DETAILED ACTION
Disposition of Claims
Claims 110-121 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250099569A1, Published 03/27/2025.
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/16/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 110 and dependent claims 111-115 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.
Claim 110 is drawn to “R4 is —(CH2)nQ, wherein Q is —OR, wherein n is selected from 1, 2, 3, 4, and 5; each R8 is H; each R6 is H;”. Formula (I) does not comprise an R8 subgroup. The specification notes at ¶[0029] that with Formula (I) R5 is defined as C1-3 alkyl, C2-3 alkenyl, or H, whereas R8 is defined as a C3-6 carbocycle or heterocycle. Therefore, it is assumed that R8 was intended to be R5 , but the claim must be amended for further clarification.
For at least these reasons, claim 110 is rejected for being indefinite. Claims 111-115 are also rejected for depending upon claim 110, but not remedying the deficiencies of claim 110.
Claims 110 and 116 and dependent claims 111-115 and 117-121 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 110 and 116 identify S155C, S290C, S190F, and V207L without expressly reciting a reference F sequence or RSV strain from which those residue numbers are counted. Further dependent claims provide further indefiniteness issues, as they claim sequences which appear to comprise these mutations (e.g. SEQ ID NO: 291), but those claims are drawn to a sequence with at least 85% identity to said sequence, and it is unclear if these recited mutations must be retained in said sequence. Further, additional sequences in the specification appear to recite a “N207L” substitution instead of a “V207L” substitution (see e.g. ¶[0863-0864] with SEQ ID NO: 290; ¶[0942-0943] with SEQ ID NO: 244) - SEQ ID NO: 6, which appears to be a WT RSV F protein sequence, appears to comprise a “V” at this position and not an “N”, but there is a “N” immediately following the “V” residue, making it critical to provide a base reference sequence to ensure that the correct substitutions are being generated. Finally, claim 117 is drawn to any “deletion of C-terminal amino acid residues relative to a wild-type RSV F glycoprotein”. As the “RSV” is not defined as a specific type (e.g. human RSV, bovine RSV, ovine RSV) and a specific “base” sequence is not provided and there are natural C-terminal variants in wild-type RSV F proteins, it is unclear how to determine whether or not the RSV F protein comprises a C-terminal mutation or not. One suggestion with this last limitation is that a specific domain found C-terminally be noted as being truncated and/or absent (e.g. cytoplasmic domain, transmembrane domain, etc.)
For at least these reasons, claims 110 and 116 are rejected for being indefinite. Claims 111-115 and 117-121 are also rejected for depending upon claim 110 or 116, but not remedying the deficiencies of claim 110 or 116.
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 110 is drawn to a vaccine comprising a messenger ribonucleic acid (mRNA) formulated in a lipid nanoparticle, wherein the mRNA comprises an open reading frame (ORF) comprising nucleosides consisting of N1-methyl-pseudouridine, adenosine, guanosine, and cytidine,
wherein the ORF encodes a respiratory syncytial virus (RSV) fusion (F) glycoprotein comprising S155C, S290C, S190F, and V207L amino acid substitutions; and
wherein the lipid nanoparticle comprises a compound of Formula (I):
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wherein:
R1 is selected from the group consisting of C5-30 alkyl, C5-20 alkenyl, and —R″M′R′;
R2 and R3 are independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl;
R4 is —(CH2)nQ, wherein Q is —OR, wherein n is selected from 1, 2, 3, 4, and 5;
each R5 is H;
each R6 is H;
M and M′ are independently selected from —C(O)O— and —OC(O)—;
R7 is H;
R is H;
R′ is selected from the group consisting of C1-18 alkyl and C2-18 alkenyl;
R″ is selected from the group consisting of C3-14 alkyl and C3-14 alkenyl; and
m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.
