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 .
DETAILED ACTION
Disposition of Claims
Claims 1-5, 8-9, 12-13, 15, 17, 19-20, 22, 27, 29-30, and 34-36 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250368688A1, Published 12/04/2025.
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/05/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
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 e.g. “www.nature.com/articles/nature17978” ¶[0165]; and “https://doi.org/10.1016/j.apsb.2016.02.001” ¶[0392].
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 5 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 5 is drawn to the circular polyribonucleotide of claim 4, wherein:
(a) the VZV glycoprotein is a mutational variant of VZV gE, or an immunogenic fragment thereof, comprising no more than 10 amino acid substitutions, deletions, or insertions relative to wild-type VZV gE;
(b) the VZV gE polypeptide is a truncated polypeptide lacking an anchor domain (ER retention domain): or
(c) the VZV gE polypeptide is a truncated polypeptide lacking a carboxy terminal tail domain.
First, the term “wild-type VZV gE” is a relative term, as there are naturally occurring variant isolates of this viral protein. As far as VZV itself, wild-type strains divide into five primary phylogenetic clades (and up to nine distinct genotypes) based on genome-wide single nucleotide polymorphisms (Grose C. J Virol. 2012 Sep;86(18):9558-65. Epub 2012 Jul 3.) While the gE protein remains relatively genetically stable, naturally-occurring, stable VZV gE (ORF68) variants are known to occur (see e.g. Shankar V, et. al. Vaccine. 2001 Jul 16;19(28-29):3830-3.) Therefore, without providing a reference “wild-type” sequence, the metes and bounds of the claim are unclear.
Second, the terms “anchor domain (ER retention domain)” and “tail domain” are unclear, as neither the specification nor the claims define the parameters of these regions, and the art delineates these regions differently (see e.g. Oliver SL. Curr Top Microbiol Immunol. 2023;438:25-58.; Berarducci B, et. al. J Virol. 2009 Jan;83(1):228-40. Epub 2008 Oct 22.; Moffat J, et. al. J Virol. 2004 Nov;78(22):12406-15.)
For at least these reasons, the metes and bounds of claim 5 are unclear.
Claims 12, 13, and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The metes and bounds of claims 12, 13, and 17 are unclear because it is unclear how the recited percentage sequence identity is to be determined. The specification states that sequence identity may be determined using either a global or a local alignment algorithm, and identifies GAP, BESTFIT, FASTA, and BLAST as suitable approaches (¶[0064]). The specification subsequently states, however, that sequence identity refers to identity “over the entire sequence”(¶[0064]). A global alignment evaluates sequences over their entire length, whereas a local alignment can identify a region of high identity without requiring alignment over the entire sequences. Therefore, different expressly permitted alignment methodologies may produce different determinations as to whether a sequence satisfies the recited 85% identity threshold, and one of ordinary skill cannot determine with reasonable certainty which sequences fall within the scope of the claims.
For at least these reasons, the metes and bounds of claims 12, 13, and 17 are unclear.
Claim 19 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 19 provides for wherein the VZV polypeptide immunogen further comprises a sequence encoding a multimerization domain. However, “polypeptides” do not normally “encode” further sequences as they are the “final” products. One suggestion is to amend the claim along the lines of “wherein the VZV polypeptide immunogen further comprises a sequence comprising a multimerization domain.”
For at least these reasons, the metes and bounds of claim 19 are unclear.
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.
VZV gE is a rather stable glycoprotein, and while substitution mutations in the glycoprotein are known in the art, it is consistently shown to be a protein of 623 amino acids in length.
Claim 1 is drawn to a circular polyribonucleotide comprising an open reading frame (ORF) encoding a varicella-zoster virus (VZV) polypeptide immunogen.
Further limitations on the circular polyribonucleotide of claim 1 are wherein the VZV polypeptide immunogen is a VZV glycoprotein or an immunogenic fragment thereof (claim 2), wherein the VZV glycoprotein is selected from VZV gE, gI, gB, gH, gK, gL, gC, gN, and gM, or an immunogenic fragment thereof (claim 3), wherein the VZV glycoprotein is VZV gE, or an immunogenic fragment thereof (claim 4), wherein:
(a) the VZV glycoprotein is a mutational variant of VZV gE, or an immunogenic fragment thereof, comprising no more than 10 amino acid substitutions, deletions, or insertions relative to wild-type VZV gE;
(b) the VZV gE polypeptide is a truncated polypeptide lacking an anchor domain (ER retention domain): or
(c) the VZV gE polypeptide is a truncated polypeptide lacking a carboxy terminal tail domain (claim 5), wherein the VZV gE polypeptide comprises amino acids 1-524, 1-546, 1-561, 1-573, or 1-623 of VZV gE (claim 8), wherein the VZV gE polypeptide comprises a Y569A mutation, a Y582G mutation, or a Y569A/Y582G double mutation (claim 9), wherein the VZV gE polypeptide comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NOs: 29-33 and 65-68 (claim 12), wherein the VZV gE polypeptide further comprises a signal sequence and the VZV gE polypeptide and the signal sequence together comprise an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NOs: 34-38 and 69-70 or wherein the VZV gE polypeptide, optionally further comprising a signal sequence, is encoded by a nucleic acid sequence having at least 85% sequence identity with the nucleic acid sequence of any one of SEQ ID NOs: 39-47 and 71-83 (claim 13); wherein the VZV polypeptide immunogen is a VZV immediate early protein or an immunogenic fragment thereof (claim 15), wherein the VZV immediate early protein is an IE63 polypeptide comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence of SEQ ID NO: 84 or wherein the VZV immediate early protein is an IE63 polypeptide, optionally further comprising a signal sequence, encoded by a nucleic acid sequence having at least 85% sequence identity with the nucleic acid sequence of SEQ ID NO: 85 (claim 17); wherein the VZV polypeptide immunogen further comprises a sequence comprising a multimerization domain (claim 19); wherein the open reading frame encoding the VZV polypeptide immunogen encodes a second polypeptide (claim 20), wherein the second polypeptide is a polypeptide immunogen (claim 22), wherein the second polypeptide is a polypeptide adjuvant (claim 27).
