DETAILED ACTION
Disposition of Claims
Claims 1-3, 5, 7, 9, 11, 13-15, 18-19, 24, 26, 28-29, 33-35, 38-39, 42, 44, 46-47, 51, 53, 55-56, 63-64, 68, 75-76, and 78-79 were pending. Claims 2, 4, 6, 8, 10, 12, 14-17, 20-23, 25, 27, 30-32, 34-37, 40-41, 43, 45, 48-50, 52, 54, 57-62, 65-67, 69-74, 77, and 80-87 are cancelled. New claims 88-89 are acknowledged and entered. Amendments to claims 1, 3, 5, 7, 9, 11, 13, 18-19, 29, 33, 38-39, 55, 63-64, 68, and 75-76 are acknowledged and entered. Claims 1, 3, 5, 7, 9, 11, 13, 18-19, 24, 26, 28-29, 33, 38-39,42, 44, 46-47, 51, 53, 55-56, 63-64, 68, 75-76, 78-79, and 88-89 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230364221A1, Published 11/16/2023.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Response to Arguments
Applicant's arguments filed 06/02/2026 regarding the previous Office action dated 12/03/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Claim Objections
(Objection withdrawn). The objection to Claim 1 is withdrawn in light of the amendments to the claim.
(Objection withdrawn). The objection to Claim 2 is withdrawn in light of the cancellation of the claim.
(Objection withdrawn). The objection to Claim 33 is withdrawn in light of the amendments to the claim.
(Objection withdrawn). The objection to Claim 55 is withdrawn in light of the amendments to the claim.
(Objection withdrawn). The objection to Claim 76 is withdrawn in light of the amendments to the claim.
(New objection). Claims 88 and 89 are objected to because of the following informalities: to place the claims in better form and remove redundancies, it is suggested that the claims be amended along the lines of the following:
“88. The composition of claim 1, wherein the first and second coronavirus spike proteins are SARS-CoV-2 spike proteins, and wherein each of the first and second spike proteins comprises one or more N-linked glycans at one or more amino acid residues selected from N1098, N1134, N1158, N1173, or N1194, with respect to SEQ ID NO:1.”
“89. The composition of claim 14, wherein the spike protein is a SARS-CoV-2 spike protein, and wherein the spike protein comprises one or more N-linked glycans at one or more amino acid residues selected from N1098, N1134, N1158, N1173, or N1194, with respect to SEQ ID NO:1.”
Appropriate correction is required.
(New objection). Claim 75 is objected to because of the following informalities: to place the claim in better form, it is suggested that the claim be amended to remove “virus” after “coronavirus”, as this is redundant.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claim 5 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the argument that the specification provides reasonable support that it would be understood the charge of the LNP in the claimed composition.
(Rejection withdrawn.) The rejection of Claims 9 and 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claim 11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
(Rejection withdrawn.) The rejection of Claim 39 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
(Rejection withdrawn.) The rejection of Claims 63-64 and dependent claims 68, 75-76, and 78-79 thereof under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claim 68 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
(New rejection – necessitated by amendment.) Claim 19 is 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 19 recites the limitation "the spike protein" in line 2. There is insufficient antecedent basis for this limitation in the claim, as claim 13 recites two different spike proteins, and it is unclear which spike protein claim 19 is referencing.
(New rejection – necessitated by amendment.) Claims 38-39 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.
Claims 38 and 39 recite the limitation "the spike protein". There is insufficient antecedent basis for this limitation in the claims, as claim 33 recites two different spike proteins, and it is unclear which spike protein each claim is referencing.
Additionally, claim 38 has the additional limitation of referencing N-linked glycosylation sites on a spike protein, but the reference protein (SEQ ID NO:1) is a SARS-CoV-2 S protein. It is unclear if said sites are meant to be homologous N-linked sites conserved or found in other CoV S proteins as well, or if these sites are only present in the SARS-CoV-2 S protein.
For at least these reasons, claims 38-39 are rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a composition comprising:
a) a first coronavirus (CoV) spike (S) protein in a prefusion complex, and
b) a second CoV S protein in a postfusion complex;
c) a stimulator of interferon genes (STING) pathway agonist encapsulated in a lipid
nanoparticle;
wherein the composition is formulated for nasal delivery.
Further limitations on the composition of claim 1 are wherein the STING pathway agonist comprises a cyclic dinucleotide (claim 3), wherein the LNP is negatively charged (claim 5), wherein the LNP has a mean diameter of no less than 30 nm and no greater than 300 nm (claim 7); wherein each of the first CoV S protein and the second coronavirus spike protein comprises one or more N-linked glycans linked to amino acid residues (claim 9); wherein the first coronavirus spike protein is a SARS-CoV-2 S protein or fragment thereof having at least 90% sequence identity to any sequence independently selected from one of SEQ ID NO: 1 - SEQ ID NO: 5 or SEQ ID NO: 8 - SEQ ID NO: 10, and the second coronavirus spike protein is a SARS-CoV-2 S protein or fragment thereof having at least 90% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 10(claim 11); and wherein the first coronavirus spike protein and the second coronavirus spike protein is a SARS CoV-2 spike protein, and wherein each of the first coronavirus spike protein and the second coronavirus spike protein comprises one or more N- linked glycans linked to amino acid residues independently selected from N1098, N1134, N1158, N1173, or N1194, with respect to SEQ ID NO: 1, or combinations thereof (claim 88).
Claim 13 is drawn to a composition comprising:
a) a first coronavirus spike protein in a prefusion complex and a second coronavirus spike protein in a postfusion complex,
b) an influenza A antigen, an influenza B antigen, or both, and
c) a STING pathway agonist encapsulated in a lipid nanoparticle,
wherein the composition is formulated for nasal delivery.
