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 are pending.
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.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/06/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: from the wording of the claim and further dependent claims (e.g. see claim 11), it appears as though claim 1 should be reciting in part b) “…a second coronavirus spike protein in a postfusion complex;…”
Appropriate correction is required.
Claim 2 is objected to because of the following informalities: the definition of the abbreviation “STING” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … stimulator of interferon genes (STING)...).
Appropriate correction is required.
Claim 33 is objected to because of the following informalities: the definition of the abbreviation “cPs” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … centipoise (cP)...).
Appropriate correction is required.
Claim 55 is objected to because of the following informalities: there should be a comma between “parabens” and “thimerosal”, as these are two separate and distinct preservatives. Appropriate correction is required.
Claim 76 is objected to because of the following informalities: the definition of the abbreviation “SARS-CoV-2” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)...).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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.
Claim 5 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 5 is drawn to “wherein the lipid nanoparticle is negatively charged.” It appears as though Applicant is claiming the overall charge of the lipid nanoparticle (LNP), which may be negative at physiological pH, but can change charge (e.g. become protonated and change to overall neutral or positive charge) if moved to a lower pH (as in endosomes). Therefore, it is unclear how the LNP is to remain negative under all physiological conditions. It is suggested this limitation be amended to clarify at what pH the LNP is intended to be negatively charged.
For at least these reasons, claim 5 is rejected on the grounds of being indefinite.
Claims 9 and 18 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 9 is drawn to specific N-linked glycosylation sites in the coronavirus spike protein. However, each CoV spike protein has a unique sequence, and the N sites listed in this claim and the reference sequence is of SARS CoV-2, and is not indicative of all N-linked glycosylation sites in other CoV S proteins. It is suggested this claim be amended to recite that these sites are in reference to only SARS CoV-2 spike proteins, or that the claim be amended to generically recite that the CoV S protein comprises N-linked glycosylation sites, and a further dependent claim be provided with the specific sites and sequences and notation that they are specific to when the CoV S protein is SARS CoV-2 S protein. Claim 18 is rejected for similar reasoning.
For at least these reasons, claims 9 and 18 are rejected on the grounds of being indefinite.
Claim 11 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 11 is drawn to the composition of claim 1, wherein the first coronavirus spike protein and the second coronavirus spike protein comprise a sequence 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. First, it should be noted that claim 1 should be amended (see objection supra) to provide proper antecedence for the “second coronavirus spike protein” limitation in claim 11. Second, it is unclear which of the recited sequences are applicable to the prefusion conformations of the spike (S) coronavirus (CoV) protein (See e.g. Fig. 2 of Shi W, et. al. Nature. 2023 Jul;619(7969):403-409. Epub 2023 Jun 7.; See also Chakraborty D, et. al. Vaccines (Basel). 2025 Mar 14;13(3):315.) Certain sequences are only found in or able to stably generate the prefusion trimeric complexes (e.g. K986P/V987P spike protein mutants), while other sequences are only able to stably generate the postfusion complexes, and from the wording of the claim, it appears as though the sequences can be used interchangeably in either prefusion or postfusion complex. It is suggested the claim be amened to recite which sequence pertain to which complex conformations, and with the percent identities claimed, it is also suggested the claims clearly reflect what substitutions/mutations/residues/etc. must be maintained in the sequence in order to allow the claimed complex to form.
For at least these reasons, claim 11 is rejected on the grounds of being indefinite.
Claim 39 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 39 recites a list of three items (i-iii) that further limit the S, M, and E proteins of claim 34 but fails to use a conjunction (e.g. “and”, “or”, or “and/or”) between the penultimate and final limitations. However, as claim 34 recites these items in the alternative, it is unclear is claim 39 requires all three of these proteins to be present, and thus requires the use of “and” between (ii) and (iii), or if claim 39 is reciting alternate embodiments of the alternate embodiments of claim 34. If claim 39 (or claim 34) meant to claim the embodiments as both (e.g. “and/or”), the claims should clearly both be amended to reflect this limitation. As claim 34 and claim 33 recite a single CoV antigen, the conjunction “or” will be used, but the claim must be amended for further clarification.
For at least the reasons set forth above, claim 39 is rejected on the grounds of being indefinite.