Claim 29 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 29 are wherein the composition further comprises a second circular polyribonucleotide, wherein the second circular polyribonucleotide comprises an open reading frame encoding a second polypeptide immunogen or a polypeptide adjuvant (claim 30).
Claim 34 is drawn to a method of inducing an immune response in a subject against VZV, the method comprising administering to the subject the circular polyribonucleotide of claim 1.
Claim 35 is drawn to a method of preventing a VZV infection in a subject, the method comprising administering to the subject the circular polyribonucleotide of claim 1.
Claim 36 is drawn to a method of treating a subject who has or is suspected to have a VZV infection, 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 1-5, 15, 19-20, 22, 29, and 30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally-occurring circular RNA (circRNA) comprising VZV antigenic open reading frames (ORFs) or fragments thereof without significantly more.
Claim 1 is directed to a circular polyribonucleotide comprising an open reading frame (ORF) encoding a VZV polypeptide immunogen. The specification defines the term “circRNA,” “circular polyribonucleotide,” “circular RNA,” and “circular polyribonucleotide molecule” as interchangeable terms (¶[0031]) and as polyribonucleotides having no free 3’ and/or 5’ ends, and does not require the circular polyribonucleotide of claim 1 to be synthetic, engineered, modified, or otherwise structurally different from a naturally occurring circular RNA. The specification further broadly defines an “immunogen” as a molecule or molecular structure comprising one or more epitopes recognized, targeted, or bound by an antibody or T-cell receptor (¶[0041]).
Yang et. al. (Yang S, et. al. Nat Commun. 2024 Jun 10;15(1):4932.) provides evidence that circular RNAs encoded by VZV occur naturally during VZV infection. Yang identified 106 full length VZV circRNAs by long-read sequencing, and further mapped full-length circRNAs to multiple VZV ORFs and demonstrated that these circRNAs are abundantly derived from coding regions across the viral genome (See e.g. entire document; abstract, Figs. 1-3). The authors experimentally confirmed 200 VZV circRNAs and detected VZV circRNAs directly in blister fluid from herpes zoster patients and in clinical VZV isolates, demonstrating that VZV-encoded circRNAs are naturally produced during infection. Importantly, Yang showed that these naturally occurring circRNAs are not limited to isolated ORFs, but frequently span and encompass multiple viral coding regions. As shown in Fig. 3 of Yang, circRNAs include sequences derived from ORF68, which encodes VZV glycoprotein E (gE), and also encompasses portions of ORF4, ORF61, ORF62, and ORF63. These ORFs encode immediate early proteins, and the circRNAs identified in Fig. 3 span at least portions of each of these genes. In addition, Figure 3 demonstrates that multiple circRNAs extend across more than one ORF, thereby producing naturally occurring multigenic circular transcripts. ORF4, ORF61, and ORF62 further include natural multimerization domains, and the circRNAs encompassing these regions therefore inherently include sequences encoding naturally multimerizing protein domains.
Under the broadest reasonable interpretation, claim 1 encompasses naturally occurring VZV encoded circular RNAs comprising one or more VZV ORFs or immunogenic fragments thereof. Nothing about the instant claims or the specification require the circRNAs to comprise engineered components, and this circRNA product therefore lacks markedly different characteristics from naturally occurring counterparts.
Under Step 2A, Prong Two, claim 1 does not integrate the judicial exception into a practical application. The claim is directed to the circRNA itself, and does not require administration, expression in a host, vaccination, or any therapeutic or prophylactic use. The recitation of an “immunogen” merely describes the encoded viral protein content and does not impose a functional limitation that alters the nature of the claimed product. Under Step 2B, claim 1 does not include additional elements, such as heterologous tags, promoters, or other structural limitations within the circRNA, to amount to significantly more than the judicial exception. Accordingly, claim 1 is not patent eligible.
Dependent claims 2-5, 15, 19-20, 22, 29, and 30 depend directly or indirectly from claim 1 and further recite circular polyribonucleotides comprising VZV sequences derived from ORF68 (gE), ORF4, ORF61, ORF62, and ORF63, including embodiments spanning multiple ORFs and incorporating sequences encoding proteins with natural multimerization domains. As shown in Yang Figure 3, these features are present in naturally occurring VZV circRNAs, including circRNAs that encompass portions of ORF68 and circRNAs spanning ORF4, ORF61, ORF62, and ORF63, as well as circRNAs that include multiple ORFs within a single circular transcript. Accordingly, these dependent claims likewise read on naturally occurring VZV circRNAs and do not recite structural or functional characteristics that are markedly different from the natural products identified in Yang.
