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 .
Applicant’s amendment, filed on 4/06/2023, is acknowledged.
Claims 1-17, 19, 21, and 22 are currently pending.
Election/Restrictions
Applicants’ election without traverse of Group I, claims 1, 3-17 and 19, directed to an immunogenic composition comprising a truncated SARS-CoV-2 antigen and a CpG TLR9 agonist, and the species of: SEQ ID NO: 1, E protein, and aluminum hydroxide, filed on 12/03/2025, is acknowledged.
Claims 2, 21 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
Claims 1, 3-17 and 19 are under examination.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 4/14/2023 and 12/03/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No 62/983,737, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. In particular the ‘737 application fails to provide support for an immunogenic composition comprising the S protein of SARS-CoV-2 comprising an S protein ectodomain without an S1/S2 furin recognition site (claim 9), residues 12-1208 of SEQ ID NO: 6 (claim 10), or the trimerization domains recited in claims 11 and 12. The ‘737 application does not claim or disclose a SEQ ID NO: 6.
The subject matter of these claims are entitled to the benefit of priority to 63/040,696, filed June 18, 2020 since the instantly claimed subject matter is supported therein.
Claim Objections
Claim 1 is objected to because of the following informalities:
The recitation in claim 1 of "wherein the SARS-CoV-2 antigen comprises a truncated, recombinant S protein devoid of signal peptide, transmembrane, and cytoplasmic domains of a full length S protein" most likely should read "wherein the SARS-CoV-2 antigen comprises a truncated, recombinant S protein devoid of a signal peptide, transmembrane, and cytoplasmic domains of a full length S protein." to correct a minor typographical error. Appropriate correction is required.
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.
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.
Claims 8-12 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.
Claim 8, as amended and submitted on 04/06/2023 recites "wherein the immunogenic composition comprises from about 750 μg to about 3000 μg of the oligonucleotide". This recitation is unclear because the amounts of oligonucleotide in a composition, such as an immunogenic composition, are expressed as concentrations, for example micrograms per milliliter (μg/ml). The above recitation seemingly indicates absolute amounts of oligonucleotide, and therefore it is not clear if these amounts refer to levels of oligonucleotide in an immunogenic composition or not. It is noted that prior to the amendment claim 8 recited "a 0.5 ml dose". Therefore, the claim is indefinite. The dependent claims 9-12 do not add clarity and therefore they are also indefinite. For purposes of compact prosecution and applying prior art, claim 8 was interpreted herein as referring to concentrations of micrograms per milliliter of an immunogenic composition (μg/ml).
Claim 17, as amended and submitted on 04/06/2023 recites "wherein the immunogenic composition comprises from about 0.05 mg to about 0.50 mg of Al+3". This recitation is unclear because the amounts of a compound comprising an aluminum salt (as recited in claim 15) in a composition, such as an immunogenic composition, are expressed as concentrations, for example milligrams per milliliter (mg/ml). The above recitation seemingly indicates absolute amounts of a compound comprising an aluminum salt and therefore it is not clear if these amounts refer to levels of a compound comprising an aluminum salt in an immunogenic com position or not. It is noted that prior to the amendment claim 17 recited "a 0.5 ml dose". Therefore, the claim is indefinite. For purposes of compact prosecution and applying prior art, claim 17 was interpreted herein as referring to concentrations of milligrams per milliliter of a compound comprising an aluminum salt in an immunogenic composition (mg/ml).
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this Office Action. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office Action.
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.
Claims 1, 3-9, 13-17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Rappouli et al. (U.S. PGPub 20060257852, in IDS filed 4/14/2023) in view of Wu et al. (Nature. 2020 Mar;579(7798):265-269. doi: 10.1038/s41586-020-2008-3. Epub 2020 Feb 3, in IDS filed 4/14/2023) and Dina et al. (U.S. Patent No. 7,745,606), as evidenced by Zhang et al. (Emerg Microbes Infect. 2022 Dec;11(1):182-194. doi: 10.1080/22221751.2021.2014284).
