, 43, 48-49, 52, 54 of copending Application No. 17/925,966 (reference application) in view of Rauch (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming circular polyribonucleotides encoding multiple immunogenic proteins. Both claim the presence of additional immunogenic peptides, such as adjuvants, and the use of IRES elements. Both claim the use of circRNA in an immunogenic composition. Both claim the use of the circRNA in methods of inducing an immune response in a subject or of preventing or treating a disorder using said circRNA. The main difference is that the instant claims require that the immunogen be fused to a multimerization domain, but such a limitation would be obvious, given the teachings of Rauch (detailed supra). Therefore, the ‘966 claims are an obvious variation of the instant claims, given what was known in the art at the time of filing, as evidenced by Rauch.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Within and up to a year from the effective filing date of the instant application, multiple public disclosures appear to have been made regarding technology similar to the instantly claimed invention. Similarly, there are also multiple disclosures that qualify as art under 35 USC 102(a)(2), yet have a common inventor and/or assignee. A comprehensive list of those disclosures is provided below; while the Office has, in good faith, attempted to compile every disclosure, the Office acknowledges that there may be other disclosures not yet of record.
With respect to disqualifying these disclosures, 37 CFR 1.130(a) discusses an “appropriate affidavit or disclosure to disqualify a disclosure as prior art by establishing that the disclosure was made by the inventor or a joint inventor.” This rule focuses on disqualifying a particular disclosure, and there is no way to provide a “blanket disclosure” that would cover any and all qualifying prior art disclosures of “circular polyribonucleotides” as instantly claimed. In other words, the Applicant cannot provide a declaration/affidavit which states that “Every listed disclosure of “circular polyribonucleotides” originated with us.”
MPEP §717.01(a)(1) is consistent with the reading of 37 CFR 1.130(a). It gives several factors to consider when evaluating a 1.130(a) declaration – for example, it requires that the declaration give “a reasonable explanation of the presence of additional authors” on the disclosure. MPEP §717.01(a)(1) also instructs:
“The evidence necessary to show that the disclosure is by the inventor or a joint inventor or another who obtained the subject matter disclosed from the inventor or a joint inventor requires case-by-case analysis, depending upon whether it is apparent from the disclosure itself or the patent application specification that the disclosure is an inventor originated disclosure.”
The requirement for “case-by-case analysis” has convinced the Office that not only does each disclosure have to be accounted for individually, as said references may still be applied in the application if it otherwise qualifies as prior art and no sufficient 37 CFR 1.130(a) declaration is of record in the present application. If the attribution facts apply to the noted references, that evidence may be provided and disqualify the relied-upon disclosure as prior art once properly made of record or otherwise considered.
Again, the Office has attempted in the interest of compact prosecution to provide as comprehensive of a list as possible so that Applicant may, if applicable, attempt to disqualify the noted references as prior art.
The following patent documents have a common inventor and/or assignee to the instant claims; potential prior art that was not rejected due to being redundant to those rejections set forth supra.
US20230212629A1
WO2022051629A1
US20230203192A1
WO2021236980A1
US20240009298A1
US20230181722A1
US20250188505A1
US20240181079A1
US20240263206A1
US20240002886A1
US20260055430A1
US20240084334A1
US20240252682A1
US20240263153A1
US20240082429A1
US20240200104A1
US20240042058A1
US20240240219A1
US20240417714A1
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
Prosecution Insights