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
Acknowledgement is hereby made of receipt and entry of the communication filed on Apr. 28, 2025. Claims 1-16 are pending and currently examined.
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 and 12-16 are 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.
A claim directed to a judicial exception must be analyzed to determine whether the elements of the claim, considered both individually and as an ordered combination, are sufficient to ensure that the claim as a whole amounts to significantly more than the exception itself. To be patent-eligible, a claim that is directed to a judicial exception must include additional features to ensure that the claim describes a process or product that applies the exception in a meaningful way, such that it is more than a drafting effort designed to monopolize the exception.
These claims are directed to an isolated immunogenic polypeptide comprising an amino acid sequence that is at least 70% identical to any one of SEQ ID NOs: 15-113, wherein the polypeptide comprises one or more modifications compared to a native coronavirus spike protein. As indicated in the 103 rejection below over GenBank: MN908947.3 and/or GenBank: QUM14479.1, the polypeptide as claimed reads on the ectodomain region (i.e., the aa 1-1208 ectodomain) contained in naturally occurring isolates disclosed in GenBank: MN908947.3 and GenBank: QUM14479.1. Merely reciting the word “isolated” does not change the fact that the peptide as claimed exist in a naturally existing product. As to claim 16, the claim reads on the enveloped coronavirus particles.
Accordingly, claims 1, 5 and 12-16 are not patentable because they read on a naturally existing product, which is a judicial exception.
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.
Claims 1-7 and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gobeil et al. (Gobeil et al., 2021, Cell Reports 34, 108630; January 12, 2021), as evidenced by GenBank: MN908947 (Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome. Dated Mar. 18, 2020).
These claims are directed to an isolated immunogenic polypeptide comprising an amino acid sequence that is at least 70% identical to any one of SEQ ID NOs: 15-113, wherein the polypeptide comprises one or more modifications compared to a native coronavirus spike protein. Claims 2-7 further specify amino acid positions for modifications based on the amino acid sequence of SEQ ID NO: 8.
It is noted that SEQ ID NO: 8 is 100% identical to the surface glycoprotein (spike protein) sequence disclosed in GenBank: MN908947.
Gobeil teaches that the severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein is the target of vaccine design efforts to end the coronavirus disease 2019 (COVID-19) pandemic. Despite a low mutation rate, isolates with the D614G substitution in the S protein appeared early during the pandemic and are now the dominant form worldwide. The authors explore S conformational changes and the effects of the D614G mutation on a soluble S ectodomain construct. Cryoelectron microscopy (cryo-EM) structures reveal altered receptor binding domain (RBD) disposition; antigenicity and proteolysis experiments reveal structural changes and enhanced furin cleavage efficiency of the G614 variant. Furthermore, furin cleavage alters the up/down ratio of the RBDs in the G614 S ectodomain, demonstrating an allosteric effect on RBD positioning triggered by changes in the SD2 region, which harbors residue 614 and the furin cleavage site. The results elucidate SARS-CoV-2 S conformational landscape and allostery and have implications for vaccine design. See Abstract.
Gobeil teaches that all genes in this study were synthesized and sequenced by GeneImmune Biotechnology (Rockville, MD). The SARS-CoV-2 spike protein ectodomain constructs used comprised the protein residues 1-1208 (GenBank: MN908947) with or without the D614G mutation, with or without the furin cleavage site RRAR (residue 682-685) mutated to GSAS or LEVLFQGP (HRV3C protease site), a C-terminal T4 fibritin trimerization motif, a C-terminal HRV3C protease cleavage site (except for the constructs where the furin site was mutated to an HRV3C site), a TwinStrepTag and an 8XHisTag. See page e3, para 4. Gobeil further teaches that spike ectodomains were harvested from filtered and concentrated supernatant using StrepTactin resin (IBA) and further purified by SEC using a Superose 6 10/300 GL Increase column preequilibrated in 2mM Tris, pH 8.0, 200 mM NaCl, 0.02% sodium azide. See page e3, para 5.
Figure 1 of Gobeil shows SARS-CoV-2 Spike (S) Protein Ectodomain Platform for Characterizing the Structures, Antigenicity, and Protease Susceptibility of the S Protein and D614G Mutant. See below:
PNG
media_image1.png
926
1462
media_image1.png
Greyscale
Figure 1 also shows the amino acid substitutions introduced into the SARS-CoV-2 spike protein in the study, including the K986P-V987P substitutions encompassed by claims 2-4, the D614G encompassed by claim 5, and the RRAR to GSAS substitution on the furin cleavage site encompassed by claims 6-7.
Regarding claims 12 and 13, SEQ ID NOs: 110 and 111, which contain some claimed sequence modifications, are about 99% identical in the region of aa 1-1208 (the spike protein ectodomain), one of skill in the art would envisage that the modified S protein(s) of Gobeil with a few substitutions introduced into the spike protein sequence of GenBank: MN908947 (identical to SEQ ID NO: 8), comprise(s) sequence(s) of at least 80% identical to SEQ ID NO: 110 or 111.