Further limitations on the composition of claim 13 are wherein each of the first CoV spike protein and second CoV spike protein comprises one or more N-linked glycans linked to amino acid residues (claim 18), wherein the spike protein comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 1 - SEQ ID NO: 5 or SEQ ID NO: 8 - SEQ ID NO: 10 (claim 19); wherein the STING pathway agonist comprises a cyclic dinucleotide (claim 24); wherein the LNP is negatively charged (claim 26); wherein the LNP has a mean diameter of no less than 30 nm and no greater than 300 nm (claim 28); further comprising one or more of a preservative, a buffer, and a humectant (claim 29).
Claim 33 is drawn to a composition comprising:
a) a first coronavirus spike protein in a prefusion complex and a second coronavirus spike protein in a postfusion complex,
b) a STING pathway agonist encapsulated in a lipid nanoparticle,
c) a preservative,
d) a buffer, and
e) a humectant;
wherein the composition comprises a viscosity of no more than 1000 centipoise (cP), and wherein the composition is formulated for nasal delivery.
Further limitations on the composition of claim 33 are wherein the spike protein comprises one or more N-linked glycans linked to amino acid residues N1098, N1134, N1158, N1173, or N1194, with respect to SEQ ID NO: 1, or combinations thereof (claim 38); wherein the spike protein comprises a sequence having at least 90% sequence identity to any one of SEQ ID NO: 1 - SEQ ID NO: 5 or SEQ ID NO: 8 - SEQ ID NO: 10 (claim 39); wherein the STING pathway agonist comprises a cyclic dinucleotide (claim 42); wherein the LNP is negatively charged (claim 44); wherein the LNP has a mean diameter of no less than 30 nm and no greater than 300 nm (claim 46); further comprising an influenza A antigen and/or influenza B (claim 47); wherein the humectant is selected from the group consisting of sorbitol, propylene glycol, and glycerin, and combinations thereof (claim 51); wherein the buffer is selected from the group consisting of citric acid, sodium citrate, monopotassium phosphate, disodium phosphate, potassium biphthalate, sodium hydroxide, sodium acetate, acetic acid, and combinations thereof (claim 53); wherein the preservative is selected from the group consisting of benzyl alcohol, parabens, thimerosal, chlorobutanol, benzethonium chloride, and benzalkonium chloride, and combinations thereof (claim 55); and wherein the composition comprises a pH of no less than 4 and no greater than 6 (claim 56).
Claim 63 is drawn to a method of administering a viral vaccine against a coronavirus to a subject, the method comprising, infusing a nose of the subject with the composition of claim 1, claim 13, or claim 33 in a spray plume, wherein the amount of the composition delivered in a spray plume contains no less than 75% and no more than 125% of a target spray volume.
Further limitations on the method of claim 63 are wherein the method is further comprising: providing an actuator comprising an actuator tip; producing an aerosol comprising droplets of the composition from the actuator tip; and dispensing the aerosol into a nose of the subject (claim 79).
Claim 64 is drawn to a method of immunizing a subject against a coronavirus, the method comprising nasally administering to the subject the composition of claim 1, claim 13 or claim 33, thereby immunizing the subject.
Further limitations on the method of claim 64 are wherein immunizing the subject further comprises reducing the severity of an infection caused by the virus comprising one or more of reducing a risk of hospitalization, increasing a likelihood that the infection is asymptomatic, decreasing a severity of a respiratory symptom caused by the virus, reducing a viral load of the virus in the subject, increasing mucosal immunity to the virus in the subject, and/or increasing production of antibodies against the virus in the subject (claim 68).
Claim 75 is drawn to a method of immunizing a subject against a coronavirus and an influenza virus, the method comprising nasally administering to the subject the composition of claim 13.
Further imitations on the method of claim 75 are wherein the coronavirus is severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)(claim 76), and wherein the influenza virus is an influenza A, an influenza B, or a combination thereof (claim 78).
Claim Rejections - 35 USC § 112(a); First Paragraph
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.
(New rejection – necessitated by amendment.) Claims 1, 3, 5, 7, 9, 11, 13, 18-19, 24, 26, 28-29, 33, 38-39,42, 44, 46-47, 51, 53, 55-56, 63-64, 68, 75-76, 78-79, and 88-89 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 specifically identified SARS-CoV-2 polypeptides, specific nasal formulations, and a specific 2’3’-cGAMP-containing lipid nanoparticle (LNP) adjuvant formulation, does not reasonably provide enablement for the substantially broader classes of coronavirus (CoV) antigens, CoV spike proteins and sequence variants, glycosylated spike proteins, multivalent CoV/influenza compositions, and methods and results encompassed by the claims. 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/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to nasal viral vaccine compositions containing CoV antigens, including CoV spike proteins in particular conformational states, together with an encapsulated STING agonist, and to compositions further comprising influenza antigens and methods of nasally administering such compositions. Amended claim 1 requires a first CoV spike protein in a prefusion complex, a second CoV spike protein in a postfusion complex, and a STING pathway agonist encapsulated in a LNP, wherein the composition is formulated for intranasal delivery. Further dependent claims encompass a CoV antigen together with an influenza A/influenza B antigen, or broadly recite a coronavirus antigen in a nasal STING/LNP formulation.