Further limitations on the mRNA vaccine of claim 110 are wherein the amino acid sequence of the RSV F glycoprotein is an amino acid sequence having at least 85% identity to SEQ ID NO: 291 (claim 111); wherein the lipid nanoparticle further comprises a PEG-modified lipid, a sterol, and a neutral lipid (claim 112), wherein the PEG-modified lipid is 1,2 dimyristoyl-sn-glycerol, methoxypolyethyleneglycol (PEG2000-DMG), the sterol is cholesterol, and the neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)(claim 113), wherein the lipid nanoparticle comprises 20-60 mol % Formula (I), 0.5-15 mol % PEG-modified lipid, 25-55 mol % sterol, and 25-55 mol % neutral lipid (claim 114); and wherein the compound of Formula (I) comprises Compound 25 (claim 115):
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Claim 116 is drawn to a vaccine comprising a messenger ribonucleic acid (mRNA) formulated in a lipid nanoparticle, wherein the mRNA comprises an open reading frame (ORF) comprising nucleosides consisting of N1-methyl-pseudouridine, adenosine, guanosine, and cytidine, wherein the ORF encodes an immunogenic fragment of a respiratory syncytial virus (RSV) fusion (F) glycoprotein,
wherein the immunogenic fragment of the RSV F glycoprotein comprises S155C, S290C, S190F, and V207L amino acid substitutions; and
wherein the lipid nanoparticle comprises a compound of Formula (I):
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wherein:
R1 is selected from the group consisting of C5-30 alkyl, C5-20 alkenyl, and —R″M′R′;
R2 and R3 are independently selected from the group consisting of C1-14 alkyl and C2-14 alkenyl;
R4 is —(CH2)nQ, wherein Q is —OR, wherein n is selected from 1, 2, 3, 4, and 5;
each R5 is H;
each R6 is H;
M and M′ are independently selected from —C(O)O— and —OC(O)—;
R7 is H;
R is H;
R′ is selected from the group consisting of C1-18 alkyl and C2-18 alkenyl;
R″ is selected from the group consisting of C3-14 alkyl and C3-14 alkenyl; and
m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.
Further limitations on the mRNA vaccine of claim 116 are wherein the immunogenic fragment of the RSV F glycoprotein comprises a deletion of C-terminal amino acid residues relative to a wild-type RSV F glycoprotein (claim 117); wherein the lipid nanoparticle further comprises a PEG-modified lipid, a sterol, and a neutral lipid (claim 118), wherein the PEG-modified lipid is 1,2 dimyristoyl-sn-glycerol, methoxypolyethyleneglycol (PEG2000-DMG), the sterol is cholesterol, and the neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)(claim 119), wherein the lipid nanoparticle comprises 20-60 mol % Formula (I), 0.5-15 mol % PEG-modified lipid, 25-55 mol % sterol, and 25-55 mol % neutral lipid (claim 120); and wherein the compound of Formula (I) comprises Compound 25 (claim 121):
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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.
Claims 110-121 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the specific tested RSV F mRNA vaccine embodiments formulated in MC3-based lipid nanoparticles, does not reasonably provide enablement for RSV F mRNA vaccines formulated with the presently claimed Formula (I) ionizable lipids, including the specific Compound 25 embodiments of claims 115 and 121. 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 an RSV mRNA vaccine comprising an mRNA encoding an RSV F glycoprotein, or an immunogenic fragment thereof, having the S155C, S290C, S190F, and V207L substitutions, wherein the mRNA comprises N1-methyl-pseudouridine and is formulated in a lipid nanoparticle comprising an ionizable lipid falling within Formula (I). Claims 110 and 116 encompass a genus of Formula (I) lipids having variation in the hydrophobic substituents, chain lengths, degree of unsaturation, linker arrangement, and ester-containing portions of the molecule. The specification describes this Formula (I) genus and its various substituent alternatives at (¶[0523-0640]). The specification also discloses individual Formula (I) species, including Compound 25 (¶[0635]). In separate passages, the specification states generally that nanoparticles comprising a Formula (I) lipid may contain an RNA, including an mRNA therapeutic or prophylactic, and may be used to deliver such mRNA to a cell and produce an encoded polypeptide (¶[0642-0644]). These passages provide general direction that Formula (I) compounds may be considered for mRNA delivery, but they do not report testing of the presently claimed RSV F mRNAs using those Formula (I) lipids.