Accordingly, Gobeil teaches each and every aspect of claims 1-7 and 12-15.
Claims 1-4 and 6-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hsieh et al. (Structure-based Design of Prefusion-stabilized SARS-CoV-2 Spikes. Science 369, 1501–1505 (2020)), as evidenced by GenBank: MN908947 (Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome. Dated Mar. 18, 2020).
These claims are described above.
Hsieh teaches that the coronavirus disease 2019 (COVID-19) pandemic has led to accelerated efforts to develop therapeutics and vaccines, and that the key target of these efforts is the spike (S) protein, which is metastable and difficult to produce recombinantly. The authors characterized 100 structure-guided spike designs and identified 26 individual substitutions that increased protein yields and stability. Testing combinations of beneficial substitutions resulted in the identification of HexaPro, a variant with six beneficial proline substitutions exhibiting higher expression than its parental construct (by a factor of 10) as well as the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. A cryo–electron microscopy structure of HexaPro at a resolution of 3.2 angstroms confirmed that it retains the prefusion spike conformation. High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). See Abstract.
Fig. 1 of Hsieh shows amino acid substitutions with proline, F817P, A892P, A899P, and A942P, and substitutions with cysteine, A879C, T791C, A893C and S884C, as well as modifications T961D and L938F.
Fig. 2 shows a series of amino acid substitutions. See below:
PNG
media_image2.png
952
1014
media_image2.png
Greyscale
Tables S1 and S2 show the expression summary of variants with single (Table S1) and combo (Table S2) amino acid substitutions, showing strategy (or purpose) of the amino acid modifications (e.g. relating to modifications in disulfide bonds, flexible regions, H-bonding, salt bridging, cavity-filling, etc.). Table S1 shows the substitution F817P which is specified in claims 2-4. Table S1 shows the substitution A570C which is shown to be paired with V963C. The A570C construct of Hsieh encompasses claim 8. Table S1 of Hsieh also discloses the substitutions of S975P, L938F, A972C/Q992C, I980C/Q992C, etc., specified in claim 10. Table S1 of Hsieh also discloses substitution pair of T547C/N978C, specified in claim 11.
Hsieh teaches that the SARS-CoV-2 S-2P variant was used as the base construct for all subsequent designs, that the S-2P base construct comprises residues 1-1208 of SARS-CoV-2 S (GenBank: MN908947) with prolines substituted at residues 986 and 987, “GSAS” substituted at the furin cleavage site (residues 682–685), and C-terminal foldon trimerization motif, HRV3C protease recognition site, Twin-Strep-tag and octa-histidine tag cloned into the mammalian expression plasmid pαH, and that using this plasmid as a template, desired mutations were introduced at selected positions within the SARS-CoV-2 S2 subunit. See supplement page 1.
Since the S protein construct of Hsieh were built based on the SARS-CoV-2 spike protein sequence of GenBank: MN908947, one of skill in the art would envisage that the modified S proteins of Hsieh with a few substitutions introduced into the spike protein sequence of GenBank: MN908947 (identical to SEQ ID NO: 8), comprise sequence of at least 80% identical to SEQ ID NO: 110 or 111 (which would inherently be at least 70% identical to at least one of SEQ ID NOs: 15-113).
Accordingly, Hsieh teaches each and every aspect of claims 1-4 and 6-15.
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.
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.
Claims 1, 4-5 and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over GenBank: MN908947.3 (Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome. Dated Mar. 18, 2020), and/or GenBank: QUM14479.1 (surface glycoprotein [Severe acute respiratory syndrome coronavirus 2]. Dated Jul. 27, 2021).
These claims are directed to an isolated immunogenic polypeptide comprising an amino acid sequence that is at least 70% identical to any one of SEQ ID NOs: 15-113, wherein the polypeptide comprises one or more modifications compared to a native coronavirus spike protein.
GenBank: MN908947.3 discloses the complete genome of SARS-CoV-2 isolate Wuhan-Hu-1. It discloses the amino acid sequence of the surface glycoprotein (gene S), also referred to as spike protein. The amino acids 1-1208 of the spike protein of GenBank: MN908947.3 is 99% identical to the aa 1-1208 of SEQ ID NO: 15. Some sequence regions that contain amino acid differences between SEQ ID NO: 15 and GenBank: MN908947.3 are shown below:
SEQ15 661 ECDIPIGAGICASYQTQTNSPGSASSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI 720
ECDIPIGAGICASYQTQTNSP A SVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI
MN 661 ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI 720
SEQ15 961 TLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA 1020
TLVKQLSSNFGAISSVLNDILSRLD EAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA
MN 961 TLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA 1020
GenBank: QUM14479.1 discloses amino acid sequence of the surface protein (spike protein) of the isolate SARS-CoV-2/human/USA/NJ-CDC-. The amino acids 1-1208 of the spike protein of GenBank: QUM14479.1 is 99% identical to the aa 1-1208 of SEQ ID NO: 15. Some sequence regions that contain amino acid differences between SEQ ID NO: 15 and GenBank: QUM14479.1 are shown below:
SEQ15 661 ECDIPIGAGICASYQTQTNSPGSASSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI 720
ECDIPIGAGICASYQTQTNSP A SVASQSIIAYTMSLG ENSVAYSNNSIAIPTNFTI
QUM 661 ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGVENSVAYSNNSIAIPTNFTI 720
SEQ15 961 TLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA 1020
TLVKQLSSNFGAISSVLNDILSRLD EAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA
QUM 961 TLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA 1020
According to the sequence alignment btw SEQ ID NO: 15 and GenBank: MN908947.3 or GenBank: QUM14479.1, GenBank: MN908947.3 and GenBank: QUM14479.1 each discloses a SARS-CoV-2 spike protein comprising an amino acid sequence that is about 99% identical to SEQ ID NO: 15 of the instant invention.