The specification describes particular SARS-CoV-2 sequences and fragments, and identifies SARS-CoV-2 spike, M, E, and ORF8 proteins, including SEQ ID NOs: 1-14, and disclose numerous sequence-identity and fragment alternatives (¶[0037-0050]). The specification also describes a SARS-CoV-2 prefusion complex containing full-length spike (S) proteins and a postfusion complex containing truncated D proteins such as SEQ ID NO: 3 or SEQ ID NO: 10 (¶[0039-0040]). The specification further identifies residues in the S protein that may be glycosylated, namely glycosylation at one or more of N1098, N1134, N1158, N1173, or N1194 relative to SEQ ID NO: 1 (¶[0040]). Example 1 more particularly describes a SARS-CoV-2 bivalent composition containing a full-length prefusion S homotrimer and a truncated postfusion S2 homotrimer. The postfusion spike proteins are stated to contain N-linked glycans at one or more of N1098, N1134, N1158, N1173, or N1194. The example further identifies 2’3’-cGAMP encapsulated in a negatively-charged DPPC/DPPG/cholesterol/DPPE-PEG2000 lipid nanoparticle and an aqueous nasal formulation containing glycerin, benzalkonium chloride, and sodium citrate (Example 1 starting at ¶[0100]).
However, the claims are not limited to the disclosed embodiments, as the claims also encompass any CoV spike proteins capable of forming the recited prefusion and postfusion complexes. For instance, the claims encompass compositions comprising S proteins of different CoV (e.g. the prefusion S protein could be from SARS-CoV-2, while the postfusion S protein could be from MERS-CoV). Claims directed to proteins having at least 90% sequence identity encompass large numbers of sequence variants without identifying which substitutions are compatible with the required folding, trimerization, conformational stability, glycosylation, and antigenic properties. The specification describes sequence identities extending much lower than 90%, fragments ranging broadly in length, and multiple substitutions and deletions (¶[0038]). The specification does not establish a sequence rule by which the skilled artisan could determine in advance which members of those sequence genera would retain the structural and immunological properties required by instant claim 1.
Claims 13 and 33 are broader in a different respect, as they recite a “coronavirus antigen” rather than a particular SARS-CoV-2 protein. The specification explains that CoV vaccines may contain antigens from SARS-CoV-2, SARS-CoV, MERS-CoV, or combinations thereof, and more generally describes viral antigens as including proteins, virions, carbohydrates, lipids, and nucleic acids (“Viral Antigens” starting at ¶[0033]). The claimed scope therefore extends substantially beyond the particular SARS-CoV-2 spike compositions described in the examples.
The newly added glycosylation claims narrow the CoV to SARS-CoV-2, but do not resolve the scope problem. The claims depend from claim 1 and requires each of the first and second SARS-CoV-2 spike proteins to contain one or more N-linked glycans at residues selected from one or more of N1098, N1134, N1158, N1173, or N1194 relative to SEQ ID NO: 1. The analogous claim depending from claim 14 likewise requires the recited SARS-CoV-2 spike protein to contain N-linked glycosylation at those same positions. These claims encompass numerous independently selected glycosylation patterns and do not specify glycan composition, glycan processing state, expression system, or a process that produces the required site occupancy. The specification states these sites “may” be glycosylated, but does not demonstrate that the full range of claimed proteins and conformations will exhibit the claimed glycosylation pattern (¶[0037][0040]).
The claimed scope therefore extends beyond the embodiments described in the specification.
State of the prior art and predictability of the art. At the time the application was filed, it was known that CoV spike proteins were structurally dynamic proteins whose prefusion state required deliberate stabilization for vaccine use. Cai et. al. (Cai Y, et. al. Science. 2020 Sep 25;369(6511):1586-1592. Epub 2020 Jul 21.) reported structures of full-length spike in both prefusion and post-fusion states and observed that “[t]he spontaneous transition to the postfusion state is independent of target cells.” Cai further reported substantial structural rearrangement between the states and N-linked glycans decorating the post-fusion structure (abstract; Figs. 1-4). This teaching indicates that obtaining and maintaining a desired spike conformation was dependent on the particular structural context and was not merely a consequence of identifying a protein as a CoV spike protein.
Hsieh et. al. (Hsieh CL, et. al. Science. 2020 Sep 18;369(6510):1501-1505. Epub 2020 Jul 23.) further demonstrates that the amount of empirical work involved in obtaining suitable prefusion spike constructs. Hsieh reported “We 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 ~10-fold higher expression than its parental construct and the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles.”(abstract). The need to construct and experimentally characterize that large panel of variants, even within SARS-CoV-2 spike itself, indicates that the effect of sequence modification on expression and conformational stability was not sufficiently predictable to permit extrapolation from a small number of sequences to the much larger identity-based genera encompassed by the instant claims.
Glycosylation was similarly site and context-dependent with regards to coronavirus spike proteins. Watanabe et. al. (Watanabe Y, et. al. Science. 2020 Jul 17;369(6501):330-333. Epub 2020 May 4.) performed mass-spectrometric analysis to provide “mapping of the glycan-processing states across the trimeric viral spike.” Watanabe further reported that SARS-CoV-2 spike glycans differed from typical host glycan processing. The reference therefore shows that identification of an asparagine glycosylation site does not, by itself, establish the processing state or resulting glycan structure at that site, which is material to the newly-added claims requiring N-linked glycans on the claimed spike proteins.
The prior art also further indicates that mucosal vaccine performance depended upon the particular vaccine platform and route of administration. Hassan et. al. (Hassan AO, et. al. Cell. 2020 Oct 1;183(1):169-184.e13. Epub 2020 Aug 19.) tested a chimpanzee adenovirus (ChAd) encoding a specifically prefusion-stabilized SARS-CoV-2 spike. Intramuscular administration of the composition produced strong systemic immunity but minimal mucosal response, whereas intranasal administration produced robust mucosal responses and markedly different protection. Hassan therefore demonstrates that the biological results of nasal administration were experimentally determined for a particular antigen, stabilization strategy, vector platform, dose, and animal model; those results did not provide a predictable rule applicable to any CoV antigen, arbitrary spike sequence variants, STING/LNP formulations, influenza combinations, and the range of clinical results encompassed by the instant claims.