Claim 29 recites an immunogenic composition comprising the circular polyribonucleotide of claim 1 and a pharmaceutically acceptable excipient. The addition of a generic excipient does not alter the nature of the underlying product-of-nature limitation, nor does it confer markedly different characteristics on the VZV circRNA. The specification describes such excipients as conventional, FDA-approved inactive ingredients and identifies their use in standard pharmaceutical formulations as routine in the art. Accordingly, claim 29 does not provide an inventive concept under step 2B. Claim 30 similarly recites compositions encoding multiple circRNA, but as shown by Yang, multiple circRNA are present during the course of natural infection.
For at least these reasons, claims 1-5, 15, 19-20, 22, 29, and 30 are not drawn to patent-eligible subject matter. One suggestion to overcome this issue is to incorporate limitations into the independent claims from dependent claims which were not included in this rejection, or to amend the independent claim to ensure that the circRNA is markedly distinct from those circRNA which are found naturally (e.g. use of non-natural sequences, heterologous sequences, heterologous tags, heterologous signal peptides, promoters, etc.)
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, 12-13, 15, 17, 19-20, 22, 27, 29-30, and 34-36 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 (circRNA) encoding the specifically tested VZV gE constructs and their use to induce gE-specific immune responses, does not reasonably provide enablement for the substantially broader scope of any circular polyribonucleotides encoding any VZV polypeptide immunogen, the VZV immunogens within the broadly claimed sequence percent identity genera, and the corresponding methods of inducing any immune response, preventing any VZV infection, or treating any existing or suspected VZV infection. 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 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 circular polyribonucleotides (circRNA) encoding varicella zoster virus (VZV) polypeptide immunogens and compositions and methods using such circRNA. The specification states that the VZV polypeptide immunogen may be a VZV glycoprotein, and identifies gE, gI, gB, gH, gK, gL, gC, gN, and gM, including immunogenic fragments thereof (¶[0004-0010]). The disclosure provides considerably greater detail for gE, including particular truncations, Y569A and Y582G substitutions, specific reference sequences, signal sequence constructs, and particular nucleic acid sequences encoding those proteins (¶[0006-0009]). The specification additionally identifies the early protein IE63 (encoded by ORF63) and provides SEQ ID NOs: 84 and 85 as exemplary immediate early protein and corresponding nucleic acid sequence (¶[0009]).
The specification describes expression of secreted or transmembrane gE from particular circRNAs in cultured cells (Examples 1-3, ¶[0482-0493]). Examples 4-5 test secreted and transmembrane gE circRNAs in mice, with Example 5 reporting that the tested circRNAs induced gE-specific antibody and T-cell responses (¶[0494-0509]). The reported in vivo experiments therefore establish that particular gE constructs can be expressed from circRNA and can induce gE-specific humoral and cellular immune responses, but they do not demonstrate the same result for the remaining VZV glycoproteins, immediate early proteins, arbitrary immunogenic fragments, or the much broader sequence variants encompassed by the pending claims.
However, the claims are not limited to the disclosed embodiments. For instance, claim 1 also encompasses any VZV polypeptide immunogen encoded by the circular polyribonucleotide. Claims 2-3 still encompass multiple structurally and functionally different VZV glycoproteins and undefined immunogenic fragments thereof. Claim 15 similarly encompasses VZV immediate early proteins and immunogenic fragments rather than the particular IE63 sequence identified in the specification. The additional multimerization, second polypeptide, composition, and administration limitations of further dependent claims do not limit the VZV immunogen to an experimentally demonstrated antigen. The claimed scope therefore extends beyond the embodiments described in the specification.
It should also be noted that claims 12, 13, and 14 add another dimension to the breadth of the invention claimed. Claim 12 encompasses gE sequences having at least 85% identity to any one of SEQ ID NOs: 29-33 and 65-68. Claim 13 encompasses amino acid sequences having at least 85% identity to SEQ ID NOs: 34-38 and 69-70, and alternatively, nucleic acid sequences having at least 85% identity to SEQ ID NOs: 39-47 and 71-83. Claim 17 similarly encompasses an IE63 protein having at least 85% identity to SEQ ID NO: 84 or IE63 encoded by a nucleic acid having at least 85% identity to SEQ ID NO: 85 (¶[0009][0016][0092-0093]). These claims are not limited to the particular disclosed sequences, to the expressly described gE substitutions, or even to the separately disclosed class of gE variants having no more than ten mutations. An 85% sequence identity genus permits a large amount of sequence variation. The specification does not identify which positions throughout these proteins may be altered, individually or in combination, while maintaining expression, folding, cellular localization, antigen presentation, and the required immunogenic status. Rather, the specification provides particular sequences and then states a substantially broader numerical identity range. The outer portion of this range would require generating additional sequences and determining experimentally whether the resulting encoded proteins retain the properties required by the claims.
