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 .
Preliminary Amendment
The preliminary amendment dated 06/12/2026 has been entered. Claims 1-3 and 15-17 are pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest possible effective filing date for the instant claims is March 30, 2021, based on the filing date of the provisional application 63/168,148.
Election/Restriction
Applicant’s election without traverse of Group I in the reply filed on 06/12/2026 is acknowledged.
Claims 4-9, 11-14, 18-19, 21 and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 10, 20 and 22 are cancelled
Claims 1-3 and 15-17 are under examination.
Applicant’s species election of the VLP mutant spike protein encoded by SEQ ID NO: 14 is acknowledged.
Claim Rejections – Improper Markush Grouping
Claims 1-3, 15-17 are rejected on the judicially-created basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims1-3, 15-17 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use that flows from the substantial structural feature for the following reasons:
The grouping consists of species of proteins and/or species of nucleic acids.
Both, the protein and the nucleic acids species have a large number of unknown sequences (amino acids or nucleotides changes that are encompassed as species based on the 90% identity to the listed SEQ ID NOs limitations of the claim). Therefore, all the potential species that are within the 90% identity will not share the same structure/function requirement that is needed from the Spike protein or RBDs to be all equally immunogenic inducing the same level of antibody response. Even minor changes in the amino acid sequences can lead to a different immune response.
Lastly, while the claims recite “Spike protein or RBD” this is not an art-recognized class of molecules as defined in MPEP 2117 as: that it was known within the art that each member could be substituted one for the other, with the expectation that the same intended result (be functionally equivalent) would be achieved. Therefore, in the instant case, the structurally different species are not art-recognized substitutions for each other.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
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 and 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming.
Claim 1 recites “A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus-like particle (VLP) comprising SEQ ID NO:7 and SEQ ID NO:8 or sequences at least 90% identical to SEQ ID NO: 7 and SEQ ID NO: 8…. further comprising a Spike protein or a receptor binding domain (RBD)”. Claim 2 recites the “VLP of claim 1, additionally comprising SEQ ID NO:9 or a sequence at least 90% identical thereto”. Claim 3 recites the VLP of claim 1 comprising a large number of species of the Spike protein or RBD or sequences that are 90% identical. The VLPs, recited in claims 1-3, must be capable of being used as a vaccine which encompasses a genus of agents.
Claims 2-3 and 15-17 are dependent from Claim 1 and do not materially limit the genus of agents, especially regarding the nature of the VLPs and which mutations within the VLP proteins will confer a reduced affinity or activity as vaccines and are therefore included in the rejection. These claims do not require that the genus of the claims possess any particular structure or other distinguishing feature that is characteristic of the genus as a whole. None of the claims above recite the genus by any structure that correlates with the function of the genus. In other words, none of the claim stipulate any structure/sequence that would be functional as vaccines. Therefore, the claims are drawn to a genus of agents for which there is inadequate written description.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice. “[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04, MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus MPEP 2163(II)(3)(a)(i)(C).
In the instant case, the only identifying characteristic present in the claim is a recitation of requisite activity (------------------function as vaccines). There is not even identification of any particular portion of any protein structure that must be conserved for said activity. Regarding the genus of the claims, the specification describes SARS-CoV-2 virus-like-particles (VLPs) assembled when the viral wild type (E, M, S) and nucleocapsid (N) proteins are co-expressed singly from individual plasmids (Figure 3) and the immunogenicity of the VLPs was evaluated by determining the neutralizing activity of immunized sera (Example 3). From the specification, it is clear that the applicant is in possession of species of the wild type species. The claims, however, are not limited to those species but also include the VLPs comprising N, M, S and E proteins or variants thereof with 90% identity, and the specification fails to provide a representative number of species within the recited genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, or representative number of species, the specification does not provide adequate written description of the claimed genus.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 ("definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is"). Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. The court in In re Alonso (Fed. Cir. 2008) citing In re Enzo, Enzo, 323 F.3d at 969 stated that [F]or purposes of satisfying the written description requirement, it is not enough merely to disclose a method of making and identifying compounds capable of being used to practice the claimed invention.