The prior art therefore showed that techniques for producing coronavirus proteins, analyzing glycosylation, stabilizing spike trimers, formulating vaccines, and measuring immune responses were available. It did not establish that changes in sequence, conformation, glycosylation, antigen combination, or delivery platform produced predictable effects on protein structure and vaccine function. The art was consequently not sufficiently predictable to support extrapolation from the particular SARS-CoV-2 embodiments described in the specification to the full breadth of the claimed compositions and methods.
Level of skill in the art. One skilled in the art would have been familiar with recombinant protein expression, protein purification, sequence analysis, formulation of lipid nanoparticles, standard immunological assays (such as ELISAs and neutralization assays), animal challenge studies, mass spectrometry for glycan analysis, and structural methods for evaluating protein conformation. However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further experimentation, which additional members of the coronavirus spike protein prefusion and postfusion conformation complexes would satisfy the claimed limitations. In particular, the skilled artisan would not have been able to determine from sequence identity alone whether an untested spike protein variant would form and remain in the claimed prefusion or postfusion complex, possess the recited glycosylation pattern, retain appropriate antigenicity, and remain useful when combined with an encapsulated STING agonist in a nasal formulation. Finally, routine assays would allow a candidate composition to be tested, but would not identify beforehand which of the broadly claimed antigen combinations would produce the claimed immune or protective results.
Working examples. The specification provides no working example reporting experimental data demonstrating the claimed vaccine activity. Instead, the specification contains three example descriptions at ¶[0099-0110]. Example 1 describes a proposed SARS-CoV-2 prefusion/postfusion vaccine containing 2’/3’-cGAMP and a specified nasal formulation. The following examples describe SARS-CoV-2/influenza and alpha/delta SARS-CoV-2 vaccine composition.
The examples state that the vaccines are administered and trigger immune responses or reduce the risk of disease, but they provide no experimental measurements supporting those statements. No antibody titers, neutralization measurements, animal challenge data, clinical trial results, structural conformation of the formulated spike complexes, or experimental glycan-occupancy data are reported. The examples therefore function as prophetic examples rather than evidence that the claimed compositions were actually made and shown to possess the asserted properties. This deficiency is particularly material to the method claims, as the specification broadly states that the claimed vaccines would be capable of or expected to achieve various immunological outcomes, without providing experimental data demonstrating such effects across the full scope of the claimed genus (¶[0002][0014][0019][0038][0048][ 0099-0110]).
This same problem applies to the newly added glycosylation claims, as Example 1 states that the postfusion spike proteins are glycosylated at one or more of N1098, N1134, N1158, N1173, or N1194 relative to SEQ ID NO: 1 (¶[0099]). It does not report experimental conformation of glycan occupancy at those residues and does not similarly establish that the prefusion protein in the same composition contains one or more of the claimed glycans, as now required by the newly presented claims.
The disclosed examples therefore do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides guidance regarding SARS-CoV-2 protein sequences and fragments, identifies example spike conformations, identifies several proposed N-linked glycosylation sites, and provides a particular cGAMP/LNP and nasal formulation (¶[0036-0049]). That guidance would assist a skilled artisan in attempting to prepare embodiments close to the specifically described SARS-CoV-2 examples. However, the specification does not provide sufficient guidance regarding operative embodiments throughout the claimed scope. In particular, the specification does not explain the relationship between percentage sequence identity and the ability of a spike protein to adopt and retain the required prefusion or postfusion conformation. It does not identify which sequence changes can be made without materially changing folding, trimerization, antigenicity, or glycan presentation, nor does it provide a general method for ensuring that both claimed SARS-CoV-2 spike proteins possess N-linked glycans at one or more of the newly claimed sites. The glycan limitation is not merely a sequence limitation, as ¶[0039] identifies positions that “may” be glycosylated, but does not teach that every claimed spike protein construct expressed under different conditions or from different cell types/systems will have a glycan at the selected position or will have the same glycan processing state. The disclosure does not explain how protein conformation, sequence variation, expression host, or production conditions affect the occupancy of the claimed sites, even though prior art showed that SARS-CoV-2 spike protein glycosylation was site-specific and subject to differential processing. The specification also fails to provide a general relationship connecting the structure of an antigen to the broad functional outcomes later claimed. The specification describes prevention, reduced disease severity, viral load reduction, transmission reduction, and various levels or durations of immunity, but do not provide experimental results or selection criteria that permit the skilled artisan to identify which members of the claimed composition genera will achieve those outcomes (¶[0090-0094]).
Quantity of experimentation necessary. To practice the full scope of the claims, one skilled in the art would need to select candidate CoV spike sequences, prepare the relevant proteins, and determine whether the proteins possess the required structural properties. Candidate spike proteins would need to be evaluated to determine whether they form the required prefusion or postfusion complexes and whether those conformations remain stable during preparation, formulation, storage, and nasal administration. Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test additional embodiments to determine whether they satisfy the claimed structural and functional limitations, especially with respect to the methods of using said compositions to vaccinate against any coronavirus. Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays; instead, the relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, one skilled in the art would need to prepare and test additional spike protein variants sequences from different CoV, or different sequence variants for the claimed SARS-CoV-2 spike variants to determine which embodiments satisfy the claimed structural and functional limitations, including which variants maintain a prefusion/postfusion conformation, which are properly immunogenic in the host, and which are glycosylated at the claimed positions.
Amgen. The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610-13 (2023).