State of the prior art and predictability of the art. At the time the application was filed, VZV gE-based vaccines were known, and one skilled in the art would have been capable of constructing and testing candidate VZV vaccines. For example, Ciaramella (US20200069793A1) teaches RNA vaccines, including mRNA vaccines, encoding VZV antigens for various glycoproteins from the virus, and identifies gE, gI, gB, gH, gK, gL, gC, gN, or gM as possible VZV glycoproteins. The reference nevertheless performs its principal immunogenicity testing using selected gE constructs, including altered signal sequences, C-terminal truncations, and particular point mutations, rather than establishing immunogenicity interchangeable for every listed VZV antigen, variant, or fragment thereof. Ciaramella further demonstrates that antigen design affected the observed result. In its gE studies, different constructs produced different antibody responses, and the reference specifically identifies VZV-gE-del_574_Y569A and GE-del_562-IgKappaSP as producing particularly strong responses, and identifies VZV-gE-del_574_Y569A as having the highest geometric mean titer among the tested constructs. The evidence indicates that the availability of an RNA-expression platform did not make the immunogenic performance of every VZV sequence or variant interchangeable or predictable; candidate antigen constructs were made and experimentally compared.
Kim et. al. (Kim AR, et. al. Immune Netw. 2018 Oct 31;18(5):e38.) separately evaluated gE, IE63, and IE62 as DNA vaccine antigens in mice. Kim measured antigen specific T-cell responses separately for each antigen and further tested IL-7 and IL-33 molecular adjuvants to alter the resulting responses. Kim also failed to establish protection against VZV infection merely from expression of an antigen or detection of an immune response. Its protection experiment used a surrogate vaccinia virus (VV) expressing gE, and the challenged animals had been immunized with the particular gE vaccine together with IL-7 or IL-33. Its later experiment in previously infected animals likewise used prior infection with VV-gE rather than an established or latent VZV infection.
Post-filing art also highlights continued issues within the VZV vaccine field. Liu et. al. (Liu J, et. al. Viruses. 2022 Jun 2;14(6):1214.) further illustrates the state of the art by teaching DNA vaccination strategies using VZV gE in combination with IE63. Although the study reports promising immunogenicity results, it also emphasizes a key limitation in the field; namely that murine models are not fully predictive of human VZV infection because mice do not support true latent VZV infection or its reactivation cycle. This post-filing evidenced is consistent with the understanding that, despite encouraging preclinical immune responses, the behavior of VZV vaccine constructs in animal models did not reliably predict clinical efficacy in humans, underscoring the inherent unpredictability that still exists in the art.
Chang et. al. (US20220288176A1, Priority 08/28/2019) further demonstrates that the immunological properties of circRNA depend on features of the RNA construct itself and were not predictable merely from the identity of an encoded antigen. Chang teaches that N6-methyladenosine (m6A) RNA is reduced or removed from of circRNA to enhance the immunogenicity of said circRNA. Foreign circRNAs are potent adjuvants that induce antigen-specific T cell activation, antibody production, and anti-tumor immunity in vivo, and reduction of any m6A modification in the foreign circRNA has been found to enhance immune gene activation and adjuvant activity. Chang is particularly relevant, as the instant specification teaches the circRNA may include m6A to increase translation efficiency and that same modification may reduce immunogenicity. Thus, even with a circRNA encoding the same antigen, the modification state of said circRNA presents another variable affecting the biological behavior of the construct.
The VZV vaccine art was sufficiently developed that one skilled in the art could construct nucleic acid vaccines, express selected VZV antigens, and measure antibody or T-cell responses. However, the art was not sufficiently predictable to support extrapolation from results with gE in limited animal models, especially animal models that could not mimic VZV latency, to every VZV protein, fragment, or sequence, especially those with the claimed 85% identity. Accordingly, the results obtained using the disclosed embodiments of circRNA and gE 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 VZV protein sequences, recombinant nucleic acid construction, RNA expression/isolation, transfection, lipid nanoparticle formulation, ELISA, flow cytometry, ELISpot, and assays for determining neutralizing antibodies or antigen-specific immune responses. 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 untested VZV proteins or fragments or variants with the claimed percent identity would function as useful immunogens when expressed from circRNA would satisfy the claimed limitations.
Working examples. The specification provides working examples directed principally to gE. Examples 1-3 measure expression of particular secreted or transmembrane gE circRNA constructs. Examples 4 and 5 administer gE-encoding circRNA constructs to mice and report expression and gE-specific humoral and cellular responses. The specification concludes from Example 5 that circular RNA encoding the tested secreted or transmembrane gE induced gE-specific immune responses. The specification does not provide corresponding working examples establishing circRNA immunogenicity for any other claimed VZV glycoprotein (e.g. gI, gB, gH, gK, gL, gC, gN, and gM), or for a representative group of immediate early proteins. It does not test variants distributed throughout the claimed 85% sequence identity range. The later examples describe additional experimental protocols, but those protocols do not supply actual result showing that the untested antigen classes or broadly varied sequences possess the claimed biological properties.