Claims 63-64 and dependent claims 68, 75-76, and 78-79 thereof 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 63 and 64 are methods that deliver the compositions of instant claims 1, 13, or 33. Said compositions are delivering coronavirus antigens (claims 1, 13, 33) with additional influenza virus antigens (claim 13). However, claims 63 and 64 are generically drawn to vaccination against “a virus”, which makes the antecedent basis of the methods unclear, as it is not clear if the vaccination with the compositions comprising the coronavirus antigens is meant to inoculate against any virus, or is only meant to inoculate against the native virus from which the coronavirus (and influenza virus) antigens were derived. Further confusion arises with the claims which are dependent upon one or more of these claims, as they appear to specify the nature of “a virus”, so under at least one reasonable interpretation, a person is being inoculated with a coronavirus antigen as in claim 1, and yet is meant to be vaccinated against influenza virus, as in claims 64 and dependent claims 75 and 78 thereof. It is suggested that claims 63 and 64 be amended to clearly recite the nature of “a virus” so that it is clear that “a virus” is referring back to the viral antigens which are present in claims 1, 13, or 33.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 63 and 64 are rejected on the grounds of being indefinite. Claims 68, 75-76, and 78-79 are also rejected since they depend from claim 63 or 64, but do not remedy these deficiencies of claim 63 or 64.
Claim 68 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.
The wording of claim 68 is confusing, and it is not exactly clear how claim 68 further limits the claim upon which it depends. Claim 68 depends upon the method of claim 64, but it is unclear from the wording of the claim if these limitations in claim 68 are a result of the administrating steps of claim 64, a mark as to whether or not said subject has been properly immunized, or if they are additional steps from other actions that are added to the method of claim 64. One suggestion for clarity is to recite the following:
“68. The method of claim 64, wherein immunizing the subject 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.”
For at least these reasons, claim 68 is 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;
wherein the composition is formulated for nasal delivery.
Further limitations on the composition of claim 1 are wherein the composition is further comprising a stimulator of interferon genes (STING) pathway agonist encapsulated in a lipid nanoparticle (LNP)(claim 2), 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 independently selected from N1098, N1134, N1158, N1173, or N1194, with respect to SEQ ID NO: 1, or combinations thereof (claim 9); wherein the first coronavirus spike protein and the second coronavirus spike protein comprise a sequence 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 (claim 11);
Claim 13 is drawn to a composition comprising:
a) a coronavirus antigen,
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 the coronavirus antigen is selected from the group consisting of a spike (S) protein, an M protein, an E protein, and an ORF8 protein (claim 14), wherein the spike (S) protein is in a prefusion complex and/or in a postfusion complex (claim 15), 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 18), wherein (i) 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; (ii)the M protein comprises a sequence having at least 90% sequence identity to SEQ ID NO: 6; and/or (iii) the E protein comprises a sequence having at least 90% sequence identity to SEQ ID NO: 7 (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 coronavirus antigen,
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 coronavirus antigen is selected from the group consisting of a spike (S) protein, a matrix (M) protein, or an envelope (E) protein (claim 34); wherein the spike protein is in a prefusion complex and/or postfusion complex (claim 35), 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: (i) 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; (ii) the M protein comprises a sequence having at least 90% sequence identity to SEQ ID NO: 6; or (iii) the E protein comprises a sequence having at least 90% sequence identity to SEQ ID NO: 7 (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 virus 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 virus, 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 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); wherein the virus is a coronavirus, an influenza virus, or a combination thereof (claim 75), 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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 11, 64, 68, 75, and 78 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Graham et. al. (US20200061185A1, Pub. 02/27/2020; hereafter “Graham”.)
The Prior Art
Graham teaches Coronavirus (CoV) spike (S) protein ectodomain trimers stabilized in a prefusion conformation, nucleic acid molecules and vectors encoding these proteins, and methods of their use and production (entire document; see abstract.) Graham teaches the ectodomain trimers and/or nucleic acid molecules can be used to generate an immune response to coronavirus in a subject, wherein a therapeutically effective amount of the coronavirus S ectodomain trimers and/or nucleic acid molecules can be administered to a subject in a method of treating or preventing coronavirus infection (entire document; see abstract.) Graham teaches inoculation of mice with a prefusion stabilized form of the CoV S trimer, and teaches inoculation of mice with wild-type S protein, which comprises a mixture of prefusion and postfusion forms of the trimer (¶[0018][0305][0326]; Fig. 5). Graham teaches the inoculation of the composition may occur via the intranasal route (¶[0035]). Graham therefore teaches every limitation of instant claims 1, 64, and 75.