In the instantly claimed invention, the specification describes particular SARS-CoV-2 sequences and proposed vaccine formulations, but the claims also encompass any coronavirus spike protein in any prefusion or postfusion conformation, as well as SARS-CoV-2 sequence variants that would still maintain the claimed functional limitations (e.g. immunogenicity, conformational structure, glycosylation pattern, clinical immunogenic outcomes, etc.). The specification does not identify a general quality or provide sufficient guidance that would allow one skilled in the art to practice that broader scope without undue experimentation, as the variables within the claimed genera are substantially large.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and/or use the full scope of the invention recited in the claims without undue experimentation.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn). The rejection of Claims 1, 11, 64, 68, 75, and 78 under 35 U.S.C. 102(a)(1) as being anticipated by Graham et. al. (US20200061185A1, Pub. 02/27/2020; hereafter “Graham”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn). The rejection of Claims 1, 9, 11, 64, 68, 75-76, and 78 under 35 U.S.C. 102(a)(2) as being anticipated by Liang et. al. (US20220016235A1, Priority 06/10/2020; hereafter “Liang) is withdrawn in light of the amendments to the claims.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn). The rejection of Claims 2-3, 7, 13-15, 18-19, 24, 28-29, 33-35, 38-39, 42, 46-47, 51, 53, 55-56, 63, and 79 under 35 U.S.C. 103 as being unpatentable over Liang as applied to claims 1, 9, 11, 64, 68, 75-76, and 78 above, and further in view of Prasad (US20220273790A1; Priority 06/18/2019 (NB: SARS CoV-2-related disclosure has priority to PCT filing of 06/17/2020; hereafter “Prasad”);
Galarza et. al. (US20190030156A1, Pub. 01/31/2019; hereafter “Galarza”);
Moniz et. al. (WO2020191361A2, Pub. 09/24/2020; hereafter “Moniz”); and
Gizurarson (US20180000834A1; Pub. 01/04/2018; hereafter “Gizurarson”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn). The rejection of Claims 5, 26, and 44 under 35 U.S.C. 103 as being unpatentable over Liang, Prasad, Galarza, Moniz, and Gizurarson as applied to claims 1, 2-3, 7, 9, 11, 13-15, 18-19, 24, 28-29, 33-35, 38-39, 42, 46-47, 51, 53, 55-56, 63-64, 68, 75-76, and 78-79, above, and further in view of Wang et. al. (Wang J, et. al. Science. 2020 Feb 21;367(6480):eaau0810.; hereafter “Wang”) is withdrawn in light of the amendments to the claims.
(New rejection- necessitated by amendment). Claims 1, 3, 5, 7, 9, 11, 13, 18-19, 24, 26, 28-29, 68, 64, 68, 75-76, 78, 88-89 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et. al. (US20220016235A1, Priority 06/10/2020; CITED ART OF RECORD; hereafter “Liang) in view of Gindy et. al. (US20160361411A1; Pub. 12/15/2016; hereafter “Gindy”.)
The Prior Art
Liang teaches immunogenic compositions which comprise recombinant peptides and proteins comprising coronavirus (CoV) viral antigens and immunogens, such as coronavirus S protein peptides (entire document; see abstract.) Liang teaches the surface antigen, such as the S protein, may be in the composition in a prefusion conformation or a postfusion conformation (¶[0041-0042][0360-0361][0433].) Liang states the conformational state permits access to different antigenic sites on the S protein and that the trimerized proteins permit an immune response to be mounted against different antigenic sites (¶[0090][0362][0413-0414][0433]). Liang teaches a bivalent vaccine comprising at least one S trimer comprising a first S protein antigen and at least one S trimer comprising a second S protein antigen, wherein the first and second S protein antigens may be from the same S protein or from different S proteins or CoV strains (¶[0017][0082]). Liang further teaches that an immunogenic composition may comprise a combination of any two or more of the trimers (¶[0495]). The compositions may be administered intranasally (¶[0052][0502][0632]). Liang teaches the composition may be within nanoparticles (¶[0045][0052][0055]) such as virus-like particles (VLPs) or lipid nanoparticles (LNPs)(¶[0509]). Liang teaches the S protein may be highly glycosylated with N-linked glycans (Fig. 4), teaches specific N-linked glycosylation sites, including N1098 and N1134, in any suitable combination, and teaches SEQ ID NO: 55, which comprises N residues at 1098, 1134, 1158, 1173, and 1194 (¶[0425]; instant claims 9, 18, 88, 89). Liang teaches the CoV may be SARS-CoV-2 (¶[0576]; instant claim 76), and teaches SEQ ID NO: 55, which is 100% identical to instant SEQ ID NO: 3 and 99.9% identical to instant SEQ ID NO: 4(See ABSS sequence alignments 17-489-572; See also below; ¶[0367][0481][0522]; instant claims 11, 19). Liang teaches methods of inducing an immune response to the SARS CoV-2 S protein antigen (¶[0052][0357][0366]), such as through the administration of a therapeutic or prophylactic vaccine (¶[0050][0502]), wherein said composition is delivered intranasally (¶[0052][0632]; reference claim 82; instant claim 64). Liang teaches the vaccination would reduce the severity, duration, or extent of infection and/or associated disease symptoms (¶[0527]) through reduction in viral load (¶[0531]; instant claim 68). Liang generically teaches viral surface protein antigens, such as influenza hemagglutinin (HA)(¶[0084][0086]), and teaches that the SARS CoV-2 S protein composition may be delivered with commercial influenza vaccines, which inherently comprise either antigens to influenza A, influenza B, or a combination of both A and B (¶[0497-0499]; instant claims 75, 78). Liang teaches the composition may be administered to reduce the severity, duration or extent of an infection and/or associated disease symptoms, after exposure or suspected exposure to the virus, or after the actual initiation of an infection (¶[0527]) and the composition would increase the production of antibodies specific for the CoV S protein in a subject (¶[0535]; instant claim 68).