However, the RSV vaccine working embodiments in the specification use MC3. Example 12 states that the RSV mRNA vaccines were “generated and formulated in MC3 lipid nanoparticles,” and identifies MRK-4 as a membrane-bound DS-CAV1 stabilized prefusion F protein (¶[0846-0849]). The later mouse studies likewise use RSV mRNAs formulated in MC3 LNPs, including the MRK-4 DS-CAV1 construct (¶[0927-0931]). The cotton rat studies again use MC3-formulated RSV mRNAs, including MRK-4, and report challenge results following vaccination (¶[0957-0963][0974]). The African Green Monkey studies further evaluate the RSV vaccine constructs in an MC3-based formulation (¶[0975-0979]).
The claims are not limited to these demonstrated MC3 formulations. Claims 110-114 and 116-120 instead require Formula (I) ionizable lipids, thereby extending the claims to lipid chemistries that were not used in the RSV working examples. Claims 115 and 121 narrow the ionizable lipid to Compound 25, but Compound 25 is itself chemically different from MC3 and is likewise not used in the RSV working examples.
The selection of Compound 25 in claims 115 and 121 does not resolve the enablement issue. Those claims identify one particular ionizable lipid, but they depend directly from claims 110 and 116 and do not import the more particular helper-lipid and molar-ratio limitations of claims 114 and 120. The remaining LNP formulation space therefore remains open, and the specification does not provide an RSV working example showing how Compound 25 should be formulated with the claimed mRNA to provide the claimed vaccine. Thus, claims 115 and 121 require more than merely making a known chemical compound; they require making and using the particular Compound 25/RSV mRNA vaccine combination that is claimed.
MC3 and Compound 25 are not interchangeable names for the same lipid structure. Compound 25, as depicted at ¶[0635], differs from MC3 in its head-group substitution, ester arrangement, and hydrophobic architecture. These structural differences are material because the specification itself recognizes that LNP behavior depends on the particular lipid and formulation selected. In support of this notion, the specification states that “[a] lipid nanoparticle formulation may be influenced by, but not limited to, the selection of the cationic lipid component, the degree of cationic lipid saturation, the nature of the PEGylation, ratio of all components and biophysical parameters such as size”(¶[0383]). The same paragraph cites evidence that changing cationic-lipid composition altered delivery to antigen-presenting cells. The specification therefore does not treat ionizable lipid identity as an immaterial variable. Rather, it recognizes that lipid identity operates together with the surrounding formulation to affect nucleic-acid delivery.
The specification provides a specific MC3-containing RNA vaccine formulation comprising MC3, cholesterol, DSPC, and PEG2000-DMG at ¶[0407]. By contrast, the Formula (I) disclosure identifies compounds and broad formulation possibilities, but does not provide a corresponding RSV vaccine formulation and biological demonstration for Compound 25 or for representative members spanning the claimed Formula (I) genus. Accordingly, the claimed scope extends materially beyond the embodiments actually demonstrated in the specification.
In addition to the breadth of the claims not being limited to the identity of the Formula (I) ionizable lipid, the claims also encompass substantial variation in the remaining components of the lipid nanoparticle. Claims 112 and 118 require only that the LNP further comprise a PEG-modified lipid, a sterol, and a neutral lipid. These claims do not limit the chemical identity of those additional lipid components or their relative amounts. Claims 113 and 119 identify PEG2000-DMG, cholesterol, and DSPC, but likewise do not specify the relative proportions of those components. Claims 114 and 120 provide molar ranges, but those ranges continue to permit substantial variation in the relative composition of the resulting nanoparticle.
The specification itself confirms that these terms encompass materially different formulation components. The specification identifies DSPC, POPC, DPPC, DOPE, and sphingomyelin as examples of neutral lipids and identifies PEG-DMG and PEG-cDMA as examples of PEG-modified lipids (¶[0400-0401]). The specification further describes substantial variation in the permitted amounts of neutral lipid, sterol, and PEG-modified lipid and provides numerous alternative molar ratios (¶[0400-0403]). Applicant therefore does not claim merely one established helper-lipid combination surrounding the selected ionizable lipid. The claims reach numerous chemically and quantitatively different LNP compositions.
This additional formulation breadth is material because the specification recognizes that LNP performance can depend on more than the identity of the ionizable lipid. As discussed at ¶[0383], “[a] lipid nanoparticle formulation may be influenced by, but not limited to, the selection of the cationic lipid component, the degree of cationic lipid saturation, the nature of the PEGylation, ratio of all components and biophysical parameters such as size.” Thus, the disclosure itself recognizes that PEGylation and component ratios are variables capable of affecting LNP behavior. The claims nevertheless encompass broad variation in those same parameters without providing representative RSV vaccine data across that scope.
