DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Summary
Claims 48-53 are pending in this office action. Claims 48-53 are new. Claims 1-47 are cancelled. Claims 54-56 are withdrawn from consideration. Applicant is encouraged to amend all withdrawn claims to be within the scope of the pending claims to expedite rejoinder upon allowance. All pending claims are under examination in this application.
Priority
The current application was filed on January 20, 2023 is a 371 of PCT/US2021/043213 filed July 26, 2021, which in turn claims domestic priority to 63/056,465 filed July 24, 2020.
Claim Objections
Claim 50 is objected to because of the following informalities: since claim 50 is new, please delete the underlined comma within the structure (indicating an amendment). Appropriate correction is required.
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 non-obviousness.
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 48-53 are rejected under 35 U.S.C. 103 as being unpatentable over Waymouth et al. (US2018/0028688A1) in view of Premkumar et al. (Science Immunology, 2020; published June 2020), Zhang et al. (CN111217918A), and Haabeth et al. (PNAS, 2018).
[The Examiner is going to introduce the references and then combine them where appropriate to reject the instant claims.]
1. Waymouth et al.
Waymouth et al. is considered the closest prior art as it teaches immolative cell-penetrating complexes for nucleic acid delivery (see title). In addition, Waymouth et al. disclose there are provided herein, inter alia, complexes, compositions and methods for the delivery of therapeutic, diagnostic and imaging agents, including nucleic acid, into a cell. The complexes, compositions and methods may facilitate complexation, protection, delivery and release of oligonucleotides and polyanionic cargos into target cells, tissues, and organs both in vitro and in vivo (see abstract).
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2. Premkumar et al.
Premkumar et al. teach the receptor-binding domain of the viral spike protein
is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients (see title). Furthermore, Premkumar et al., disclose that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible
for a pandemic of severe respiratory illness. People infected with this highly contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by polymerase chain reaction (PCR) testing of symptomatic patients for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor-binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses,
the RBD represents a promising antigen for detecting CoV-specific antibodies in people. Here, we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control individuals) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD’s performance as an antigen for reliable detection of SARS-CoV-2–specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) for antibodies induced by SARS-CoVs. We observed a strong correlation between levels of RBD-binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which
reveal the early kinetics of SARS-CoV-2 antibody responses, support using the RBD antigen in serological diagnostic assays and RBD-specific antibody levels as a correlate of SARS-CoV-2 neutralizing antibodies in people (see abstract).
3. Zhang et al.
Zhang et al. teach novel coronavirus S protein two-region subunit nano vaccine based on lumazine synthase (see title). Additionally, Zhang et al., disclose that the present invention teaches a novel coronavirus S protein two-region subunit nano vaccine based on lumazine synthase. A receptor binding domain (RBD) and a fusion peptide (FP) of viruses are double antigens together to connect lumazine synthase (LS) derived from Aquifex aeolicus strain (lumazine synthase, LS) to form a fusion protein LS-RBD-FP to achieve antigen multimerization; and then an eukaryotic cell expression system is used for expression, and a LS self-assembly function can be used to form sixty-mer nano-antigen. The scheme can overcome shortcomings of insufficient immunogenicity of RBD monomers. The obtained vaccine can significantly increase levels of neutralizing antibodies of hosts against the viruses, the produced antibodies have ability to strongly block the viruses from invading target cells, besides, a preparation method of the vaccine is simple, easy to purify and high in safety, and the vaccine can be quickly applied to clinical trials (see abstract).
4. Haabeth et al.
Haabeth et al. teach mRNA vaccination with charge-altering releasable
transporters elicits human T cell responses and cures established tumors in mice (see title). Also, Haabeth et al., disclose in vivo delivery of antigen-encoding mRNA is a promising approach to personalized cancer treatment. The therapeutic efficacy of mRNA vaccines is contingent on safe and efficient gene delivery, biological
stability of the mRNA, and the immunological properties of the vaccine. Here we describe the development and evaluation of a versatile and highly efficient mRNA vaccine-delivery system that employs charge-altering releasable transporters (CARTs) to deliver antigen-coding mRNA to antigen-presenting cells (APCs). We demonstrate
in human peripheral blood mononuclear cells that CART vaccines can activate a robust antigen-specific immune response against mRNA-encoded viral epitopes. In an established mouse model, we demonstrate that CARTs preferentially target professional APCs in secondary lymphoid organs upon i.v. injections and target local APCs upon s.c. injection. Finally, we show that CARTs co-formulated with mRNA and a Toll-like receptor ligand simultaneously transfect and activate target cells to generate an immune response that can treat and cure mice with large, established tumors (see abstract).
Combination of Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al.
Regarding instant claim 48, Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. teach a cell-penetrating complex comprising a ribonucleic acid comprising a sequence encoding a viral protein. The necessary citations of Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. that pertain to instant claim 48 are presented in Table I.