The examples also fail to demonstrate prevention of VZV infection in a challenge model. Most significantly for instant claim 36, the specification provides no working example in which a subject having an established, latent, reactivated, or otherwise existing VZV infection is treated by the administration of the claimed circRNA. The disclosed examples therefore do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides substantial guidance regarding the production of circRNA along with gE and IE63 sequences. It also identifies assays that could be used to determine expression, antibody responses, T-cell responses, and neutralizing activity. The disclosure therefore provides the skilled artisan with tools for preparing and evaluating additional candidates. However, the specification does not provide sufficient guidance regarding the selection of functional embodiments throughout the entire claimed scope. In particular, the specification does not explain which VZV proteins or fragments outside the tested gE species will produce the desired immune response when expressed from circRNA, which substitutions within the 85% identity genera will preserve the relevant antigenic structures, or which sequence changes will disrupt protein folding, trafficking, antigen presentation, or antigenic immunogenicity. The artisan may also have to determine an appropriate circRNA modification state because the specification notes that modifications to the circRNA may be made to affect both translation efficiency and immune recognition, and the art has recognized that modifications to the circRNA itself can dramatically affect the stability and immunogenicity of the circRNA. The specification likewise does not provide a rule by which one skilled in the art could identify operative variants without preparing and testing them. This issue is particularly apparent because the specification separately describes gE variants having “no more than” ten mutations, while claims 12 and 13 reach the considerably broader universe defined by 85% sequence identity (¶[0006-0009]). The specification does not explain why the data obtained from the disclosed gE constructs may be reasonably extrapolated to sequences containing much greater degree of variation permitted at the outer boundary of those claims.
Quantity of experimentation necessary. To practice the full scope of claims 1-3 and 15, one skilled in the art would need to select additional VZV proteins and fragments, prepare circRNAs encoding those candidates, confirm expression, and determine whether the expressed proteins possess the recited immunogenic properties. For claims 12, 13, and 17, the artisan would additionally need to generate sequence variants across a large sequence space and test whether each candidate retains the required properties. 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 the candidate sequence was expressed, retained relevant antigenic epitopes, or induced the required immune response in the appropriate host. 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 gE variants and fragments, other VZV glycoproteins and fragments thereof, and other IE63 variants to determine which embodiments satisfy the desired immunogenic properties.
Claims 34 and 35 require use of the broadly claimed circRNA to induce an immune response against VZV or prevent VZV infection. The gE mouse studies provide support for induction of a gE-specific immune response, but those results do not demonstrate that circRNAs encoding the entire genus of VZV polypeptide immunogens encompassed by claim 1 will produce an effective immune response. Claim 35 is broader still in requiring prevention of VZV infection, a result not demonstrated by any actual VZV challenge experiment in the specification. The prior art reinforces the distinction between measuring an immune response and establishing protection. As set forth supra, Kim separately measured antigen-specific responses and then conducted a challenge experiment using a surrogate VV-gE infection, rather than treating immune response measurements themselves as proof of protection against VZV. Accordingly, the gE immunogenicity results in the instant application do not reasonably enable prevention with every circular polyribonucleotide encompassed by claim 1 without further experimentation.
With respect to claim 36, there is an additional deficiency as claim 36 is not limited to prophylactic vaccination before VZV disease, as it recites treating a subject who “has or is suspected to have” a VZV infection. The specification expressly contemplates subjects having previously diagnosed VZV infection, asymptomatic or dormant VZV infection, and shingles, including decreasing the frequency or severity of shingles symptoms (¶[0024-0025]). The specification provides no working example demonstrating that administration of a claimed circRNA treats an established VZV infection, eliminates or alters latent VZV, treats reactivated virus, or decreases the frequency or severity of shingles. The demonstrated gE-specific antibody and T-cell responses do not themselves establish therapeutic effectiveness against an infection already present in a subject. The disclosure therefore provides the proposed therapeutic use, but not experimental evidence or other technical guidance establishing how the disclosed circRNA immunization is expected to accomplish that result across the scope of claim 36.
This distinction was recognized in the prior art in the VZV field, as a large clinical trial by Oxman et. al. (Oxman MN, et. al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005 Jun 2;352(22):2271-84.) evaluated vaccination for prevention of herpes zoster and reported reduced herpes zoster morbidity in vaccinated older adults. That evidence of prophylactic vaccination does not establish that administration of a vaccine after a subject has an active, latent, or reactivated VZV infected constitutes effective treatment of that infection. Again, with Kim, similar studies showed immune boosting after previous exposure using mice that had been infected with a surrogate VV-gE virus and then immunized 60 days later. The reported endpoint was enhancement of antigen-specific cellular immunity, not treatment or clearance of an established VZV infection. Accordingly, the prior art does not supply the missing guidance necessary to extrapolate the instant gE immunogenicity data to the therapeutic scope of instant claim 36.
To practice claim 36 across its scope, one skilled in the art would need to determine which circRNA immunogens, doses, formulations, treatment schedules, and disease states would produce a therapeutic effect in subjects already infected with VZV. Such work would require more than confirming expression of the encoded antigen, as it would require testing whether vaccination after infection alters viral replication, latency or reactivation, shingles manifestations, or another meaningful measure of treatment. The specification does not provide sufficient guidance to predict those results without such experimentation.
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 describes particular gE circRNA constructs and their ability to produce gE-specific immune responses, but the claims also encompass substantially broader classes of VZV proteins and fragments, sequence variants, prevention of infection, and treatment of an existing or suspected infection. 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 undue experimentation.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and/or use the full scope of the invention recited in the claims without undue experimentation.