The breadth is particularly significant for claims 115 and 121. Although these claims narrow the Formula (I) compound to Compound 25, claims 115 and 121 depend directly from claims 110 and 116, respectively. They do not require PEG2000-DMG, cholesterol, DSPC, or any particular relative amount of Compound 25 or another LNP component. Accordingly, selection of Compound 25 does not reduce claims 115 and 121 to a single defined LNP formulation. Those claims continue to encompass Compound 25 in a broad range of nanoparticle environments, including different helper lipids and different relative component amounts.
The specification does not provide working mRNA RSV vaccine examples spanning that formulation space. Rather, the RSV vaccine experiments use MC3-containing nanoparticles. The disclosure therefore leaves one skilled in the art not only to determine whether Compound 25 can replace MC3, but also to determine which surrounding lipid components and relative amounts permit a Compound 25-containing nanoparticle to encapsulate and deliver the claimed RSV mRNA with sufficient expression for use as the claimed vaccine. Identification of Compound 25 narrows one formulation variable, but does not resolve the remaining formulation-dependent variables.
State of the prior art and predictability of the art. At the time the application was filed, one skilled in the art understood that ionizable lipids could be used to formulate lipid nanoparticles for nucleic-acid delivery. However, the art also showed that biological performance depended on the particular ionizable lipid and formulation rather than merely on membership in the general class of ionizable lipids.
Jayaraman et al. (Jayaraman M, et. al. Angew Chem Int Ed Engl. 2012 Aug 20;51(34):8529-33. Epub 2012 Jul 10.) evaluated a series of ionizable amino lipids for in vivo nucleic-acid delivery and reported a strong relationship between ionizable-lipid properties and biological potency. The authors found an optimum apparent pKa range for the system tested, but also reported that “significant potency differences were found for lipids with similar pKa values” and explained that an optimal pKa was a necessary but not sufficient requirement for good in vivo activity because structural features such as the linker also contributed to performance. Jayaraman further identifies DLin-MC3-DMA as one of the highly active lipids examined, underscoring that MC3 performance reflected properties of that particular chemical structure rather than establishing a general rule applicable to structurally different ionizable lipids.
Kauffman et al. (Kauffman KJ, et. al. Nano Lett. 2015 Nov 11;15(11):7300-6. Epub 2015 Oct 20.) addressed LNP formulation specifically for mRNA delivery in vivo. Kauffman stated that the relative ratios of the amine-containing lipid, phospholipid, cholesterol, and PEG-lipid “can have profound effects on the formulation potency” and used fractional factorial and definitive screening designs to optimize mRNA LNP compositions. The need for systematic optimization rather than treating helper-lipid identity and proportion as interchangeable variables is evidence that selecting an ionizable lipid and additional helper lipids did not, by itself, establish which surrounding formulation would provide effective mRNA delivery.
Basha et al. (Basha G, et. al. Mol Ther. 2011 Dec;19(12):2186-200. Epub 2011 Oct 4.) compared LNP formulations containing different ionizable cationic lipids for nucleic-acid delivery to antigen-presenting cells. The reference reports materially different delivery and silencing behavior among the tested lipid structures, with DLinKC2-DMA formulations described as “the most potent formulations” and as the most potent intracellular delivery agents among those tested. Basha additionally showed that changing nanoparticle size affected delivery behavior, further illustrating that performance reflected the interaction of lipid chemistry and formulation characteristics rather than lipid identity alone. The instant specification itself cites Basha when explaining that changing cationic-lipid composition can change delivery to antigen-presenting cells (¶[0383]). This disclosure is consistent with the prior art discussed above and weighs against treating the successful MC3 RSV results as predictive of Compound 25 or the broader Formula (I) genus.
The art was therefore not sufficiently predictable to support extrapolation from an MC3-formulated RSV mRNA vaccine to the full Formula (I) scope now claimed, and the same concern remains for Compound 25. Although only one ionizable lipid must be evaluated under instant claims 115 and 121, the prior art did not provide a rule establishing that an mRNA formulation successful with MC3 could be converted to a Compound 25 formulation without empirical formulation and biological testing.