Liang therefore teaches each of the claimed first and second CoV S protein complexes and expressly teaches combining multiple CoV S trimer antigens in a vaccine, and teaches the S proteins may be in a prefusion or postfusion conformation. It would have been obvious to one of ordinary skill at the time of filing to select a prefusion and a postfusion S protein trimer in light of the guidance from Liang to have access to different antigenic sites on the S protein. However, Liang fails to teach that the composition further comprises a STING pathway agonist encapsulated in a lipid nanoparticle (LNP) as required by instant claim 1. However, such limitations were known in the art and would be an obvious modification to the teachings of Liang, as shown by the teachings of Gindy.
Gindy teaches lipid nanoparticle (LNP) formulations, containing cationic lipids, for use as vaccine adjuvants and/or as antigen delivery systems (entire document; see abstract; reference claim 1.) Gindy teaches that their LNP formulations may be used with immunostimulatory compounds, including STING agonists, to enhance humoral and/or cellular immunogenicity of vaccine antigens (¶[0012][0018][0033][0103]; reference claims 1,16,30). Gindy teaches that the STING agonists include 3′3′-cGAMP, 2′3′-cGAMP, 2′2′-cGAMP, c-di-AMP, c-di-GMP, c-di-IMP, c-di-UMP, DMXAA or acylated conjugates or prodrugs thereof, and that the agonist may be physically encapsulated in the LNP before or after LNP preparation, or the agonist may be adsorbed, covalently coupled, ionically-interacted or formulated onto the surface of the LNP (¶[0012]; instant claims 3, 24). Gindy further teaches that the compositions may be administered intranasally (¶[0016]) and can be used to treat disease caused by coronaviruses such as SARS (¶[0138]). Gindy teaches the LNP may be negatively charged (¶[0086]; instant claims 5, 26), and have a mean geometric diameter of about 100-200 nm (¶[0129-0130]; instant claims 7, 28). Gindy teaches preservatives, stabilizers, dyes, and other agents may be within the pharmaceutical composition (¶[0154]; instant claim 29).
One of ordinary skill would therefore have had reason to incorporate the encapsulated STING agonist LNP formulation into the coronavirus S trimer vaccine of Liang to enhance the immune response to the recombinant subunit antigens and to provide an established nanoparticle/vaccine delivery system. The modification would have also been compatible with the intranasal administration system of Liang because Gindy expressly teaches their composition may also be administered intranasally, and to treat CoV related infections. Therefore, arriving at the limitations of instant claims 1, 13, and 75 would have been obvious, given the teachings of Liang and Gindy.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Liang in order to add a specific adjuvant encapsulated within an LNP, thereby providing a STING agonist such as a cyclic dinucleotide in a known vaccine delivery platform. One would have been motivated to do so, given the suggestion by Gindy that the LNP could comprise these known adjuvants and trigger an enhanced immune response to antigens in the composition, wherein STING agonists are known in the art to trigger type I interferons and robust antigen-specific T cell and antibody responses. There would have been a reasonable expectation of success, given the knowledge that Liang teaches soluble CoV S trimer antigens in prefusion and postfusion conformations as suitable components of multivalent vaccines for intranasal administration, and also given the knowledge that Gindy teaches LNP-encapsulated STING agonists as vaccine adjuvants suitable for administration with protein antigens delivered intranasally. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
US-17-489-572-55 (SEQ ID NO: 3 (Qy) vs SEQ ID NO: 55 (Db, ‘572))
Query Match 100.0%; Score 3054; DB 1; Length 1273;
Best Local Similarity 100.0%;
Matches 588; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 686 SVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGD 745
Qy 61 STECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQI 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 746 STECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQI 805
Qy 121 LPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 806 LPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLL 865
Qy 181 TDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIAN 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 866 TDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIAN 925
Qy 241 QFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 926 QFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLD 985
Qy 301 KVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGK 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 986 KVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGK 1045
Qy 361 GYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1046 GYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVT 1105
Qy 421 QRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVD 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1106 QRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVD 1165
Qy 481 LGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLI 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1166 LGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLI 1225
Qy 541 AIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT 588
||||||||||||||||||||||||||||||||||||||||||||||||
Db 1226 AIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT 1273
US-17-489-572-55 (SEQ ID NO: 4 (Qy) vs SEQ ID NO: 55 (Db, ‘572))
Query Match 99.9%; Score 6715; DB 1; Length 1273;
Best Local Similarity 99.9%;
Matches 1272; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFS 60
Qy 61 NVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIV 120
Qy 121 NNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 NNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLE 180
Qy 181 GKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQT 240
Qy 241 LLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETK 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETK 300
Qy 301 CTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISN 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 CTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISN 360
Qy 361 CVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIAD 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 CVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIAD 420
Qy 421 YNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 YNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPC 480
Qy 481 NGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVN 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 NGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVN 540
Qy 541 FNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITP 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 FNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITP 600
Qy 601 GTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSY 660
||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||
Db 601 GTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSY 660
Qy 661 ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI 720
Qy 721 SVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQE 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 SVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQE 780
Qy 781 VFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDC 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 VFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDC 840
Qy 841 LGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAM 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 LGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAM 900
Qy 901 QMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALN 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 QMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALN 960
Qy 961 TLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 TLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRA 1020
Qy 1021 SANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPA 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 SANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPA 1080
Qy 1081 ICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDP 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 ICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDP 1140
Qy 1141 LQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDL 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 LQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDL 1200
Qy 1201 QELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDD 1260
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1201 QELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDD 1260
Qy 1261 SEPVLKGVKLHYT 1273
|||||||||||||
Db 1261 SEPVLKGVKLHYT 1273
Response to Arguments
Applicant’s arguments, see “Remarks”, filed 06/02/2026, with respect to the rejections of the claims under 35 USC 102 and 35 USC 103 have been fully considered and are persuasive with respect to Liang failing to teach the limitations of instant claim 2, which have now been incorporated into instant claim 1. Therefore, the rejections have been withdrawn. However, upon further consideration, new grounds of rejection are made in view of Gindy, and the other arguments presented regarding Liang which were not persuasive will be addressed herein.