Alignment btw GenBank: MN908947.3 and GenBank: QUM14479.1 indicates that there are several amino acid differences between the two protein sequences. See below:
D614
MN 601 GTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSY 660
GTNTSNQVAVLYQ VNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSY
QUM 601 GTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSY 660
MN 661 ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI 720
ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLG ENSVAYSNNSIAIPTNFTI
QUM 661 ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGVENSVAYSNNSIAIPTNFTI 720
Accordingly, each one of GenBank: MN908947.3 and GenBank: QUM14479.1 can be considered as comprising one or more modifications compared to the other. However, GenBank: MN908947.3 and GenBank: QUM14479.1 are silent if the disclosed spike protein sequences are of an “isolated immunogenic polypeptide.”
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 produce an “isolated” SARS-CoV-2 spike protein based on the teachings of GenBank: MN908947.3 and/or GenBank: QUM14479.1. One would have been motivated to do so, e.g., to study the spike protein experimentally.
Regarding claims 4-5, GenBank: MN908947.3 contains D614 while GenBank: QUM14479.1 contains G614. See sequence alignment above.
Regarding claim 16, GenBank: MN908947.3 and GenBank: QUM14479.1 both disclose two SARS-CoV-2 clinical isolates. One of skill in the art would envisage that the disclosed viral isolates can exist as virus particles, which can be considered as lipid nanoparticles, since the SARS-CoV-2 virus is coated by a lipid envelope.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Gobeil et al. (Cell Reports 34, 108630; January 12, 2021) and/or Hsieh et al. (Science 369, 1501–1505 (2020)), as evidenced by GenBank: MN908947 (Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome. Dated Mar. 18, 2020), as applied above, in view of Ho et al. (International Journal of Pharmaceutics, 607 (2021) 121024).
Claim 16 is directed to a composition comprising the coronavirus spike protein polypeptide of claim 1 and further comprising a lipid nanoparticle. Here, the lipid nanoparticle is narrowly interpreted as a non-viral lipid nanoparticle.
Relevance of Gobeil, Hsieh and GenBank: MN908947 is set forth supra. However, they are silent on a nano-viral lipid nanoparticle to be included in a composition comprising SARS-CoV-2 S protein antigens.
Ho teaches that the objective of the study is to provide comprehensive information on lipid squalene nanoparticle (SQ@NP)-adjuvanted COVID-19 vaccines regarding modulating immune response and enhancing vaccine efficacy. After being adjuvanted with SQ@NP, the SARS-CoV-2 spike (S) subunit protein was intramuscularly (i.m.) administered to mice. Serum samples investigated by ELISA and virus neutralizing assay showed that a single dose SQ@NP-adjuvanted S-protein vaccine can induce antigen-specific IgG and protective antibodies comparable with those induced by two doses of nonadjuvanted protein vaccine. When the mice received a boosting vaccine injection, anamnestic response was observed in the groups of adjuvanted vaccine. Furthermore, the secretion of cytokines in splenocytes, such as interferon (IFN)-γ, interleukin (IL)-5 and IL-10, was significantly enhanced after adjuvantation of S-protein vaccine with SQ@NP; however, this was not the case for the vaccine adjuvanted with conventional aluminum mineral salts. Histological examination of injection sites showed that the SQ@NP-adjuvanted vaccine was considerably well tolerated following i.m. injection in mice. These results pave the way for the performance tuning of optimal vaccine formulations against COVID-19. See Abstract.
Accordingly, teachings of Ho indicate that lipid nanoparticles can be used together with SARS-CoV-2 S protein antigen vaccines as adjuvant, with advantages of increasing the host immune response to the vaccine antigens.
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 Gobeil, Hsieh, GenBank: MN908947 and Ho to arrive at the invention as claimed. One would have been motivated to do so to introduce the prefusion-stabilized SARS-CoV-2 spike antigens disclosed in Gobeil and Hsieh into the study of Ho so that the advantage of the lipid nanoparticle as adjuvant would be evaluated. There is a reasonable expectation of success that the lipid nanoparticle adjuvant of Ho can also enhance host immune response to the modified spike protein antigens of Gobeil and Hsieh.
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
Prosecution Insights