Accordingly, the results obtained using the disclosed MC3 formulations would not have reasonably established that the broader Formula (I) scope, or the particular Compound 25 vaccine combination of claims 115 and 121, could be practiced without further experimentation. The experimentation required for claims 115 and 121 is not limited to confirming that a single known Compound 25 formulation works, as the claims encompass Compound 25 with materially different PEG-modified lipids, neutral lipids, sterols, and relative component amounts. One skilled in the art would need to prepare and evaluate additional formulations to determine which combinations provide suitable particle formation, mRNA encapsulation and delivery, antigen expression, and use as the claimed RSV vaccine. The specification does not provide sufficient predictive guidance to identify those combinations without such empirical formulation and biological testing.
Additionally, the breadth of the claimed invention is not limited only to variations in the lipid nanoparticle, as the claims also encompass substantial variations in the structure of the mRNA carried by the LNP. Although claims 110 and 116 require the open reading frame to contain N1-methyl-pseudouridine in place of uridine and require expression of the recited RSV F antigen, the claims do not require a particular synonymous nucleotide sequence encoding that antigen. The claims likewise do not require a particular 5′ untranslated region, 3′ untranslated region, 5′ cap structure, poly(A) tail configuration, or codon-optimization scheme. Accordingly, many structurally different mRNAs fall within the claims even before the additional breadth of the Formula (I) LNP is considered. At the time of filing, the art recognized that these mRNA structural features were not merely incidental portions of an interchangeable mRNA molecule. Rather, modifications to the noncoding regions, coding sequence, cap, poly(A) tail, and nucleotide chemistry could materially change stability and the amount or duration of protein produced from an otherwise antigen-equivalent mRNA.
Holtkamp et. al. (Holtkamp S, et. al. Blood. 2006 Dec 15;108(13):4009-17. Epub 2006 Aug 29.; CITED ART OF RECORD IN 12/16/2024 IDS;) investigated structural modifications of antigen-encoding mRNA and specifically examined the region 3′ of the coding sequence. Holtkamp reported that a 120-nucleotide poly(A) tail, an unmasked free 3′ end, and tandem β-globin 3′ UTRs “each independently enhanced RNA stability and translational efficiency.” The resulting increase in antigen expression also increased antigen-specific peptide/MHC complexes and T-cell stimulatory activity. Mockey et. al. (Mockey M, et. al. Biochem Biophys Res Commun. 2006 Feb 24;340(4):1062-8. Epub 2005 Dec 27.) similarly demonstrated that the particular combination of mRNA cap and poly(A) tail substantially affected protein output. The authors reported approximately 20-fold greater luciferase expression using an ARCA 5′ cap rather than the conventional cap and approximately 35-fold further improvement when the poly(A) tail was increased from 64 to 100 adenosines. The optimized ARCA-capped, A100-tailed construct produced approximately 700-fold greater expression than the comparison CAP/A64 construct, showing that ostensibly peripheral mRNA structural features could produce very large differences in expression.
Kuhn et. al. (Kuhn AN, et. al. Gene Ther. 2010 Aug;17(8):961-71. Epub 2010 Apr 22.) further examined different synthetic 5′ cap structures in antigen-encoding RNA. Kuhn reported that particular phosphorothioate cap analogs “profoundly enhance RNA stability and translational efficiency” in immature dendritic cells and also provided increased protein expression and antigen-specific T-cell responses in vivo. Thus, even where the encoded protein was held constant, changing the chemical structure at the 5′ end of the RNA materially affected the stability and biological expression of the RNA vaccine.
Thess et. al. (Thess A, et. al. Mol Ther. 2015 Sep;23(9):1456-64. Epub 2015 Jun 8.; CITED ART OF RECORD IN 12/16/2024 IDS;) showed that coding-sequence and untranslated-region design were likewise material variables. Their sequence-engineering approach “adapts the codon usage” and selects 5′ and 3′ UTRs in a “target and application specific manner,” and the authors found that optimization of both the open reading frame and regulatory untranslated regions was important for protein expression. The sequence-engineered mRNAs were also successfully delivered after LNP encapsulation in large animals, demonstrating that mRNA performance depended on deliberate engineering of the RNA itself rather than simply placing any coding sequence for the desired protein into an LNP. Thess additionally describes optimization of the coding region to improve translation and mRNA half-life by preferential use of GC-rich codons. This is consistent with the broader state of the art summarized by Sahin et. al. (Sahin U, et. al. Nat Rev Drug Discov. 2014 Oct;13(10):759-80. Epub 2014 Sep 19.), which identified codon bias, codon order, UTR composition, cap chemistry, and poly(A) structure as established variables affecting therapeutic mRNA performance. Sahin specifically cites prior work showing that cap and poly(A) modifications affect stability and translation and that codon usage affects heterologous protein expression.