Graham teaches further components of the instant claims. Graham teaches that the inoculation of the composition would ameliorate signs or symptoms of a disease or pathological condition from viral infection, including preventing or reducing the risk of viral infection, wherein such a measurement of treatment efficacy can be made in delayed onset of clinical symptoms of infection or reduction in viral load (¶[0072]; instant claim 68). Graham teaches the S protein immunogen can be combined with other vaccine immunogens, such as influenza virus vaccine or varicella zoster virus (VZV) vaccine, wherein influenza virus vaccines inherently comprise HA antigens from influenza A viral strains, influenza B viral strains, or both influenza A and B viral strains (¶[0276]; instant claim 78). As instant claim 11 is drawn to a “sequence having at least 90% identity to any sequence independently selected from one of SEQ ID NOs: 1-5 or 8-10”, this is interpreted as any sequence comprising SEQ ID NOs: 1-5 or 8-10 or fragments thereof. As Graham teaches sequences for SARS CoV S proteins, said sequences share homology with SARS CoV-2 S proteins, with at least a portion of instant SEQ ID NO:8 (Db) aligning with 100% identity to reference SEQ ID NO: 6 (Qy) from Graham, and thus teaches the limitations of instant claim 11:
Qy 1 VVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 949 VVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQ 1008
Qy 61 QLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQ 104
||||||||||||||||||||||||||||||||||||||||||||
Db 1009 QLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQ 1052
For at least these reasons, Graham teaches the limitations of instant claims 1, 11, 64, 68, 75, and 78, and anticipates the invention encompassed by said claims.
Claims 1, 9, 11, 64, 68, 75-76, and 78 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Liang et. al. (US20220016235A1, Priority 06/10/2020; hereafter “Liang.)
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].) The compositions may be administered intranasally (¶[0052][0502][0632]). Liang therefore teaches every limitation of instant claim 1. 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). Liang teaches SEQ ID NO: 55, which is 100% identical to instant SEQ ID NO: 4 (See ABSS sequence alignments; ¶[0367][0481][0522]; instant claim 11). As Liang teaches the sequence is glycosylated with N-linked glycans, and teaches SEQ ID NO: 55 which comprises N residues at 1098, 1134, 1158, 1173, and 1194, Liang teaches the limitations of instant claim 9. 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 claims 64, 75-76). 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 claim 78).
For at least these reasons, Liang teaches the limitations of instant claims 1, 9, 11, 64, 68, 75-76, and 78, and anticipates the invention encompassed by said claims.
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 2-3, 7, 13-15, 18-19, 24, 28-29, 33-35, 38-39, 42, 46-47, 51, 53, 55-56, 63, and 79 are rejected 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”.)
The Prior Art
The teachings of Liang have been set forth supra. While Liang teaches compositions which comprise both pre- and post-fusion forms of SARS CoV-2 S protein complexes, and teaches that said complexes 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), Liang is silent as to said adjuvants being STING agonists. However, the use of STING agonists, especially when delivered by nanoparticles, was suggested in the art as a means to adjuvant vaccine compositions, as evidenced by the teachings of Moniz. Further motivation to utilize STING agonists in SARS CoV-2 S protein compositions is evident from the teachings of Prasad, while Galarza provides further motivation to deliver nanoparticles which comprise both pre-fusion and post-fusion forms of the viral surface fusion proteins. Furthermore, while Liang teaches the use of intranasal sprays for delivery of the composition, Liang fails to get into specifics on the viscosity of the nasal spray or how much antigen is delivered per spray. However, these adjustments for the specific intranasal delivery method are common optimization steps in the art, as evidenced by Gizurarson.
Moniz teaches extracellular vesicles (EVs) which comprise a payload, wherein said payload may include antigens, adjuvants, and/or immune modulators (entire document; see abstract.) Said EVs range in size from 20 nm to 1000 nm (¶[0099]; instant claims 7, 28, 46). Moniz teaches the STING agonist may comprise a cyclic dinucleotide (¶[0189]; instant claims 3, 24, 42). Moniz teaches the viral antigen may comprise antigens from coronaviruses, such as SARS CoV-2, influenza A virus, and/or influenza B virus (¶[0036][0175][0534]; reference claim 90; instant claims 13, 47).