Rappouli et al. teaches immunogenic compositions comprising SARS virus antigens (¶[0008], [0122], [0560], [0561]): “The invention relates to nucleic acids and proteins from Severe Acute Respiratory Syndrome (SARS) virus. These nucleic acids and proteins can be used in the preparation and manufacture of vaccine formulations for the treatment or prevention of SARS. Such vaccine formulations may include an inactivated ( or killed) SARS virus, an attenuated SARS virus, a split SARS virus preparation and a recombinant or purified subunit formulation of one or more SARS viral antigens…”
Rappouli et al. further teaches the immunogenic compositions also comprising immunostimulatory oligonucleotides such as a TLR9 agonist comprising a single stranded, unmethylated CpG motif (¶[0879]-[0881]): “Immunostimulatory oligonucleotides suitable for use as adjuvants in the invention include nucleotide sequences containing a CpG motif (a sequence containing an unmethylated cytosine followed by guanosine and linked by a phosphate bond)…the CpG sequence may be directed to TLR9…”
Rappouli et al. does not teach immunogenic compositions comprising a SARS-CoV-2 antigen, that is a truncated recombinant spike (S) protein devoid of signal peptide, transmembrane, and cytoplasmic domains, or a CpG motif that is 10-35 nucleotides in length (i.e., the limitations of instant claim 1).
Wu et al., in the same field of endeavor, teaches the full genomic sequence of SARS-CoV-2 (Abstract, pages 265-267): “Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here “WH-Human 1” coronavirus (and has also been referred to as “2019-nCoV”).”
Wu et al. further teaches a recombinant truncated SARS-CoV-2 fragment comprising the RBD domain of the spike protein (pg. 270, Figs. 7 and 8): “[t]o better understand the potential of WHCV to infect humans, the receptor binding domain (RBD) of its spike protein was compared with those of SARS-CoVs and bat SARS-like CoVs…”. The sequence for this fragment is designated “WH-human 1” in Figs. 7 and 8. The RBD domain sequence in Fig. 7 lacks the signal peptide, TM domain, and cytoplasmic domain.
Dina et al., in the same field of endeavor, teaches compositions comprising a viral antigen and immunomodulatory polynucleotides (Abstract), including SEQ ID NO: 102, which is 13 nucleotides in length and comprises a nucleotide sequence which comprises a segment that is 100% identical to instant SEQ ID NO: 1 (i.e., the limitations of instant claim 3):
Qy 1 TGACTGTGAACGTTCGAGATGA 22
||||||||||||||||||||||
Db 1 TGACTGTGAACGTTCGAGATGA 22
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have incorporated the SARS-CoV-2 sequences of Wu et al. and the immunomodulatory polynucleotides taught by Dina et al. into the immunogenic compositions taught by Rappouli et al. for the benefit of formulating a vaccine composition against SARV-CoV-2 for an enhanced immune response. See MPEP 2144.07. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
One of ordinary skill in the art would have had reasonable expectation of success in incorporating the SARS-CoV-2 sequences of Wu et al. and the immunomodulatory polynucleotides taught by Dina et al. into the immunogenic compositions taught by Rappouli et al. given that the methods of formulating vaccine compositions comprising viral sequences and known immunomodulatory polynucleotides such as TLR9 agonists are well known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Regarding claims 4-6, Rappouli et al. further teaches immunostimulatory oligonucleotides such as a TLR9 agonist comprising a single-stranded, unmethylated CpG motif also bear modifications such as phosphorothioate modifications, or other modifications such as guanine replaced by 2’-deoxy-7-deazaguanosine (¶[0879]-[0881]): “[t]he CpG's can include nucleotide modifications/ analogs such as phosphorothioate modifications…the guanosine
may be replaced with an analog such as 2'-deoxy-7- deazaguanosine…”.
Regarding claims 7 and 8, Rappouli et al. further teaches the immunostimulatory oligonucleotides are single-stranded oligodeoxynucleotides of CpG ODNs (¶[0881]), wherein the dose can be adjusted to reach a suitable concentration, as determined by techniques accepted and routine in the art (¶[1124]). Rappouli et al. further teaches concentrations on the order of 5-20µg of recombinant spike antigen, alone or mixed with an equal volume of adjuvant, in 100 µL of the composition (¶[1532]). These amounts are equivalent to 50-200 µg/mL. It is noted that the courts have stated where the claimed ranges "overlap or lie inside the ranges disclosed by the prior art" and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See MPEP 2144.05.01. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Further, the range recited in claim 8 is considered to be one determined by routine optimization according to one of skill in the art in view of the teachings of Rappouli et al. (¶[1532]).