Nucleoside chemistry constituted another material variable in the art. Svitkin et. al. (Svitkin YV, et. al. Nucleic Acids Res. 2017 Jun 2;45(10):6023-6036. Online 2017 Feb 23.), published online shortly before the priority date of the instant application, directly compared modified mRNAs and reported that N1-methyl-pseudouridine “outperforms several other nucleoside modifications” in translation capacity. The reference further explains that N1-methyl-pseudouridine altered translation through effects on immune/eIF2α-dependent inhibition and ribosome behavior.
The instant claims select N1-methyl-pseudouridine for the open reading frame. Therefore, nucleoside identity itself is not relied upon as an unbounded variable within claims 110 and 116. Rather, the significance of Svitkin et. al. is that the art understood mRNA performance to be sensitive to molecular design even when the encoded protein was unchanged. Fixing one such variable, N1-methyl-pseudouridine, does not fix the remaining variables concerning UTR identity, cap chemistry, poly(A) configuration, synonymous codon selection, or GC content.
The state of the art also showed that optimization of the mRNA could not be considered independently from optimization of the LNP used to deliver it. Reichmuth et. al. (Reichmuth AM, et. al. Ther Deliv. 2016;7(5):319-34.; CITED ART OF RECORD IN 12/16/2024 IDS;) explained that efficient mRNA vaccine delivery was a key problem and that LNPs could “protect the mRNA against degradation” and “facilitate endosomal escape.” The reference therefore distinguishes the requirements placed on the mRNA molecule itself from the additional barriers that must be addressed by the delivery vehicle before the encoded antigen can be expressed.
Accordingly, the state of the art did not treat an mRNA-LNP vaccine as the simple combination of an interchangeable mRNA cargo and an interchangeable nanoparticle carrier. The amount and persistence of antigen expression depended upon structural choices within the mRNA, while encapsulation, protection from degradation, cellular delivery, and endosomal release depended substantially on the LNP and its formulation. The ultimate protein output therefore reflected successful operation of both portions of the composition. This adds a further dimension to the unpredictability discussed above with respect to the claimed Formula (I) lipids. The RSV working examples establish biological performance for particular RSV mRNAs delivered using MC3 LNPs. Those results do not establish that every mRNA architecture encompassed by the claims can be combined with every claimed Formula (I) LNP formulation and provide sufficient stability, delivery, intracellular release, and antigen expression to make and use the claimed RSV vaccine.
Level of skill in the art. One skilled in the art would have been familiar with mRNA synthesis, lipid nanoparticle preparation, particle-size measurements, encapsulation assays, cellular expression studies, and immunogenicity testing. Such a person would also have understood how to adjust lipid ratios and evaluate candidate formulations.
However, the existence of known methods for making and testing candidate LNPs does not establish that one skilled in the art would have known in advance which Formula (I) compounds and surrounding formulations would successfully deliver the claimed RSV mRNA, nor does technical skill supply the missing information for Compound 25 and LNPs comprising said lipid. A skilled artisan could perform experiments using Compound 25, but would still need those experiments to determine how that structurally different lipid should be formulated with other helper lipids and at what ratios, and whether the resulting composition successfully delivers and expresses the claimed RSV F mRNA as a vaccine. This distinction is important, as enablement is not established merely because the skilled artisan knows how to conduct the experiments needed to determine whether an untested embodiment works.
Working examples. The specification provides several working examples directed to RSV F mRNA vaccines formulated in MC3 LNPs. Example 12 tests several RSV F constructs, including MRK-4 membrane-bound DS-CAV1, in mice (¶[0846-0849]). Example 13 provides additional mouse immunogenicity studies using MC3-formulated RSV mRNAs (¶[0927-0931]). Examples 14 and 15 extend the biological testing to cotton rats and African Green Monkeys (¶[0957-0979]).