Table I
Instant Claim 48
Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. Citations
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Waymouth et al. disclose all the necessary chemistry and substitutions for the cell-penetrating complex (see title, abstract and paragraphs [0005-0011]; also see claims within Waymouth et al.). Waymouth et al. disclose the desired formula I:
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as a hybrid between paragraphs [0008] and [0010] within Waymouth et al. Additionally, Waymouth et al. supports all the elected species [substituted aryl = R1A, H = R2A, L1 is -O-, L2 is a bond; see paragraphs [0008] and [0010] within Waymouth et al.; z4 and z5 are 1; z1 and z3 are each 6, and z2 is 9; see paragraphs [0217-0228] within Waymouth et al.; for instant claim 34; R3A would be equivalent to R1A of instant claim 14).
[The Examiner has identified the first structure (boxed) for rejection purposes.]
Waymouth et al. disclose the structure of LP1 (see paragraph [0167-0168] within Waymouth et al.). Furthermore, Waymouth et al. disclose the preference of the oleyl, nonenyl, and dodecyl groups for substitution on R201 or R202(see paragraph [0267] within Waymouth et al.).
Waymouth et al. disclose the pH-sensitive immolation (IM) moiety (see parargraph [0151] within Waymouth et al.).
The difference between Waymouth et al. and the instant application is the biological target. Waymouth et al. targets broadly both infectious diseases and cancer (see claims 60 and 61 within Waymouth et al.). The instant application focuses on the encoding of a viral protein, wherein the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein.
However, the Premkumar et al. and Zhang et al. disclosures support the encoding of a viral protein, wherein the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein.
Premkumar et al. disclose the receptor-binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients (see title and abstract within Premkumar et al.). Furthermore, Premkumar et al. disclose a simple antibody detection assay that also predicts individual-level risk of disease will be a major advance for vaccine development and immunogenicity of vaccines because SARS-CoV-2 neutralization assays are time-consuming and require biosafety level-3 (BSL-3) containment (see page 6 of 9, paragraph 2 within Premkumar et al.).
Zhang et al. disclose the development of the receptor-binding domain and fusion peptide (FP) of a virus as dual antigens (see claim 1 within Zhang et al.). Zhang et al. specifically uses the SARS-CoV-2 antigen (see claim 3 within Zhang et al.) which is the surface spike protein (see claim 4; and paragraph [0022]l; both within Zhang et al.).
Finally, Haabeth et al. disclose mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice (see title and abstract within Haabeth et al.). Supporting the use of mRNA vaccines and the drug-delivery system [mRNA charge-altering releasable transporters (mRNA-CART)].
Therefore, the combination of the Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. references make instant claim 48 obvious to a skilled artisan (POSITA; person of ordinary skill in the art).
[The remainder of the instant claims are either directly or indirectly dependent on instant claim 48, which is taught in full by the combination of Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al.]
Regarding instant claim 49, Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. teach the appropriate n21, n22, and z2 values for
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Waymouth et al. disclose the appropriate n21, n22, and z2 values for the above analogue [Waymouth et al. disclose the structure of LP1 (see paragraph [0167-0168] within Waymouth et al.). Furthermore, Waymouth et al. disclose the preference of the oleyl, nonenyl, and dodecyl groups for substitution on R201 or R202(see paragraph [0267] within Waymouth et al.). Waymouth et al. disclose the pH-sensitive immolation (IM) moiety (see parargraph [0151] within Waymouth et al.); for specific embodiments disclosing the above values, see paragraphs [0220] and [0222] within Waymouth et al.].
Regarding instant claim 50, Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. teach wherein the second cationic amphipathic polymer has the formula:
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Please see Table I of instant claim 48 and the discussion and citations within instant claim 49 for the necessary rejection text.
Regarding instant claim 51, Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. teach wherein n23 is 13, z6 is 11 and R203 is dodecyl. Please see Table I of instant claim 48 and the discussion and citations within instant claim 49 for the necessary rejection text.
Regarding instant claim 52, Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. teach wherein the nucleic acid adjuvant is selected from a DNA adjuvant, a toll-like receptor (TLR) agonist, one or more unmethylated CpG oligonucleotides, the nucleic acid identified by SEQ ID NO: 1, and the nucleic acid identified by SEQ ID NO:2. Waymouth et al. disclose teach wherein the nucleic acid adjuvant is selected from a DNA adjuvant (see paragraph [0328] within Waymouth et al.), or a toll-like receptor (TLR) agonist (see paragraph [0334] within Waymouth et al.).
Regarding instant claim 53, Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. teach a pharmaceutical composition comprising a therapeutically effective amount of a cell-penetrating complex of instant claim 14 and a pharmaceutically acceptable excipient. Waymouth et al. disclose pharmaceutical compositions can have a cell-penetrating complex, which has a nucleic acid non-covalently bound to a cationic amphipathic polymer, as an active ingredient and further contain pharmaceutically acceptable excipients or additives depending on the route of administration (see paragraph [0333] within Waymouth et al.).
Analogous Art
The Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. references are directed to the same field of endeavor as the instant claims, that is, a cell-penetrating complex comprising a ribonucleic acid comprising a sequence encoding a viral protein, as disclosed within instant claim 48.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the cell-penetrating complex comprising a ribonucleic acid disclosed by Waymouth et al., using the teachings of Premkumar et al. and Zhang et al., and further in light of the claim-specific features described in Haabeth et al., in order to arrive at the subject matter of the instant claims.
The Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. references all have considerable overlap with the preparation of a cell-penetrating complex comprising a ribonucleic acid encoding of a viral protein, wherein the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein. In this instance, Waymouth et al. supplies the chemistry and substituents of the cell-penetrating complex comprising ribonucleic acid, Premkumar et al. and Zhang et al. supplies biology evidence of the encoding of a viral protein within the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein, while Haabeth et al. supports the drug-delivery using a cell-penetrating complex. All references are directed to the preparation of preparation of a cell-penetrating complex comprising a ribonucleic acid encoding of a viral protein, wherein the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the four references when seeking to improve or adapt a preparation of a cell-penetrating complex comprising a ribonucleic acid encoding of a viral protein, wherein the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein.
Starting with Waymouth et al., the skilled person only had to try the necessary claim limitations disclosed by Premkumar et al., Zhang et al., and Haabeth et al. The combination of Waymouth et al., Premkumar et al., Zhang et al., and Haabeth et al. would allow one to arrive at the present application without employing inventive skill. This combination of the cell-penetrating complex comprising ribonucleic acid taught by Waymouth et al. along with the use of the necessary claim limitations taught by Premkumar et al., Zhang et al., and Haabeth et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the cell-penetrating complex comprising ribonucleic acid disclosed by Waymouth et al. with the use of the necessary claim limitations taught by Premkumar et al., Zhang et al., and Haabeth et al. Incorporating the disclosure of Waymouth et al. into the encoding of a viral protein, wherein the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein presented by Premkumar et al. and Zhang et al., and further in light of the drug delivery support of a cell-penetrating complex disclosed by Haabeth et al. represents a predictable use of prior art elements according to their established functions, consistent with MPEP §2143 and KSR.
Furthermore, the additional claim limitations taught by Premkumar et al., Zhang et al., and Haabeth et al. would have been viewed by a POSITA as routine design optimizations or known modifications to expand the preparation of cell-penetrating complexes comprising ribonucleic acid for a different therapeutic target. Implementing these features in Waymouth et al.’s cell-penetrating complex comprising ribonucleic acid would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Waymouth et al., supplemented by Premkumar et al., Zhang et al., and Haabeth et al. provides all the elements of the claimed invention. The resulting cell-penetrating complex comprising ribonucleic acid constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Response to Arguments
Applicant's arguments filed May 18, 2026 have been fully considered but they are not persuasive.
The instant claim amendments were sufficient to address claim objection and the 35 U.S.C. §112(b) rejections. Therefore, they are all withdrawn from the non-final office action dated March 3, 2026.
The amendments did not necessitate a new ground of rejection.
Applicant Argument: The Applicant argues that Waymouth et al. does not teach where the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein.
Examiner’s Rebuttal: This is precisely why the Examiner has brought in the Premkumar et al. and Zhang et al. references. The difference between Waymouth et al. and the instant application is the biological target. Waymouth et al. targets broadly both infectious diseases and cancer (see claims 60 and 61 within Waymouth et al.). The instant application focuses on the encoding of a viral protein, wherein the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein.
However, the Premkumar et al. and Zhang et al. disclosures support the encoding of a viral protein, wherein the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein.
Premkumar et al. disclose the receptor-binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients (see title and abstract within Premkumar et al.). Furthermore, Premkumar et al. disclose a simple antibody detection assay that also predicts individual-level risk of disease will be a major advance for vaccine development and immunogenicity of vaccines because SARS-CoV-2 neutralization assays are time-consuming and require biosafety level-3 (BSL-3) containment (see page 6 of 9, paragraph 2 within Premkumar et al.).
Zhang et al. disclose the development of the receptor-binding domain and fusion peptide (FP) of a virus as dual antigens (see claim 1 within Zhang et al.). Zhang et al. specifically uses the SARS-CoV-2 antigen (see claim 3 within Zhang et al.) which is the surface spike protein (see claim 4; and paragraph [0022]l; both within Zhang et al.).
Both Premkumar et al. and Zhang et al. use the RBD within SARS-CoV-2, for different purposes than the instant application. These disclosures give insight into the importance of the receptor-binding domain of the viral spike protein. This would allow a skilled artisan (POSITA) to target the RBD region by encoding a viral protein, wherein the viral protein is the soluble receptor binding domain (RBD) of a SARS-CoV-2 spike protein for the purpose of vaccine development.
Finally, Haabeth et al. disclose mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice (see title and abstract within Haabeth et al.). Supporting the use of mRNA vaccines and the drug-delivery system [mRNA charge-altering releasable transporters (mRNA-CART)]. This is an example within the prior art pertaining to vaccine technology.
[Furthermore, Applicant may also argue impermissible hindsight reasoning. However, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight [or piece-meal reasoning.] But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).]
Thus, the 35 U.S.C. §103 rejection for instant claims 48-53 is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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