Regarding claim 9, Zhang et al. is provided as an evidentiary reference to demonstrate the sequence of the SARS-CoV-2 S1/S2 furin recognition site (Figure 1), which is ASYQTQTNSPRRARSVASQSIIAYTMSLG. This recognition site is not found in the RBD fragment taught by Wu et al. in Fig. 7.
Regarding claim 13, Rappouli et al. further teach compositions comprising one or more SARS-CoV antigens, including a membrane (M) protein, a nucleocapsid (N) protein, and an envelope (E) protein (¶[0657]). Additionally, as indicated above, Wu et al. specifically teaches the full genomic sequence of SARS-CoV-2, which also includes these elements (Abstract, pg. 265-267).
Regarding claims 14-17, Rappouli et al. further teaches compositions can further comprise an aluminum salt adjuvant such as aluminum hydroxide (¶[0011], [0914]). Rappouli et al. does not explicitly teach the concentration of the aluminum salt present in the composition. However, the use of such compounds in compositions is well known and routine in the art, see Rappouli et al. (¶[0914]). Accordingly, the range recited in claim 17 is considered to be one determined by routine optimization according to one of skill in the art in view of the teachings of Rappouli et al. (¶[0914]).
Regarding claim 19, the immunogenic composition of claim 1 was rendered
obvious by the teachings of Rappouli et al., Wu et al. and Dina et al., as evidenced by Zhang et al. Rappouli et al. further teach kits comprising the SARS composition and instructions for administration to humans to induce an immune response, including intramuscular administration (¶[0181], [0028], and [0862]).
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.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Rappouli et al. (supra) in view of Wu et al. (supra) and Dina et al. (supra), as evidenced by Zhang et al. (supra), as applied to claims 1, 3-9, 13-17, and 19 above, and further in view of Simon-Loriere et al. (U.S. Patent 11,759,516).
Simon-Loriere et al. claims priority to provisional application 62/976,148, filed on 2/13/2020, which is before the effective filing date of the instant application for claim 10 (6/18/2020). Simon-Loriere et al. is prior art under 35 U.S.C § 102(a)(2).
The combined teachings of Rappouli et al., Wu et al., and Dina et al, as evidenced by Zhang et al., have been discussed supra. The combined teachings do not teach a S protein ectodomain that comprises residues 14-1208 of instant SEQ ID NO: 6.
Simon-Loriere et al., in the same field of endeavor, teaches recombinant SARS-CoV-2 spike antigens as immunogenics or vaccines (Col. 1, lines 26-26): “The invention relates to an immunogenic or vaccine composition against the 2019 novel coronavirus…comprising a nucleic acid construct encoding a SARS-CoV-2 coronavirus Spike (S) protein…the invention also relates to said nucleic acid construct, derived vector, antigen encoded by said nucleic acid…”, including SEQ ID NO: 30, which comprises an amino acid sequence that is 99.7% identical to residues 14-1208 of instant SEQ ID NO: 6:
Qy 1 QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 14 QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGT 73
Qy 61 NGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 74 NGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEF 133
Qy 121 QFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 134 QFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFV 193
Qy 181 FKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGD 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 194 FKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGD 253
Qy 241 SSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 254 SSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIY 313
Qy 301 QTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSAS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 314 QTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSAS 373
Qy 361 FSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 374 FSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCV 433
Qy 421 IAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQ 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 434 IAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQ 493
Qy 481 SYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 494 SYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLT 553
Qy 541 ESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQ 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 554 ESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQ 613
Qy 601 DVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICAS 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 614 DVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICAS 673
Qy 661 YQTQTNSPGSASSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTK 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 674 YQTQTNSPGSASSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTK 733
Qy 721 TSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPP 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 734 TSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPP 793
Qy 781 IKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQ 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 794 IKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQ 853
Qy 841 KFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQ 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 854 KFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQ 913
Qy 901 NVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAI 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 914 NVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAI 973
Qy 961 SSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECV 1020
|||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||
Db 974 SSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECV 1033
Qy 1021 LGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1034 LGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREG 1093
Qy 1081 VFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELD 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1094 VFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELD 1153
Qy 1141 KYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQ 1195
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1154 KYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQ 1208
Simon-Loriere et al. further teaches the spike protein antigen further comprising the K986P and V987P mutations (Col. 6, lines 20-25): “In some particular embodiments, the S antigen comprises a mutation which stabilizes the Spike trimer. Such mutations which are well-known in the art include the K986P and V987P mutations (S-2P variant)”.