These examples provide meaningful evidence that MC3-based formulations of the disclosed RSV mRNAs can be made and used, but they do not provide a representative Formula (I) RSV vaccine example. More particularly, none of the disclosed RSV working examples identified above tests Compound 25 as the ionizable lipid.
The lack of a Compound 25 RSV working example is not, standing alone, the basis for rejecting claims 115 and 121. Rather, that absence is significant when considered together with the chemical difference between MC3 and Compound 25, the specification's own recognition that lipid identity and formulation parameters (e.g. mRNA, helper lipids, etc.) influence LNP performance, and the prior art showing that mRNA LNP formulations required empirical optimization. The disclosed MC3 examples therefore do not establish enablement of the Formula (I) genus or of the specific Compound 25/RSV mRNA vaccine combination.
Guidance in the specification. The specification provides substantial guidance for preparation of RSV mRNAs and identifies numerous LNP components and formulation ranges. It describes Formula (I) compounds at ¶[0523-0541], identifies particular Formula (I) structures including Compound 25 at ¶[0635], and states generally that Formula (I) nanoparticles may be used to deliver mRNA and produce an encoded polypeptide (¶[0642-0644]). Those disclosures tell the skilled artisan that Formula (I) compounds are candidates for mRNA delivery, and they do not provide a structure-function relationship that permits the artisan to predict which Formula (I) compounds will reproduce the successful RSV vaccine results obtained with MC3. The specification does not provide a demonstrated correlation between the claimed Formula (I) structures and successful delivery of the presently claimed RSV F mRNAs.
The same deficiency applies to Compound 25, albeit in a narrower form. The specification tells the artisan which ionizable lipid to try, but it does not explain how Compound 25 should be formulated for the claimed RSV mRNA vaccine or establish that the MC3 formulation conditions can simply be transferred to Compound 25. The generic Formula (I)/mRNA statements at ¶[0642-0644] do not answer that technical question. This is particularly relevant because the specification expressly recognizes that lipid selection, saturation, PEGylation, component ratios, and particle size can influence an LNP formulation (¶[0383]). Thus, the disclosure itself identifies several formulation-dependent variables but does not provide a predictive method for resolving them when MC3 is replaced by Compound 25 or by another claimed Formula (I) lipid.
The specification provides considerable disclosure concerning possible mRNA components and LNP components. However, describing alternatives that may be used does not itself provide guidance as to which combinations of those alternatives will provide an operative formulation. The claims leave open mRNA features affecting translation and persistence while simultaneously leaving open LNP features affecting protection and delivery. In particular, the claims do not require a particular 5′ UTR or 3′ UTR, a particular 5′ cap structure, a defined poly(A) tail length, or one nucleotide sequence encoding the recited antigen. Numerous synonymous coding sequences may encode the same claimed RSV F protein, with different codon distributions and GC content. The claims therefore encompass different mRNA structures even though the antigen amino acid sequence and N1-methyl-pseudouridine requirement are maintained.
The LNP scope compounds this breadth. Claims 110 and 116 encompass the Formula (I) ionizable-lipid genus, while claims 115 and 121 select Compound 25 without specifying a particular PEG-modified lipid, neutral lipid, sterol, or relative amount of those additional components. Thus, even claims 115 and 121 encompass a substantial combination space in which different mRNA architectures may be paired with different Compound 25-containing LNP formulations. The specification does not provide a rule correlating the untranslated regions, cap structure, poly(A) configuration, synonymous coding sequence, and LNP composition with the amount and duration of RSV F antigen expression, nor does the specification demonstrate that the mRNA architecture successfully tested in an MC3 formulation can be transferred to the full range of Formula (I) formulations, including the broad Compound 25 formulations of claims 115 and 121, without further optimization.