Claims 1-3 and 15-17 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 the wild type N, S, M and E proteins, does not reasonably provide enablement for variants consisting of at least 90% identity. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that the claimed SARS-CoV-2 VLPs comprising a very wide range of sequences for the membrane, envelope, spike proteins and potentially also the nucleocapsid protein can be used as vaccines. Thus, the cited claims are deemed very broad since these claims read on a very broad genus for each viral proteins, comprising distinct sequence species as long as they are at least 90% identical to the wild type
Nature of the invention: Claims 1-3 of the instant application are drawn to SARS-CoV-2 VLP comprising the membrane, envelope, spike proteins and potentially also the nucleocapsid protein, Claims 15-17 of the instant application are drawn to the SARS-CoV-2 VLP vaccine comprising a carrier and an (mucosal) adjuvant
Level of skill of one skilled in this art is high.
State of the Art and Predictability/Unpredictability in the Art: : The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, conservative replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). As the reference illustrates, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). This substitution need not be at a position where said residue would contact the target protein and the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. Furthermore, it is clear that the utility of the recited VLPs requires SARS-CoV-2 proteins found in nature. VLPs comprising proteins mutated such that they are insoluble or cannot have native confirmations would be ineffective at generating protective or therapeutic immune responses.
US Pat. 5,840,839 (Nov. 24, 1998) teaches at column 19 that finding a peptide that binds to a MHC molecules and stimulates immune response is not a trivial matter. The ‘839 patent at column 19, lines 53 to 67 teaches that structure a T cell epitope that stimulates immune response in context of MHC molecules is unpredictable in the current state of art. The ‘839 patent at columns 19-20, and Table 1 teaches that the various candidate T cell epitopes selected based on theoretical binding motif of one class of MHC molecule, i.e. HLA-A31 do not work when they are experimentally tested as shown in Table 1. This suggests that theoretically selected T cell binding motifs have to be tested experimentally in order to determine whether they are actually T cell epitopes or not. Mutations encompassed by the claims allow for T cell epitope mutation and so the functionality of the immunogens as broadly as currently claimed is unpredictable.
Guidance of the Specification/Working Examples: The specification describes SARS-CoV-2 virus-like-particles (VLPs) assembled when the viral wild type (E, M, S) and nucleocapsid (N) proteins are co-expressed singly from individual plasmids (Figure 3) and the immunogenicity of the VLPs was evaluated by determining the neutralizing activity of immunized sera (Example 3). From the specification, it is clear that the applicant has enabled VLPs consisting of the wild type species. The claims, however, are not limited to those species but also include the VLPs comprising N, M, S and E proteins or variants thereof with 90% identity,
The Quantitation of Experimentation Required: In the instantly claimed invention, the breadth of the different species claimed, including the breadth of possible viruses to be tested (and not all of those species will be found in nature as scape mutants), the breadth of possible assays to calculate the immunogenicity of such species, and the breadth of possible samples comprising said virus(es), would cause a skilled artisan to have to perform an undue amount of experimentation on the extremely large amount of possible mutations encompassed by said claims in order to determine if the method as claimed is enabled
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 and 3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Swann (Scientific Reports, (2020) 10:21877 1-5) as evidenced by QHD43419.1 (GenBank: QHD43419.1. membrane glycoprotein [Severe acute respiratory syndrome coronavirus 2]. VRL 18-MAR-2020. https://www.ncbi.nlm.nih.gov/protein/1791269093), QHD43418.1 (GenBank: QHD43418.1 envelope protein [Severe acute respiratory syndrome coronavirus 2] VRL 18-MAR-2020. https://www.ncbi.nlm.nih.gov/protein/1791269092) and YP_009724390 (GenBank: YP_009724390 surface glycoprotein [Severe acute respiratory syndrome coronavirus 2]. VRL 18-JUL-2020 https://www.ncbi.nlm.nih.gov/protein/YP_009724390.1).
Swann teaches non-infectious SARS-CoV-2 virus like particles (VLPs) that can be assembled by co-expressing the viral proteins S (spike), M (membrane) and E (envelope) in mammalian cells. The assembled SARS-CoV-2 VLPs possess S protein spikes on particle exterior, making them ideal for vaccine development (Abstract, entire article). Also, Figure 1A shows a schematic representation of transfection and VLP harvest and only S, M and E proteins are transfected. No viral genome is transfected to harvest the VLPs.