Adding these two point mutations to SEQ ID NO: 30 of Simon-Loriere et al. yields a spike protein that comprises a sequence that is 100% identical to residues 14-1208 of instant SEQ ID NO: 6:
Qy 1 QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 14 QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGT 73
Qy 61 NGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 74 NGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEF 133
Qy 121 QFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 134 QFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFV 193
Qy 181 FKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGD 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 194 FKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGD 253
Qy 241 SSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 254 SSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIY 313
Qy 301 QTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSAS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 314 QTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSAS 373
Qy 361 FSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 374 FSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCV 433
Qy 421 IAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQ 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 434 IAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQ 493
Qy 481 SYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 494 SYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLT 553
Qy 541 ESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQ 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 554 ESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQ 613
Qy 601 DVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICAS 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 614 DVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICAS 673
Qy 661 YQTQTNSPGSASSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTK 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 674 YQTQTNSPGSASSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTK 733
Qy 721 TSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPP 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 734 TSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPP 793
Qy 781 IKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQ 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 794 IKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQ 853
Qy 841 KFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQ 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 854 KFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQ 913
Qy 901 NVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAI 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 914 NVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAI 973
Qy 961 SSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECV 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 974 SSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECV 1033
Qy 1021 LGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1034 LGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREG 1093
Qy 1081 VFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELD 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1094 VFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELD 1153
Qy 1141 KYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQ 1195
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1154 KYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQ 1208
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have replaced the SARS-CoV-2 sequences of Wu et al. and the immunomodulatory polynucleotides taught by Dina et al. into the immunogenic compositions taught by Rappouli et al. with the SARS-CoV-2 antigen taught by Simon-Loriere et al. with a reasonable expectation of success, as one with ordinary skill in the art would appreciate the amino acid sequences taught in Wu et al. and Simon-Loriere et al. can both be used as SARS-CoV-2 immunogenic compounds. One would have been motivated to make this change for the purposes of developing a SARS-CoV-2 immunogenic/vaccine with the spike protein sequence of Simon-Loriere et al.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Rappouli et al. (supra) in view of Wu et al. (supra) and Dina et al. (supra), and Simon-Loriere et al. (supra), as evidenced by Zhang et al. (supra), as applied to claims 1, 3-10, 13-17, and 19 above, and further in view of Li et al. (Viral Immunol. 2013 Apr;26(2):126-32. doi: 10.1089/vim.2012.0076, on IDS submitted 12/03/2025).
The combined teachings of Rappouli et al. Wu et al. Dina et al., and Simon-Loriere et al., as evidenced by Zhang et al., have been discussed supra. The combined teachings do not teach the SARS-CoV-2 antigen further comprising a C-terminal T4 trimerization domain (i.e., the limitations of instant claims 11 and 12).
Li et al., in the same field of endeavor, teaches that fusion of C-terminal T4 trimerization domain to SARS antigens, including the ectodomain of the spike protein (Abstract and Introduction): “To make trimeric recombinant spike proteins, we exploited a 27-amino acid sequence, called the foldon domain, which was identified in the bacteriophage T4 fibritin protein…).