Prasad teaches rationally engineered Carrier Proteins (reCaPs) geared towards producing Multifunctional Chimeric recombinant Fusion Proteins (MCFPs) useful as vaccine candidates. The key components of the MCFPs are (i) genetically engineered carrier proteins; (ii) polypeptide antigens; (iii) linker peptides, optionally fused to heterologous T-cell epitopes; (iv) Dual Function Peptides (DFP) which can act as a purification aids as well having the non-covalent affinity to bind to an adjuvant. Prasad also teaches recombinantly expressed Self-Assembling Adjuvanted Nanoparticles (SAANPs), comprising reCaPs fused with various polypeptide and protein antigens, useful as vaccine candidates (entire document; see abstract.) Prasad teaches the antigens may be from the spike (S) protein of SARS CoV-2 (¶[0124-0125]). Prasad teaches “chimeric fusion proteins” (CFPs), which refers to a hybrid protein produced by recombinant protein expression via the translation of a fusion gene which results in multiple polypeptides with functional properties derived from one or more parent proteins (¶[0025][0051]). Prasad teaches the antigen and/or adjuvant may be incorporated into or entrapped within VLPs or lipid vesicles (¶[0067][0080]) and said compositions may include adjuvants, such as STING agonists (¶[0069]; instant claim 2). Prasad teaches influenza A antigens (¶0083]) and viral surface protein antigens from viral fusion proteins, wherein said viral fusion proteins are present within a VLP in both the prefusion and postfusion form of the viral fusion protein (¶[0191]).
Galarza teaches respiratory syncytial virus (RSV) vaccine compositions, wherein the RSV vaccine antigens are the surface fusion (F) glycoprotein in both the prefusion and postfusion conformations encapsulated within a virus-like particle (VLP)(entire document; see abstract), which, under broadest reasonable interpretation, can be interpreted as a lipid nanoparticle as it both comprises glycolipids (as the VLP was produced in mammalian cells, see ¶[0059][0144]) and is a nanoparticle that is 90-100 nm in diameter (entire document; see abstract; Fig. 2, ¶[0050].) Galarza teaches the VLPs are delivered to the host intranasally (¶[0133]).
Gizurarson teaches liquid pharmaceutical compositions comprising a therapeutic agent and an alkoxy-polyethylene glycol, for example, methoxy-polyethylene glycol, for administration of the therapeutic agent to the mammal, specifically via application to a nasal membrane during intranasal administration (entire document; see abstract.) Gizurarson teaches viral vaccines, such as influenza vaccines, can be delivered in these compositions (¶[0061]). Gizurarson teaches the compositions would have a low viscosity at room temperature of about 5 cP to about 25 cP (¶[0042]; instant claim 33), and would be delivered in a clinically relevant volume of about 25-300 uL (¶[0059][0077]) as larger volumes drain out anteriorly through the nostrils or posteriorly through the pharynx (¶[0008]). Gizurarson teaches the smaller volumes are ideal in order to reproducibly deliver the correct dosage of therapeutic agent (¶[0007-0010]). Gizurarson teaches the pH of the compositions can be from about 4.5 to about 8.5 (¶[0013][0041]). Gizurarson teaches the intranasal devices would be delivered via a spray device that provides a plume of spray droplets that contact the nasal mucosa, with a number of commercially available devices on the market that can easily be utilized by the patient or care giver (¶[0078-0079]; instant claim 79).
Given what was known in the art as evidenced by Liang, it would be obvious to deliver SARS CoV-2 prefusion and postfusion S protein compositions via intranasal delivery, especially in combination with other agents, such as adjuvants and/or other antigens. Given the teachings of Gizurarson, one of skill in the art would know about reagents and devices for low viscosity and reproducible administration of therapeutic viral vaccines. Given what was known in the art with respect to adjuvants, it would be obvious to try and use STING agonists as adjuvanting agents in the compositions for intranasal delivery, given the teachings of Moniz and Prasad. Further motivation to deliver prefusion and postfusion antigens is given by Galarza, which teaches viral respiratory fusion proteins delivered intranasally via VLPs which express both conformations of the surface protein antigen. Taken as a whole, with what was known in the art at the time of filing as evidenced by the combined teachings of Liang in view of Galarza, Moniz, Prasad, and Gizurarson, one of skill in the art would find it obvious to arrive at the limitations of instant claims 13, 33, and 63 and further dependent claims 2-3, 7, 14-15, 18-19, 24, 28-29, 34-35, 38-39, 42, 46-47, 51, 53, 55-56, and 79.
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 generate compositions optimized for intranasal delivery, thereby producing a SARS CoV-2 vaccine platform that was less invasive that current intramuscular injection platforms. One would have been motivated to do so, given the suggestion by Gizurarson that the composition could be optimized for intranasal delivery through maintaining low viscosity and using commercially-available actuators. There would have been a reasonable expectation of success, given the knowledge that intranasal delivery of protein antigens was known and suggested in the art for coronavirus antigens, as taught by Prasad and Galarza, and also given the knowledge that delivery of a mixture of both prefusion and postfusion forms of the CoV S protein was suggested, as taught by Liang, Prasad, and Galarza. There would be further reasonable expectation of success, given the teachings of Moniz and Prasad, which taught the usefulness of STING agonists as vaccine adjuvants. 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.