Claims 1, 12-13, 15, 17, 19-20, 22, 27, 29-30, and 34-36 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 pre-AIA the inventor(s), 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, 12-13, 15, 17, 19-20, 22, 27, 29-30, and 34-36 recite either directly or through incorporation of the limitations of instant claim 1, a circular polyribonucleotide comprising an ORF encoding a “VZV polypeptide immunogen”. Claim 15 narrows the VZV polypeptide immunogen only to a VZV immediate early protein or an immunogenic fragment thereof. The specification describes that the circular polyribonucleotide (circRNA) may encode a VZV polypeptide immunogen and identifies VZV glycoproteins, including gE, gI, gB, gH, gK, gL, gC, gN, and gM. The disclosure then provides substantially more detailed structural disclosure for gE, including particular truncations, point mutations, and the sequences of SEQ ID NOs: 29-47 and 65-83. For the immediate early protein grouping, the specification identified IE63 and SEQ ID NOs: 84-85 (¶[0004-0019]). The later limitations concerning multimerization domains, additional polypeptides, compositions, and methods of administration do not further define the structure of the first VZV polypeptide immunogen (¶[0013-0026]).
However, the scope of claim 1 is not limited to the embodiments described in the specification, namely gE, IE63, the specifically identified VZV glycoproteins, or the disclosed sequences. Claim 1 broadly encompasses any VZV polypeptide, including a fragment thereof, that satisfies the recited immunogen limitation when encoded by the circular polyribonucleotide. Likewise, claim 15 is not limited to IE63 but encompasses other VZV immediate early proteins and immunogenic fragments thereof.
The specification does not describe a sufficient number of species representative of the broadly claimed scope. The detailed sequence disclosure is concentrated principally on gE and IE63. Naming additional VZV proteins as possible immunogens does identify structural features common to the substantially broader claimed genus which would allow one skilled in the art to recognize which additional species fall within the scope of the claimed invention. Instead, one skilled in the art would be required to select additional VZV proteins and fragments thereof not described in the specification and determine whether those additional embodiments satisfy the recited limitations.
The claimed VZV polypeptides are defined, at least in part, by the recited function of being “immunogens”. However, the specification does not establish a correlation between the disclosed structural features common to the disclosed gE and IE63 species and the recited function (e.g. immunogen) sufficient to identify the additional VZV proteins and fragments falling within the scope of the claimed genus. The specification describes gE sequences, but does not identify structural features common to the broader claimed genus of other unrelated VZV proteins or fragments which would allow one skilled in the art to recognize other members of the genus. The disclosure of the desired function, without a sufficient description of the claimed genus, does not demonstrate possession of the full scope of the claim. Claims 19-20, 22, and 27 do not cure this deficiency. The additional recitations of a multimerization domain, a second polypeptide, a second immunogen, or a polypeptide adjuvant leave the first polypeptide defined broadly as the VZV polypeptide immunogen of claim 1. Claims 29 and 30 likewise retain that unsupported genus in the recited immunogenic composition. Claims 34-36 require administration of the claim 1 circRNA but do not narrow the VZV polypeptide immunogen to a structurally supported class.
Claims 12, 13, and 17 additionally encompass broad sequence genera defined by a percent sequence identity while remaining an immunogen. For example, the specification describes particular gE truncations and Y596A and Y582G substitutions and separately describes gE variants containing no more than ten mutations (¶[0089-0091], Tables 1-2). The specification further identifies SEQ ID NOs: 84 and 85 for IE63 (¶[0092-0093]). However, claims 12, 13, and 17 also encompass additional sequences having 85% sequence identity and satisfying the recited requirement that the encoded protein be the recited VZV immunogen. The specification does not identify which positions may be altered while retaining the recited function, describe representative variants across the claimed scope, or identify structural features sufficient to distinguish operative variants from other sequences. While the disclosed gE substitutions and truncations provide examples of selected changes, they do not establish possession of the substantially broader range of sequence variation permitted by claims 12 and 13. Claim 13 additionally has heterologous signal sequence embodiments with the claimed gE sequence, but the specification provides limited guidance with which signal sequences can be used and still maintain the claimed immunogenicity. The claim permits substantial variation in the combined gE and signal sequence, or alternatively in the nucleic acid encoding said signal/gE polypeptide, without identifying which changes are compatible with the overall claimed gE immunogen. Claim 17 is centered on a single identified IE63 amino acid and nucleotide sequence, and the specification fails to describe a representative group of IE63 sequences across the claimed percentage identity genus or identify which positions may be varied while retaining the claimed characteristics required of the IE63 immunogen. Accordingly, the disclosure does not demonstrate possession of the broader claimed group of sequences.
For at least these reasons, the disclosure does not reasonably convey to one skilled in the art that the inventor had possession of the full scope of the subject matter recited in claims 1, 12-13, 15, 17, 19-20, 22, 27, 29-30, and 34-36 at the time the application was filed.
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, 29-30, and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chang et. al. (US20190345503A1, Pub. 11/14/2019; hereafter “Chang”.)
The Prior Art
Chang teaches the use of circular RNAs generated with exogenous introns to stimulate an innate immune response (entire document; see abstract.) Chang teaches that the circRNA can have an ORF for encoding an immunogenic polypeptide, such as a polypeptide from a virus (reference claims 1, 7-8). Chang teaches said viral polypeptide may be from VZV (¶[0142][0146]; instant claim 1). Chang teaches that the circRNA may be within pharmaceutical compositions comprising pharmaceutically acceptable carriers or excipients (¶[0025][0150-0161]; reference claim 44; instant claim 29). Chang teaches these compositions may comprise one or more additional agents, such as additional immunogenic circRNAs (¶[0025][0160]; instant claim 30). Chang teaches these circRNA are used to enhance an innate immune response for treating such viral diseases as VZV infection (¶[0142]; instant claim 34).