Applicant argues that Liang fails to teach the claimed combination because Liang allegedly requires the coronavirus (CoV) spike protein to be in either a prefusion or a postfusion conformation, rather than providing both conformations in the same vaccine composition. This argument is not persuasive. Liang expressly teaches that the S protein peptides of its trimerized recombinant polypeptides may be in a prefusion conformation or may be in a postfusion conformation (¶[0605]), and further teaches that “the conformation state allows for access to different antigenic sites on the S protein peptides” (¶[0433]). Liang separately teaches a bivalent vaccine comprising at least one S-trimer comprising a first S protein antigen and at least one S trimer comprising a second S protein antigen, wherein the first and second antigens may be derived from the same S protein. Liang further teaches immunogenic compositions containing “a combination of any two or more of the trimers”(¶[0495]).
The rejection does not rely on Liang as expressly describing in a single sentence a bivalent vaccine having one prefusion trimer and one postfusion trimer. Rather, Liang teaches both conformational states as suitable coronavirus S trimer antigens, expressly teaches combining first and second S trimer antigens in a bivalent vaccine, and provides a rationale for using different conformational states. A person of ordinary skill would have had reason to select one of the S trimers in the prefusion and an S trimer in the postfusion conformation as disclosed by Liang and place them into a bivalent composition in order to present different antigenic sites to the immune system. The fact that Liang identifies the two conformations as alternatives for an individual S trimer does not teach away from using different alternatives for the separately recited first and second S trimers. The mere disclosure of multiple alternatives does not constitute a teaching away, absent criticism, discrediting, or discouragement of the claimed alternative (MPEP §2145.X.D.1.) Therefore, this line of argument is unpersuasive.
Applicant further argues that Liang requires the CoV spike protein to be fused to a C-terminal propeptide to stabilize the trimer, whereas the presently claimed antigens are soluble and are stabilized through formulation or by inclusion of a separate stabilizing agent. This argument is not persuasive. Liang expressly teaches that its surface antigen may be free of the transmembrane and cytoplasmic domains and “can be soluble” (¶[0016][0019]), and further states that the resulting protein itself can be soluble and need not directly bind a lipid bilayer. Accordingly, the presence of the C-terminal trimerization domain of Liang does not establish that Liang’s spike antigen is insoluble or otherwise outside the recited soluble-antigen limitation.
Moreover, the new rejection is now made in view of the teachings of Gindy, not on just Liang. Gindy expressly teaches “one or more formulated antigens in an acceptable carrier, such as a stabilizer, buffer, and the like” and further teaches that its compositions may be administered “with or without stabilizers, buffers, and the like”(¶[0150]). Gindy also teaches compositions prepared for storage or administration in which preservatives and stabilizers may be provided (¶[0154]). Thus, even assuming that the claim requires stabilization by the formulation or by a separate stabilizing agent, Gindy expressly provides that feature.
The claim, as currently drafted, does not require that the soluble spike proteins be stabilized only by the formulation or separate stabilizing agent, or require that the spike proteins be free of a heterologous trimerization domain. The use of a C-terminal propeptide in Liang does not exclude the resulting soluble S trimer from additionally being formulated with a stabilizer as taught by Gindy. No incompatibility between these teachings has been identified, and obviousness rejections do not require the literal bodily incorporation of one reference into another, merely that the combined teachings would have suggested the claimed invention to a person of ordinary skill in the art (MPEP §2145.III). Therefore, this line of argument is not persuasive.
Therefore, the disclosure of Liang and the disclosure of Gindy render obvious the invention as instantly claimed, and the references would have suggested the presently claimed composition to one of ordinary skill in the art with a reasonable expectation of success.
(New rejection- necessitated by amendment). Claims 33, 38-39, 42, 44, 46-47, 51, 53, 55, 56, 63, and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Liang and Gindy as applied to claims 1, 3, 5, 7, 9, 11, 13, 18-19, 24, 26, 28-29, 68, 63-64, 68, 75-76, 78, and 88-89 above, and further in view of Quay et. al. (US20080255067A1; 10/16/2008; hereafter “Quay”) and Gu (US20040126381A1; Pub. 07/01/2004; hereafter “Gu”.)
The Prior Art
The teachings of Liang and Gindy have been set forth supra. While Liang teaches the S protein complex compositions may be combined with other antigens and/or adjuvants, or additional components such as citrate, acetate (including sodium acetate), phosphate, or sulfate buffers to maintain the pH of the solution of about 6 (¶[0503-0505]; instant claims 29, 53, 56), preservatives such as benzyl alcohol (¶[0504]; instant claim 55), or the humectants sorbitol or glycerin (¶[0503][0518]; instant claim 51),and Gindy teaches the CoV-antigen compositions may comprise STING agonists encapsulated within LNPs, and both teach intranasal delivery of the composition, neither specifically teach or suggest a specific viscosity of said composition. However, adjusting the excipients and components for intranasal delivery of compositions was known in the art, as shown by the teachings of Quay.
