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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Mar. 17, 2026 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Mar. 17, 2026. Claims 1-2, 4-9 and 14-20 are pending and currently examined.
Claim Objections
Claim 1 recites “wherein the self-replicating RNA molecules are encapsulated in, bound to or adsorbed on a cationic lipid, a liposome, a lipid nanoparticle and combinations thereof” and “a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable vehicle.” These two phrases appear to have language or expression issues. By using the conjunction word “and”, the first phrase appears to require all of the specified agents (“a cationic lipid, a liposome, a lipid nanoparticle and combinations thereof”). In the second phrase, the specification does not differentiate the words “carrier” and “vehicle”. Thus, they appear to refer to a same product or concept of a product.
Applicant is invited to clarify and/or make appropriate amendment.
Claim Rejections - 35 USC § 112
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.
(Previous Rejection – Maintained and Modified Necessitated by Amendment) Claims 14-20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
These claims are amended to become method claims.
Claim 14 recites “utilizing a pharmaceutically acceptable carrier and/or pharmaceutically acceptable vehicle in administering the pharmaceutical composition of claim 1”. This limitation renders the claims unclear. First, the pharmaceutical composition of claim 1 already comprises a pharmaceutically acceptable carrier and/or vehicle. It is not clear what the relationship between the “pharmaceutically acceptable carrier and/or pharmaceutically acceptable vehicle” comprised in the composition of claim 1 and the one that is “utilized” in the method of claim 14. Secondly, it is not clear how the carrier/vehicle is to be utilized in the claimed method.
Claim 15 recites “The method of claim 14, further comprising: administering the pharmaceutical composition of claim 1 to a subject to vaccinate a subject against SARS-CoV-2.” It is not clear what difference there is between claims 14 and 15. Considering that claim 14 recites administering the subject already, does claim 15 require administering a subject at least twice?
Claim 19 recites “such as annually or bi-annually”. It is not clear if this limitation is required or not.
Applicant is invited to clarify and/or make appropriate amendment.
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.
(Previous Rejection – Withdrawn) Claims 1-2 and 10-20 were rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter because it is directed to a judiciary exception.
This rejection is withdrawn in view of the amendment filed on Mar. 17, 2026.
Claim Rejections - 35 USC § 102
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.
(Previous Rejection – Withdrawn) Claims 1-2 and 10-20 were rejected under 35 U.S.C. 102(a) as being anticipated by Gao et al. (Science 369, 77–81 (2020)).
This rejection is withdrawn in view of the amendment filed on Mar. 17, 2026.
Claim Rejections - 35 USC § 103
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 of this title, 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.
(Previous Rejection – Maintained) Claims 1-2, 4-9 and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Erasmus et al. (bioRxiv [Preprint]. 2020 May 28:2020.05.28.121640) in view of Ahmed et al. (Viruses 2020, 12, 254; published: 25 February 2020) and/or Dutta et al. (J Virol 94:e00647-20; published on Jun. 16, 2020).
The base claim 1, as amended, is directed to a pharmaceutical composition comprising
- a sequence encoding a SARS-CoV-2 Spike protein antigen and a sequence encoding a SARS-CoV-2 Nucleocapsid antigen, wherein the sequence encoding the SARS-CoV-2 Spike protein antigen and the sequence encoding the SARS-CoV-2 Nucleocapsid protein antigen are comprised in an effective amount of one or more self-replicating RNA molecules, wherein the self-replicating RNA molecules are derived from an alphavirus and comprise a sequence encoding for nonstructural alphavirus proteins, and wherein the self-replicating RNA molecules are encapsulated in, bound to or adsorbed on a cationic lipid, a liposome, a lipid nanoparticle and combinations thereof; and
- a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable vehicle.
Claims 14-20, as amended, are directed a method of inducing an immune response in a subject comprising administering the pharmaceutical composition of claim 1.
Erasmus teaches a single-dose replicating RNA vaccine against SARS-CoV-2. The authors developed repRNA-CoV2S, a stable and highly immunogenic vaccine candidate comprised of an RNA replicon formulated with a novel Lipid InOrganic Nanoparticle (LION) designed to enhance vaccine stability, delivery and immunogenicity. Intramuscular injection of LION/repRNA-CoV2S elicits robust anti-SARS-CoV-2 spike protein IgG antibody isotypes indicative of a Type 1 T helper response as well as potent T cell responses in mice. A single-dose administration in nonhuman primates elicited antibody responses that potently neutralized SARS-CoV-2. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection from SARS-CoV-2 infection. See Abstract.
Figure 1 of Erasmus shows the structure and characterization of the repRNA-CoV2S construct. See below.
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Accordingly, Erasmus teaches a vaccine composition comprising a self-replicating RNA construct, repRNA-CoV2S, comprising a sequence encoding a SARS-CoV-2 Spike antigen and a sequence from an alphavirus, VEEV strain TC-83 (see page 5, para 1), encoding the alphavirus nonstructural proteins nsP1, nsP2, nsP3, nsP4, that confer the construct the ability to self-replicate. Erasmus further teaches that the repRNA-CoV2S construct is incorporated in Lipid InOrganic Nanoparticle (LION), which also functions as an adjuvant (see page 5, para 2). However, Erasmus is silent on a SARS-CoV-2 vaccine construct comprising a sequence encoding SARS-CoV-2 nucleocapsid (N) protein antigen built on the same alphavirus platform.
Ahmed teaches that the authors sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally-determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, they identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. Their findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2. See Abstract.