For at least these reasons, Chang teaches the limitations of instant claims 1, 29-30, and 34, and anticipates the invention encompassed by said claims.
Claims 1, 29-30, and 34 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Wesselhoeft et. al. (US20240042015A1; Priority 05/19/2020; hereafter “Wesselhoeft”.)
The Prior Art
Wesselhoeft teaches compositions comprising circRNA and methods of use thereof (entire document; see abstract). Wesselhoeft teaches the circRNA encodes an antigenic polypeptide from Varicella zoster virus (VZV)(¶[0044][0140][0252][0266-0267]; reference claims 82-84; instant claim 1). Wesselhoeft teaches pharmaceutical compositions which comprise the circRNA encoding the antigenic polypeptide which comprise a diluent and a buffer, or a polycationic compound, or any other standard pharmaceutical carrier, diluent, or excipient (¶[0027-0030][0190][0311][0336]; reference claims 41-43; instant claim 29). Wesselhoeft teaches that the circRNA may be co-administered with additional therapeutic agents (¶[0359]) such as one or more circRNA vaccines (¶[0134][0137-0138]; instant claim 30). Wesselhoeft teaches administering the circRNA vaccine to induce an antigen-specific immune response (reference claims 82-84, 89, 91-92; instant claim 34).
For at least these reasons, Wesselhoeft teaches the limitations of instant claims 1, 29-30, and 34, 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.
Claim(s) 2-5, 8-9, 12-13, 15, 17, 19-20, 22, 27, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Chang as applied to claims 1, 29-30, and 34 above, or over Wesselhoeft as applied to claims 1, 29-30, and 34 above;
and further in view of Martin et. al. (US20260115280A1, Priority 07/14/2021; hereafter “Martin”), and
further in view of Park et. al. (US20180117141A1; Pub. 05/03/2018; hereafter “Park”);
Nagaike et. al. (US20110189233A1; Pub. 12/14/2012; hereafter “Nagaike”); and
Ciaramella (US20200069793A1; Pub. 03/05/2020; hereafter “Ciaramella”); and
as evidenced by Yu et. al. (US20130316366A1; Pub. 11/28/2013; hereafter “Yu”); and
Anderson et. al. (US20230040275A1, Priority 11/19/2019; hereafter “Anderson”.)
The Prior Art
The teachings of Wesselhoeft and Chang have been set forth supra. While both teach a circRNA encoding a VZV antigen, neither Wesselhoeft nor Chang teach specific VZV antigens, such as gE or IE63. However, sequences for both were known in the art and were specifically noted for expression as VZV antigens, as evidenced by the teachings of Martin, Park, Nagaike, and Ciaramella.
Martin teaches SEQ ID NO: 2, which is a VZV antigen that is 100% identical to instant SEQ ID NO: 3 (see ABSS alignment for 18/552,863). Martin teaches a composition which induces an immune response against Varicella zoster virus comprises an optionally truncated VZV glycoprotein or a fragment thereof, wherein said truncated gE glycoprotein comprises SEQ ID NO: 1 (¶[0017]; instant claims 2-4, 12). Martin teaches gE truncated to remove the carboxy terminal anchor region (¶[0068]; instant claims 5, 8). Martin teaches the gE may be mutated to comprise a non-native signal peptide on the N-terminus to improve cleavage (¶[0085]), and that the VZV compositions may comprise an adjuvant (¶[0302-0303]). Martin teaches the VZV glycoprotein may be gE, gB, gH, gI, gC, IE62, or IE63, namely IE63 and gE (¶[0286][0303]) and the composition can include one or more VZV antigens (Figs. 1-9; ¶[0136-0144][0283-0286]; instant claim 15, 20, 22). IE62 inherently comprises a DNA-binding and dimerization domain, functioning naturally as a homodimer, and therefore meets the limitation of instant claim 19. Martin teaches the VZV antigen may be used in methods to prevent and/or decreasing the severity of infection of VZV (¶[0153][0157][0159][0274]; instant claims 34-36).
While Martin teaches the composition would include adjuvants, and that the VZV antigen may be encoded from a vector-based system (¶[0282]), Martin does not teach that the vector encodes both the VZV antigen and the adjuvant. However, having the vector encode both the antigen and adjuvant would be obvious to a skilled artisan, rendering instant claim 27 obvious to a skilled artisan.
While Martin teaches the composition may comprise a gE variant, including gE variants with different signal peptides, Martin fails to specifically teach Y569A and/or Y582G mutants or SEQ ID NO:34-38 or 69-70 which are gE mutants with different signal peptides. And while Martin teaches the gE may additionally comprise an IE63 protein, Martin does not directly disclose IE63 sequences. However, said mutations and sequences were known in the art, as shown by the teachings of Park and Nagaike.
Park teaches SEQ ID NO:3, which is 97.4% identical to instant SEQ ID NOs: 37 and 38 (see ABSS sequence alignments in file wrapper for 15/520,282). These sequences mainly differ in the signal peptides, as Instant SEQ ID NOs: 37 uses an INHC1 signal peptide (human plasma protease C1 inhibitor (encoded by the SERPING1 gene); MASRLTLLTLLLLLLAGDRASS; see e.g. Yu, Table 3 of signal sequences, namely SEQ ID NO:428 with 100% identity) and SEQ ID NO: 38 uses the gaussian luciferase secretion signal (gLuc, MGVKVLFALICIAVAEAK; see e.g. Anderson; ¶[0017] SEQ ID NO: 25 with 100% sequence identity). Martin teaches the gE may use heterologous signal peptides, and therefore as signal peptides were known in the art, these peptides could be replaced for the native gE peptide. Regardless, even if the signal peptides are not replaced, Park still teaches sequences with at least 85% identity to those of SEQ ID NOs: 37 and 38 (instant claim 13).