Quay teaches cyanocobalamin and water pharmaceutical compositions, wherein said composition is suitable for intranasal administration, has a viscosity less than about 1000 cPs, and wherein said solution of cyanocobalamin has a bioavailability of cyanocobalamin when administered intranasally (entire document; see abstract.) Quay teaches the intranasal delivery of cyanocobalamin (vitamin B12) to supplement the diets of those with B12 deficiencies, as intranasal delivery overcomes oral intake issues of the vitamin (¶[0002-0006]). Maintaining a viscosity below 1000 centipoise (cPs) for intranasal delivery ensures the formulation can be properly atomized into a fine spray, uniformly coat the nasal mucosa, and allow the active compound to quickly diffuse through mucus rather than being trapped or rapidly cleared. Quay teaches that intranasal formulation generally contains a buffering agent to maintain the pH between 4 and 6 preferably about 5, a humectant to inhibit drying of the mucous membranes and a preservative (¶[0059]; instant claim 56) and teaches that a humectant may be sorbitol, propylene glycol glycerol, or glycerin (¶[0061]; instant claim 51). Quay teaches a preferred formulation is comprised of cyanocobalamin, citric acid, sodium citrate, and water wherein the viscosity is less than 1000 cPs (¶[0060]; instant claim 53), and that a preferred preservative is benzalkonium chloride (¶[0062]; instant claim 55). Quay teaches the use of an actuator to produce an aerosol or plume of said solution, wherein the spray pattern ellipticity ratio of said aerosol is between 1.00 and 1.40 when measured at a height of 30 cm distance from the actuator tip, for dispensing the composition as an aerosol into the nose of the subject, wherein 0.1 mL is delivered per dose and can be analyzed as to the plume pattern and droplet size (¶[0014-0017][0028][0032-0053][0132-0136]; Fig. 1B; reference claim 1; instant claims 63, 79).
Although the active agent of Quay is cyanocobalamin rather than a vaccine antigen, Gu establishes that the formulation principles taught by Quay were conventionally applicable to intranasal vaccine formulations. Gu expressly teaches that immunogenic compositions including vaccines may be prepared as inhalables, sprays and the like (¶[0037]) and Gu further teaches that immunogenic compositions and vaccines may contain pharmaceutically acceptable excipients, such as glycerol, and may further contain pH buffering agents and mucosal adjuvants or delivery systems (¶[0038]). Gu teaches pharmaceutically acceptable humectants can be employed including, for example sorbitol, propylene glycol or glycerol (¶[0046]), and teaches the use of preservatives including, for example, Parabens, thimerosal, chlorobutanol, or bezalkonium chloride (¶[0048]). Gu states that those skilled in the art will recognize that the components of the compositions must be selected to be chemically inert with respect to the active agent, and will present no problem to those skilled in chemical and pharmaceutical principles, or problems can be readily avoided by reference to standard texts or by simple experiments (not involving undue experimentation), from this disclosure (¶[0049]). Gu further teaches that intranasal vaccine compositions may be formulated using conventional pharmaceutical procedures and may contain usual ingredients, such as stabilizers, buffers, and mucosal adjuvants or delivery systems (¶[0050-0052]).
It would have been obvious to one of ordinary skill in the art to formulate the intranasal vaccine composition of Liang and Gindy using the low-viscosity nasal vehicle taught by Quay, including a preservative, a buffer, and humectant, in order to provide a pharmaceutically acceptable nasal formulation that inhibits drying and irritation of the nasal mucosa, maintains a stable formulation pH, improves shelf life, and remains readily administrable as a nasal spray. One would have been further motivated to do so given the express teaching of Gu that the same class of excipients are suitable for intranasal immunogenic compositions and vaccines. There would have been a reasonable expectation of success because Quay teaches the claimed low viscosity vehicle as suitable for intranasal administration, while Gu confirms that aqueous nasal vaccine formulations conventionally employ buffers, humectants, preservatives, and mucosal adjuvants or delivery systems. The proposed modification therefore represents predictable use of known nasal formulation components for their established functions in the intranasal vaccine composition of Liang and Gindy, and in light of the teachings of Quay and Gu, the limitations of instant claims 33, 38-39, 42, 44, 46-47, 51, 53, 55, 56, 63, and 79 would be obvious.
It would have been obvious to one of ordinary skill in the art to modify the intranasal coronavirus vaccine compositions taught by Liang and Gindy to further formulate the composition with the preservative, buffer, humectant, and low viscosity nasal vehicle taught by Quay in order to provide a stable and pharmaceutically acceptable formulation suitable for intranasal delivery, thereby facilitating administration to the nasal mucosa while reducing drying and irritation and improving formulation stability and shelf life. One would have been motivated to do so, given the suggestion by Quay that aqueous intranasal pharmaceutical compositions may contain a preservative, buffering agent, and humectant, and may have a viscosity below 100 cPs to provide a suitable low-viscosity nasal formulation. One would have been further motivated to do so in view of Gu, which teaches that intranasal immunogenic compositions and vaccines may include conventional excipients such as buffering agents, humectants, and preservatives. There would have been a reasonable expectation of success, given the knowledge that Liang teaches intranasal administration of the CoV S trimer vaccine composition, that Gindy teaches nasal administration of vaccine compositions containing LNP-encapsulated STING agonists, and also given the knowledge that Quay and Gu teach that conventional excipients are suitable for the delivery of active agents intranasally. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Double Patenting
The text regarding nonstatutory double patenting was presented in a previous Office action.
(Rejection withdrawn.) The provisional rejection of Claims 13-15, 18-19, 24, 26, 28-29, 63-64, 68, 75-76, and 78-79 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-6, 9, 11 of copending Application No. 18/568,769 in view of Liang and Wang (supra) is withdrawn in light of the amendments to the claims.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20230285539A1. Teaches SARS-CoV-2 mRNA vaccines for intranasal delivery. Not utilized as rejection would be redundant to those set forth supra.
US20210393769A1. Teaches SARS-CoV-2 mRNA vaccines with prefusion S protein for intranasal delivery. Not utilized as rejection would be redundant to those set forth supra.
Zhang Y, et. al. Nano Lett. 2023 Apr 12;23(7):2593-2600. Epub 2023 Mar 21. Post-filing art related to the instant claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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