Dutta discusses about the potential of the nucleocapsid protein of SARS-CoV-2 as a target for vaccine development. It teaches that, in construct to the S protein which has a high mutation rate, the N gene is more conserved and stable, with 90% amino acid homology and fewer mutations over time. N proteins of many coronaviruses are highly immunogenic and are expressed abundantly during infection. High levels of IgG antibodies against N have been detected in sera from SARS patients, and the N protein is a representative antigen for the T-cell response in a vaccine setting, inducing SARS-specific T-cell proliferation and cytotoxic activity. The middle or C-terminal region of the SARS-CoV N protein have been shown to be important for eliciting antibodies against SARS-CoV during the immune response. Several reports offer important and timely insights relevant to the SARS-CoV-2 N protein, a vaccine target that has some distinct advantages over other potential SARS-CoV-2 antigens. Because of the conservation of the N protein sequence, the expanding knowledge of its genetics and biochemistry, and its strong immunogenicity, the N protein of SARS-CoV-2 should be strongly considered as a vaccine candidate for SARS-CoV-2. See pages 1 and 2.
Accordingly, teachings of both Ahmed and Dutta suggest that the nucleocapsid protein of SARS-CoV-2 is a potential vaccine target.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Erasmus, Ahmed and Dutta to arrive at the invention as claimed. One would have been motivated to do so to evaluate the vaccine potential of a self-replicating alphavirus-based nucleic acid construct, similar to that of Erasmus, that comprises a sequence encoding a SARS-CoV-2 nucleocapsid antigen, as well as the vaccine potential of a combination of both the S and N proteins of SARS-CoV-2.
Regarding claims 6-7, Erasmus teaches using the full-length S protein in the repRNA-CoV2S vaccine construct while Ahmed discloses potential immunogenic epitopes in the S and N proteins of SARS-CoV-2 that can be targeted (see Tables 3-4). One of skill in the art would have found it obvious to select regions of the S protein to be included for expression in a nucleic acid vaccine construct for best protection effect through routine experimental optimization, including a truncated form of the S protein as claimed, unless there is evidence that the claimed truncated form is critical.
Regarding claims 8-9, Erasmus teaches that following RNA transcription and capping, repRNA-COV2S, was transfected into BHK cells (see Figure 1 legend) and that the RNA replicon was transcribed from template DNA and capped with NEB Vaccinia Capping System (See line 342). Erasmus is silent on the existence of a poly A tail downstream of the SAR-CoV-2 S gene. Since poly A is commonly included downstream of a gene to be expressed, one of skill in the art would have assumed that the construct disclosed in Erasmus comprises a poly A sequence.
Response to Applicant’s Arguments
Applicant’s arguments in the response filed on Mar. 17, 2026 are fully considered. Arguments regarding withdrawn rejections are moot. Applicant’s arguments relevant to the current rejections addressed as follows.
To the 103 rejection over Erasmus, Ahmed and Dutta, Applicant argues that there is no motivation to combine the virus-derived replicon RNA (repRNA), delivered in Venezuelan equine encephalitis virus-like RNA particles (VRP) of Erasmus with the epitopes of Ahmed and/or Dutta. Applicant argue that Ahmed is not an enabling prior art and lacks detailed enabling methodology or suggestion to successfully modify Erasmus to a multi-epitope vaccine. Applicant argues that although Dutta mentioned that the nucleocapsid gene has more conserved gene sequence and elicits a strong immune response, Dutta also remains silent on the combination of S and N antigens as a promising therapeutic target in the successful development of a multi-epitope vaccine. Applicant argues that in accordance with MPEP 2145(X.)(B.), it may not have been obvious to those of ordinary skill in the art to combine the self-replicating RNA derived from an alphavirus with encoding sequences of the SARS-CoV-2 spike protein and nucleocapsid simultaneously as a multi-epitope vaccine to successfully overcome the innate and adaptive immune response or interference.
Applicant’s arguments are not persuasive.
One cannot show nonobviousness only by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091,231 USPQ 375 (Fed. Cir. 1986). Erasmus teaches a vaccine composition comprising a self-replicating RNA construct, repRNA-CoV2S, comprising a sequence encoding a SARS-CoV-2 Spike antigen and a sequence from an alphavirus, VEEV strain TC-83 (see page 5, para 1), encoding the alphavirus nonstructural proteins nsP1, nsP2, nsP3, nsP4, that confer the construct the ability to self-replicate. Erasmus further teaches that the repRNA-CoV2S construct is incorporated in Lipid InOrganic Nanoparticle (LION), which also functions as an adjuvant (see page 5, para 2). Teachings of Erasmus indicate that it is contemplated and practiced at the time of instant invention to construct an alphavirus virus vector expressing a SARS-CoV-2 antigen (S protein) as a vaccine candidate against SARS-CoV-2 infection. At the same time, teachings of Ahmed and Dutta indicate that SARS-CoV-2 nucleocapsid protein (N protein) is also a potential target antigen for SARS-CoV-2 vaccines. One of skill in the art would have reasonably been motivated by the teachings of these three references to construct an alphavirus vector expressing the nucleocapsid protein to evaluate the vaccine efficacy of an alphavirus replicon expressing a SARS-CoV-2 N protein as a vaccine candidate, as well as combination of alphavirus replicons expressing both S and N proteins. Such a combination of multiple antigens in one vaccine composition is commonly practiced at the time of invention, as indicated in the prior art reference Deming et al. presented by Applicant in the previous response.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571) 272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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