Li et al. further teaches methods of fusing the T4 trimerization domain to the spike protein, including the T4 trimerization sequence of instant SEQ ID NO: 10 (“Construction of recombinant viruses and production of recombinant proteins” section):
Qy 1 GYIPEAPRDGQAYVRKDGEWVLLSTF 26
||||||||||||||||||||||||||
Db 13 GYIPEAPRDGQAYVRKDGEWVLLSTF 38
Li et al. teaches multiple different SARS-CoV-2 antigen/T4 fusions, including a spike protein devoid of signal, TM and cytoplasmic tail domains (“S-foldon”, Fig 1, cropped and annotated below):
PNG
media_image1.png
303
716
media_image1.png
Greyscale
Li et al. teaches that the Spike-Foldon trimers elicited the most neutralizing activities (pg. 129 and Fig 3, cropped below): “sera from the mice immunized with S-foldon showed the strongest neutralizing activities, with a geometric mean neutralizing titer of 659.6. This titer is 3.8-, 7.3-, and 2.8-fold higher than that of sera from the mice immunized with S1, S1-foldon, and S, respectively…”
PNG
media_image2.png
406
801
media_image2.png
Greyscale
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have fused a T4 foldon trimerization domain taught by Li et al. to the spike protein immunogenic composition taught by combined teachings of Rappouli et al. Wu et al. Dina et al., and Simon-Loriere et al., as evidenced by Zhang et al. with a reasonable expectation of success, as Li et al. teaches methods of doing so. One would have been motivated to make this change to induce trimerization of the SARS-CoV-2 spike protein, increasing its neutralizing activities in a subject, as taught by Li et al.
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.
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, 3-17 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,296,002 (herein Pat ‘002) in view of Rappouli et al. (U.S. PGPub 20060257852 supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
Pat ‘002 claims immunogenic compositions comprising a recombinant SARS-CoV-2 spike protein comprising, an aluminum hydroxide adjuvant, and a CpG ODN TLR9 agonist comprising SEQ ID NO: 8 (claims 1). Pat ‘002 additionally claims the spike protein comprising the amino acid sequence of SEQ ID NO: 1, which is 100% identical to residues 14-1208 of instant SEQ ID NO: 6 (i.e., the limitations of instant claims 1, 9, 10, and 14-16; Pat ‘002 claim 2):
Qy 1 QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 14 QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGT 73
Qy 61 NGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 74 NGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEF 133
Qy 121 QFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 134 QFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFV 193
Qy 181 FKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGD 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 194 FKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGD 253
Qy 241 SSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 254 SSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIY 313
Qy 301 QTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSAS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 314 QTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSAS 373
Qy 361 FSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 374 FSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCV 433
Qy 421 IAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQ 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 434 IAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQ 493
Qy 481 SYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 494 SYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLT 553
Qy 541 ESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQ 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 554 ESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQ 613
Qy 601 DVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICAS 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 614 DVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICAS 673
Qy 661 YQTQTNSPGSASSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTK 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 674 YQTQTNSPGSASSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTK 733
Qy 721 TSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPP 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 734 TSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPP 793
Qy 781 IKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQ 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 794 IKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQ 853
Qy 841 KFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQ 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 854 KFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQ 913
Qy 901 NVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAI 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 914 NVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAI 973
Qy 961 SSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECV 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 974 SSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECV 1033
Qy 1021 LGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1034 LGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREG 1093
Qy 1081 VFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELD 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1094 VFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELD 1153
Qy 1141 KYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQ 1195
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1154 KYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQ 1208
Pat ‘002 additionally claims the CpG ODN of SEQ ID NO: 8, which is 100% identical to instant SEQ ID NO: 1 and contains instant SEQ ID NO: 3 (i.e., the limitations of instant claim 3; Pat ‘002 claim 1):
Qy 1 TGACTGTGAACGTTCGAGATGA 22
||||||||||||||||||||||
Db 1 TGACTGTGAACGTTCGAGATGA 22
Pat ‘002 additionally claims the limitations of instant claim 8 (Pat ‘002 claim 5), instant claim 17 (Pat ‘002 claim 4), as well as the immunogenic compositions further comprising a T4 trimerization domain that comprises SEQ ID NO: 2 (claim 1), which is 32 nucleotides in length and comprises a sequence that is 100% identical to instant SEQ ID NO: 10 (i.e., the limitations of instant claims 11 and 12):
Qy 3 GYIPEAPRDGQAYVRKDGEWVLLSTF 28
||||||||||||||||||||||||||
Db 1 GYIPEAPRDGQAYVRKDGEWVLLSTF 26
Pat ‘002 does not claim the limitations of instant claims 4-7, 13, or 19.