QHD43419.1, QHD43418.1 and YP_009724390 are simply disclosing the amino acid sequences for these proteins. QHD43419.1. teaches the amino acid sequence of the membrane protein which is 100% identical to SEQ ID NO: 7. See sequence alignments below. QHD43418.1. teaches the amino acid sequence of the envelope protein which is 100% identical to SEQ ID NO: 8. See sequence alignments below. YP_009724390 teaches the amino acid sequence of the spike protein which is 100% identical to SEQ ID NO: 1. See sequence alignments below:
MEMBRANE PROTEIN
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998
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ENVELOPE PROTEIN
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950
994
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SPIKE PROTEIN
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1009
945
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Therefore, the reference teachings anticipate the claimed invention.
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.
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 1-3 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Swann (Scientific Reports, (2020) 10:21877 1-5) as evidenced by QHD43419.1 (GenBank: QHD43419.1. membrane glycoprotein [Severe acute respiratory syndrome coronavirus 2]. VRL 18-MAR-2020. https://www.ncbi.nlm.nih.gov/protein/1791269093), QHD43418.1 (GenBank: QHD43418.1 envelope protein [Severe acute respiratory syndrome coronavirus 2] VRL 18-MAR-2020. https://www.ncbi.nlm.nih.gov/protein/1791269092), YP_009724390 (GenBank: YP_009724390 surface glycoprotein [Severe acute respiratory syndrome coronavirus 2]. VRL 18-JUL-2020 https://www.ncbi.nlm.nih.gov/protein/YP_009724390.1), Rauch (US 20190351048 A1, Publication date Nov 21, 2019) and QIA98613 (GenBank QIA98613 nucleocapsid phosphoprotein [Severe acute respiratory syndrome coronavirus 2]. VRL 06-APR-2020
https://www.ncbi.nlm.nih.gov/protein/QIA98613.1).
Swann, QHD43419.1, QHD43418.1 and YP_009724390 teachings have been discussed above and are incorporated herein in their entirety.
Swann, QHD43419.1, QHD43418.1 and YP_009724390, 1 do not teach the VLP comprising the nucleocapsid SEQ ID NO: 9 (instant claim 2) and do not teach the VLP vaccine with a carrier or an adjuvant such as saponin (instant claims 15-17).
Rauch teaches a MERS Coronavirus mRNA-based vaccine comprising MERS
coronavirus encoding a spike protein (S), a spike fragment (S1), an envelope protein (E), a membrane protein (M) or a nucleocapsid protein (N) ([0124], [0130], [0131], [0146], claims 3, 16, 29 and 70). This Vaccine can comprise a VLP [0163]-[0169], at least one pharmaceutically acceptable carrier ([0393], [0475]) and an adjuvant component ([0501], [0504]-[0512]) including saponins (page 65, 1st column second line and page 47, 2nd column, first paragraph)
Rauch does not teach SEQ ID NO: 9 (SARS-CoV-2 Nucleocapsid)
QIA98613 teaches the SARS-CoV-2 nucleocapsid protein which is 100% identical to instant SEQ ID NO: 9, see alignment below:
NUCLEOCAPSID PROTEIN
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It would have been obvious to one of ordinary skill in the art to combine the teachings of Swann, QHD43419.1, QHD43418.1 and YP_009724390 to develop VLPs containing the SARS-CoV-2 M, E, and S proteins with the teachings of Rauch and QIA98613 to incorporate the N protein to the VLP vaccine. One of ordinary skill would have been motivated to do so because Rauch teaches MERS Coronavirus VLPs comprising N, M, E and S RNAs which can be translated into their corresponding proteins since Swann demonstrates that the VLP comprising the SARS-CoV-2 (M, E and S) proteins can also be used to generate vaccines. So, using either proteins or RNA can lead to successful vaccines. It would further be obvious that utilizing the N. M. E. and S proteins from either MERS or SARS-CoV-2 can lead to successful vaccines for either virus since they both are considered coronaviruses and their N. M. E. and S proteins are highly related. There would be a reasonable expectation of success because the development of VLP-based vaccines has been investigated by several research labs for different and unrelated viruses.
It would further have been obvious to combine the teachings of Swann, QHD43419.1, QHD43418.1 and YP_009724390 with the teachings of Rauch and QIA98613 and incorporate a pharmaceutically acceptable carrier and adjuvants such as saponin to the VLPs as taught by Rauch. One of ordinary skill would have been motivated to do so because the use of carriers and adjuvants may enhance the immune response to the VLPs. There would be a reasonable expectation of success because the successful use of carriers and adjuvants is common in the field of vaccine development.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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