Nagaike teaches SEQ ID NO: 37, which is 100% identical to instant SEQ ID NO: 84 (see alignment in ABSS search results in file wrapper for 10/591,787; ¶[0348]). Nagaike teaches ORF63, which encodes IE63 (instant claim 17).
Ciaramella teaches RNA encoding VZV antigenic polypeptides, namely gE (reference claims 1, 9-10, 12-13, 15-21), wherein said gE comprises a Y582G or Y569A mutation (reference claims 22-23; instant claim 9).
Given the teachings of Wesselhoeft or Chang, a skilled artisan would be apprised as to the use of circRNA to deliver VZV antigenic proteins in order to raise an immune response against VZV. Given the teachings of Martin, a skilled artisan would be motivated to specifically choose gE and specific C-terminal truncations and/or signal peptide variants as the primary antigen, as this is the most antigenically relevant VZV protein and the basis of the VZV commercial subunit vaccines. Given the teachings of Martin, one would be further motivated to combine IE63, an immediate early protein which would be useful in controlling reactivated VZV, along with gE to treat a variety of VZV infections. Given the teachings of Park, Nagaike, and Ciaramella, a skilled artisan would be apprised as to the specific sequences of the antigenic VZV gE and IE63 proteins in the art, as well as antigenically relevant variants known to modulate subcellular trafficking, prevent unwanted endocytosis, and to optimize antigen expression on the cell surface and Golgi network. Therefore, a skilled artisan would find the further limitations of instant claims 2-5, 8-9, 12-13, 15, 17, 19-20, 22, 27, and 34-36 obvious, given what was known in the VZV art at the time of filing.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Wesselhoeft or Chang in order to utilize the most antigenically relevant VZV proteins, thereby generating circRNA VZV compositions expressing such antigens as gE or IE63. One would have been motivated to do so, given the suggestion by Martin that gE and specific truncations and specific variants thereof were the most antigenically relevant. There would have been a reasonable expectation of success, given the knowledge that sequences for gE and IE63, which was important to fight latent or reactivated VZV infections, were known in the art, as taught by Park, Nagaike, and Ciaramella. 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 1-5, 8-9, 12-13, 15, 17, 19-20, 22, 27, 29-30, and 34-36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 8-13, 15-23, and 25-26 of copending Application No. 18/712,809 in view of Ciaramella (US20200069793A1; 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, 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 instant 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 instant claims are an obvious species of the ‘809 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 1-5, 8, 12, 15, 19-20, 22, 27, 29-30, 34-36 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 Chang and Martin (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, and the expression of adjuvants from the circRNA. 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 instant claims require that the immunogen be a VZV immunogen domain, and the reference claims require the presence of an IRES before the encoded immunogen(s), but such limitations would be obvious, given the teachings of Chang and Martin (detailed supra). Chang further teaches that IRES may be operably linked to the immunogenic polypeptides within the circRNA (¶[0029][0033][0085]). 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 Chang and Martin.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, 8, 12, 15, 19-20, 22, 27, 29-30, 34-36 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 Chang and Martin (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 herpesvirus proteins. 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 that said immunogens are separated by spacers and IRES, and the instant claims are drawn to a different herpesvirus, VZV, and antigenic proteins thereof. However, both Chang and Martin suggest the circRNA deliver antigenic proteins from herpesviruses, including HSV and VZV, and the use of antigenic proteins from one herpesviruses are often used as the motivation to try an antigenically and/or functionally similar protein for vaccine platforms from another herpesvirus. Chang further teaches that IRES may be operably linked to the immunogenic polypeptides within the circRNA (¶[0029][0033][0085]). Therefore, the ‘254 claims are an obvious species of the instant claims, especially given the teachings of Chang and Martin.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, 8, 12, 15, 19-20, 22, 27, 29-30, 34-36 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 Chang and Martin (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. 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 from VZV, while the reference claims require the multiple immunogens on the circRNA to be separated by IRES. However, both Chang and Martin suggest the circRNA deliver one or more antigenic proteins, including VZV proteins and other pathogens, and the open-ended comprising language utilized in the instant claims allows for the presence of additional, unrecited material (¶[0104][0175]). Furthermore, the adjuvanting material could be a protein from another pathogen, such as MPL or bacterial toxins. Chang further teaches that IRES may be operably linked to the immunogenic polypeptides within the circRNA (¶[0029][0033][0085][0104]). Therefore, the ‘966 claims are an obvious species of the instant claims, especially given the teachings of Chang and Martin.
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
US20230193311A1
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
US20210077616A1: Teaches VZV gE, specifically C-terminally truncated 537aa protein, together with adjuvant. Not utilized as rejection would be redundant to those set forth supra.
US20240148861A1. Post-filing art relevant to instant claims as it teaches mRNA encoding VZV gE and different gE variants.
US20250236646A1. Post-filing art relevant to instant claims as it teaches mRNA encoding VZV gE and different gE variants.
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
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