Rappouli et al., in the same field of endeavor, teaches immunogenic compositions comprising SARS virus antigens (¶[0008], [0122], [0560], [0561]). Rappouli et al. further teaches the immunogenic compositions also comprising immunostimulatory oligonucleotides such as a TLR9 agonist comprising a single stranded, unmethylated CpG motif (¶[0879]-[0881]). Rappouli et al. further teach compositions comprising one or more SARS-CoV antigens, including a membrane (M) protein, a nucleocapsid (N) protein, and an envelope (E) protein (¶[0657]). Rappouli et al. additionally teaches teach kits comprising the SARS composition and instructions for administration to humans to induce an immune response, including intramuscular administration (¶[0181], [0028], and [0862]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the invention claimed by Pat ‘002 in view of Rappouli et al. to have used modified CpG single-stranded nucleotides with the modifications recited in instant claims 4-7, the additional SARS-CoV-2 elements in instant claim 13, and put the immunogenic composition in a kit with a reasonable expectation of success, as Rappouli teaches these elements for used in SARS immunogenic compositions that one with ordinary skill in the art would be able to apply to the invention of Pat ‘002. One would have been motivated to make these changes for the purposes of making an immunogenic composition to vaccinate a subject against COVID-19/SARS-CoV-2.
The invention encompassed by the instant claims was a prima facie obvious variant of the invention claimed by Pat ‘002 in view of Rappouli et al.
Claims 1, 3-8, 13-17, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,684,669 (herein Pat ‘669) in view of Rappouli et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
Pat ‘669 claims SARS-CoV-2 immunogenic compositions comprising a SARS-CoV-2 spike protein of SEQ ID NO: 3, a CpG ODN of SEQ ID NO: 4, and an alum adjuvant (claim 1).
SEQ ID NO: 3 of Pat ‘669 comprises a spike protein that devoid of signal peptide, a TM domain, or a cytoplasmic domain, meeting the limitations of instant claim 1.
SEQ ID NO: 4 of Pat ‘669 comprises a nucleotide sequence that is 22 nucleotides in length and is 100% identical to instant SEQ ID NO: 1, meeting the limitations of instant claim 3. Pat ‘669 additionally claims aluminum hydroxide adjuvants (i.e., the limitations of instant claim 14-16; Pat ‘669 claim 3), overlapping TLR9 agonist dosage values to those of instant claim 8 (i.e., the limitations of instant claim 8; Pat ‘669 claim 8), and kits comprising the immunogenic compositions (i.e., the limitations of instant claim 19; Pat ‘669 claims 17 and 18).
Pat ‘669 does not claim the limitations of instant claims 4-7, 13, or 17.
The invention encompassed by the instant claims was a prima facie obvious variant of the invention claimed by Pat ‘669 in view of Rappouli et al. for the same reasons discussed for Pat ‘002 supra.
Regarding claim 17, Rappouli et al. further teaches compositions can further comprise an aluminum salt adjuvant such as aluminum hydroxide (¶[0011], [0914]). Rappouli et al. does not explicitly teach the concentration of the aluminum salt present in the composition. However, the use of such compounds in compositions is well known and routine in the art, see Rappouli et al. (¶[0914]). Accordingly, the range recited in claim 17 is considered to be one determined by routine optimization according to one of skill in the art in view of the teachings of Rappouli et al. (¶[0914]).
Therefore, the invention encompassed by the instant claims was a prima facie obvious variant of the invention claimed by Pat ‘669 in view of Rappouli et al.