Claims 5, 26, and 44 are rejected 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”.)
The Prior Art
The teachings of Liang, Prasad, Galarza, Moniz, and Gizurarson have been set forth supra. While Liang teaches the delivery of the SARS CoV-2 antigens via LNPs, Liang fails to teach negatively-charged LNPs. None of the teachings of Prasad, Galarza, Moniz, or Gizurarson, alone or in combination, cure this deficiency. However, the use of negatively-charged LNPs for the encapsulation of certain adjuvants for viral vaccine compositions, such as STING agonists, was known in the art, as evidenced by the teachings of Wang.
Wang teaches mucosal adjuvants using stimulator of interferon genes (STING) agonists with nanoparticles to breach the integrity of pulmonary surfactant (p. 1, “Rationale”). Wang teaches they synthesized a series of liposomes, based on pulmonary surfactant (PS) constituents, to encapsulate cGAMP(fig. S1A). The negatively charged nano4 was closest to PS in terms of lipid composition and charge, and Wang teaches it was the only liposome that, when intranasally administered with whole inactivated A/Vietnam/1203/2004(VN04) H5N1 vaccine, vigorously stimulated the production of serum immunoglobulin G (IgG) and broncho-alveolar lavage fluid (BALF) IgA, concomitant with no body weight loss over vaccine-alone controls (fig. S1, B to E). By contrast, liposomes that were neutral (such as nano1), replaced anionic phosphatidylglycerol (DPPG) with cationic 1,2-dipalmitoyl-3-trimethylammonium-propane (DPTAP) (such as nano3 or naon5), or lacked polyethylene glycol, molecular weight2000 (PEG-2000) (such as nano2 and nano3)showed substantially less adjuvanticity while causing significant loss in body weight (fig. S1,A to E; p. 1, ¶ bridging middle and rt. Cols.)
Given the combined teachings of Liang, Prasad, Galarza, Moniz, and Gizurarson, one of skill would find it obvious to generate compositions comprising SARS CoV-2 S proteins in pre- and post-fusion conformations along with STING agonist adjuvants and lipid nanoparticles. Given the further teachings of Wang, it would be obvious if the composition of Liang, Prasad, Galarza, Moniz, and Gizurarson was delivered intranasally to use negatively-charged LNPs for delivery of the STING agonists, given the data supporting the immune response generated by said LNPs over other LNPs with different charges. Therefore, arriving at the limitations of instant claims 5, 26, and 44 would be obvious to a skilled artisan, given the combined teachings of Liang, Prasad, Galarza, Moniz, Gizurarson, and Wang.
It would have been obvious to one of ordinary skill in the art to modify the methods/compositions taught by Liang, Prasad, Galarza, Moniz, Gizurarson in order to use negatively charged LNPs, thereby facilitating delivery of the STING agonist adjuvants. One would have been motivated to do so, given the suggestion by Wang that the use of the negatively charged LNPs produced a superior response over other LNPs with neutral or positive charges. There would have been a reasonable expectation of success, given the knowledge that STING agonists were known adjuvanting materials, as taught by Moniz, Prasad, and Wang, and also given the knowledge that the negatively charged LNPs would still be useful when delivered intranasally, as taught by Wang. 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 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 13-15, 18-19, 24, 26, 28-29, 63-64, 68, 75-76, and 78-79 are provisionally rejected 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). Both sets of claims are drawn to compositions comprising coronavirus (CoV) antigens and lipid nanoparticles (LNPs). Both sets of claims are drawn to the composition comprising CoV spike (S) protein antigens, envelope (E) protein antigens, matrix/membrane (M) protein antigens, and ORF8 antigens. Both sets of claims provide that the composition comprises an adjuvant. Both claim that influenza antigens may be in the composition.
The main difference is the instant claims provide for the S protein antigen to be in pre- and post-fusion conformations and the adjuvant is a STING agonist in a negatively charged LNP, and the reference claims are delivering the antigens via nucleic acids, such as through viral vectors. However, such differences would be obvious distinctions given the prior art, as evidenced by the teachings of Liang and Wang (detailed supra). Further, Liang teaches the SARS CoV-2 antigens may be delivered via viral vectors, such as ChAdOx1 vectors (¶[0659]) or include adjuvants such as alum (aluminum hydroxide)(¶[0064]). Therefore, the differences between the two claim sets are obvious variants, and do not render the claims patentably distinct, especially in light of the teachings of Liang and Wang.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671