Claims 9 and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,684,669 (Pat ‘669, supra) in view of Rappouli et al. (supra), as applied to claims 1, 3-8, 13-17, and 19 above, and further in view of Simon-Loriere et al. (U.S. Patent 11,759,516, supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
The invention encompassed by instant claims 1, 3-8, 13-17, and 9 are a prima facie obvious variant of the invention claimed by Pat ‘669 in view of Rappouli et al. for the reasons discussed supra. Pat ‘669 in view of Rappouli et al. does not teach a specific spike protein sequence without a S1/S2 furin recognition site (i.e., the limitations of instant claims 9 and 10).
Simon-Loriere et al., in the same field of endeavor, teaches recombinant SARS-CoV-2 spike antigens as immunogenics or vaccines (Col. 1, lines 26-26): “The invention relates to an immunogenic or vaccine composition against the 2019 novel coronavirus…comprising a nucleic acid construct encoding a SARS-CoV-2 coronavirus Spike (S) protein…the invention also relates to said nucleic acid construct, derived vector, antigen encoded by said nucleic acid…”, including SEQ ID NO: 30, which comprises an amino acid sequence that is 99.7% identical to residues 14-1208 of instant SEQ ID NO: 6).
Simon-Loriere et al. further teaches the spike protein antigen further comprising the K986P and V987P mutations (Col. 6, lines 20-25): “In some particular embodiments, the S antigen comprises a mutation which stabilizes the Spike trimer. Such mutations which are well-known in the art include the K986P and V987P mutations (S-2P variant)”.
Adding these two point mutations to SEQ ID NO: 30 of Simon-Loriere et al. yields a spike protein that comprises a sequence that is 100% identical to residues 14-1208 of instant SEQ ID NO: 6 (see 35 U.S.C § 103 rejection supra).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the invention claimed by the combined teachings of Pat ‘669 and Rappouli et al. further in view of Simon-Loriere et al. to use the specific SARS-CoV-2 sequences taught by Simon-Loriere et al. in the immunogenic compositions claimed by Pat ‘669 in view of Rappouli et al. with a reasonable expectation of success, as both references concern COVID-19 vaccines that one with ordinary skill in the art would appreciated can be used together. One would have been motivated to make this change for the purposes of developing a SARS-CoV-2 immunogenic/vaccine.
The invention encompassed by the instant claims was a prima facie obvious variant of Pat ‘669 in view of Rappouli et al., and further in view of Simon-Loriere et al.
Claims 11 and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,684,669 (Pat ‘669, supra) in view of Rappouli et al. (supra) and Simon-Loriere et al. (supra), as applied to claims 1, 3-10, 13-17, and 19 above, and further in view of Li et al. (Viral Immunol. 2013 Apr;26(2):126-32. doi: 10.1089/vim.2012.0076, in IDS filed 12/03/2025, supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
The invention encompassed by instant claims 1, 3-10, 13-17, and 9 are a prima facie obvious variant of the invention claimed by Pat ‘669 in view of Rappouli et al. and Simon-Loriere et al. for the reasons discussed supra. The combined teachings do not teach the SARS-CoV-2 antigen further comprising a C-terminal T4 trimerization domain (i.e., the limitations of instant claims 11 and 12).
Li et al., in the same field of endeavor, teaches that fusion of C-terminal T4 trimerization domain to SARS antigens, including the ectodomain of the spike protein (Abstract and Introduction): “To make trimeric recombinant spike proteins, we exploited a 27-amino acid sequence, called the foldon domain, which was identified in the bacteriophage T4 fibritin protein…).
Li et al. further teaches methods of fusing the T4 trimerization domain to the spike protein, including the T4 trimerization sequence of instant SEQ ID NO: 10 (“Construction of recombinant viruses and production of recombinant proteins” section).
Li et al. teaches multiple different SARS-CoV-2 antigen/T4 fusions, including a spike protein devoid of signal, TM and cytoplasmic tail domains (Fig. 1).
Li et al. teaches that the Spike-Foldon trimers elicited the most neutralizing activities (pg. 129 and Fig 3, cropped below): “sera from the mice immunized with S-foldon showed the strongest neutralizing activities, with a geometric mean neutralizing titer of 659.6. This titer is 3.8-, 7.3-, and 2.8-fold higher than that of sera from the mice immunized with S1, S1-foldon, and S, respectively…”
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have fused a T4 foldon trimerization domain taught by Li et al. to the spike protein immunogenic composition taught by combined teachings of Pat ‘669 in view of Rappouli et al. and Simon-Loriere et al. with a reasonable expectation of success, as Li et al. teaches methods of doing so. One would have been motivated to make this change to induce trimerization of the SARS-CoV-2 spike protein, increasing its neutralizing activities in a subject.
The invention encompassed by the instant claims was a prima facie obvious variant of the invention claimed by Pat ‘669 in view of Rappouli et al. and Simon-Loriere et al., and further in view of Li et al. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3-10, 13-17, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/592,811 (herein App ‘811) in view of Rappouli et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘811 claims immunogenic compositions comprising a recombinant SARS-CoV-2 spike protein comprising SEQ ID NO: 14 or 15 (claims 1 and 2). SEQ ID NO: 14 and 15 are both 97.8% identical to residues 14-1208 of instant SEQ ID NO: 6 and have the S1/S2 furin recognition site abolished via the GSAS mutations at positions 679-682 (i.e., the limitations of instant claims 1, 9, 10). App ‘811 additionally claims the adjuvant comprising aluminum hydroxide (claim 3) at doses of 250-1500µg (claim 4), meeting the limitations of instant claims 14-17. App ‘811 further claims the immunogenic compositions further comprising unmethylated CpG ODNs of SEQ ID NO: 7 (claim 5), which is 22 nucleotides in length and 100% identical to instant SEQ ID NO: 1, meeting the limitations of instant claim 3.
App ‘811 does not claim the limitations of instant claims 4-8, 13, or 19.
The invention encompassed by the instant claims was a prima facie obvious variant of App ‘811 in view of Rappouli et al. for the same reasons discussed for Pat ‘002 and ‘669 supra. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 11 and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 19, 21, and 22 of copending Application No. 18/592,811 (App ‘811 supra) in view of Rappouli et al., as applied to claims 1, 3-10, 13-17, and 19 above, and further in view of Li et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
The invention encompassed by instant claims 1, 3-10, 13-17, and 19 was a prima facie obvious variant of the invention claimed by App ‘811 in view of Rappouli et al. for the reasons discussed supra. The combined teachings do not teach the SARS-CoV-2 antigen further comprising a C-terminal T4 trimerization domain (i.e., the limitations of instant claims 11 and 12).
The invention encompassed by the instant claims was a prima facie obvious variant of App ‘811 in view of Rappouli et al., and further in view of Li et al. for the same reasons discussed for Pat ‘669 supra. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3-10, 13-17, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 19, 21, and 22 of copending Application No. 17/908,221 (herein App ‘221) in view of Simon-Loriere et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘221 claims immunogenic compositions comprising a SARS-CoV-2 antigen and a TLR9 agonist CpG that is 10-35 nt in length (claim 1) App ‘221 additionally claims the limitations of instant claims 2-8 (App ‘221 claims 2-8) and instant claims 13-17 and 19 (App ‘221 claims 13-17 and 19).
App ‘221 does not claim a specific spike protein sequence without a S1/S2 furin recognition site (i.e., the limitations of instant claims 9 and 10).
The invention encompassed by the instant claims was a prima facie obvious variant of App ‘221 in view of Simon-Loriere et al. for the same reasons discussed for Pat ‘669 supra. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 11 and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 19, 21, and 22 of copending Application No. 17/908,221 (App ‘221 supra) in view of Simon-Loriere et al. (supra), as applied to claims 1, 3-10, 13-17, and 19 above, and further in view of Li et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
The invention encompassed by instant claims 1-17, 13-17, and 19 was a prima facie obvious variant of the invention claimed by App ‘221 in view of Simon-Loriere et al. for the reasons discussed supra. The combined teachings do not teach the SARS-CoV-2 antigen further comprising a C-terminal T4 trimerization domain (i.e., the limitations of instant claims 11 and 12).
The invention encompassed by the instant claims was a prima facie obvious variant of App ‘221 in view of Simon-Loriere et al., and further in view of Li et al. for the same reasons discussed for Pat ‘669 supra. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MAHER M HADDAD/Primary Examiner, Art Unit 1641