Quantity of experimentation necessary. To practice claims 110-114 and 116-120 across their scope, one skilled in the art would first need to select Formula (I) lipids across the claimed chemical space and prepare LNPs containing the claimed RSV mRNA. Candidate formulations would then need to be evaluated to determine whether acceptable nanoparticles are formed and whether the mRNA is adequately encapsulated, delivered, and expressed. Where a candidate lipid did not provide suitable performance, the artisan would need to alter the formulation and test again. A skilled artisan would also need to account for the mRNA architecture used with the selected LNP. Different UTRs, cap structures, poly(A) configurations, and synonymous coding sequences can alter stability and protein output even though each mRNA encodes the same RSV F antigen.
The biological question would remain after a physically acceptable particle was obtained. The artisan would need to determine whether delivery of the mRNA provides sufficient expression of the claimed RSV F antigen for use of the composition as the recited vaccine. The specification does not provide a predictive threshold or structural rule that allows this determination to be made without testing.
Claims 115 and 121 require less compound-selection work because Compound 25 has already been chosen. They nevertheless require substantial experimentation that the MC3 examples do not resolve. One skilled in the art would need to prepare a Compound 25 LNP containing the claimed RSV mRNA, determine suitable formulation conditions, characterize delivery and expression, and determine whether the resulting composition can be used as the claimed RSV vaccine. Because claims 115 and 121 do not otherwise fix the remaining LNP formulation, unsuccessful initial formulations would require additional adjustment of the surrounding lipid composition, mRNA, or other formulation conditions.
Thus, the distinction between the broad Formula (I) claims and claims 115 and 121 concerns the type and quantity of experimentation, not whether an enablement problem exists. The genus claims require both selection among untested Formula (I) structures and subsequent formulation optimization. Claims 115 and 121 remove the first step, but still leave the artisan to develop and verify an untested Compound 25/RSV mRNA formulation without a demonstrated relationship to the MC3 system.
Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work based on the specification. Instead, one skilled in the art would need to prepare and test additional formulations to determine whether they provide the delivery and expression required to make and use the claimed RSV mRNA vaccine. Although the individual methods used to prepare and test candidate formulations were known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays. The relevant inquiry is whether the specification provides sufficient guidance to identify and practice embodiments falling within the full scope of the claims without undue experimentation. Here, further empirical formulation and biological testing is required to supply information that is not provided by the specification.
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 RSV F and DS-CAV1 mRNA vaccine constructs that were actually formulated and tested using MC3 LNPs. The specification separately describes a broad Formula (I) lipid genus, including Compound 25, and generically states that Formula (I) nanoparticles may contain an mRNA therapeutic or prophylactic. The claims, however, encompass the materially different combination of the claimed RSV F mRNAs with Formula (I) ionizable lipids rather than the demonstrated MC3 chemistry.
The specification does not identify a general quality shared by MC3 and the claimed Formula (I) lipids that would permit one skilled in the art to predict successful RSV mRNA vaccine delivery. Nor does it provide sufficient guidance showing how changes in lipid chemistry should be accommodated by changes in formulation. The Formula (I) genus claims therefore leave the artisan to identify operative lipids and formulations through empirical testing.
Claims 115 and 121 do not avoid this issue merely because Compound 25 is specifically identified. For those claims, the specification identifies the lipid to be tried but still does not provide an enabling bridge between the demonstrated MC3 RSV vaccine and the claimed Compound 25 RSV vaccine. The artisan must determine experimentally how the different lipid structure affects nanoparticle formulation, mRNA delivery, and expression of the RSV antigen. Selection of one candidate therefore narrows the research assignment but does not supply the information needed to make and use the claimed Compound 25 vaccine without undue experimentation.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and use the full scope of the invention recited in claims 110-121 without undue experimentation. The specification demonstrates RSV F mRNA vaccines formulated with MC3 and separately describes Formula (I) lipids and their generic use with mRNA. It does not provide sufficient guidance or representative data connecting those separate teachings so that the claimed Formula (I)-based RSV vaccines can be practiced across their scope without empirical screening and optimization.
The same conclusion applies to claims 115 and 121. Although these claims select Compound 25 and therefore do not require screening among the full Formula (I) genus, the claimed Compound 25/RSV mRNA vaccine remains materially different from the MC3 vaccine actually demonstrated. In view of the known dependence of mRNA LNP performance on ionizable-lipid structure and formulation conditions, identifying Compound 25 as the lipid to be tested does not enable the artisan to make and use the claimed vaccine without the further formulation and biological experimentation discussed above. Accordingly, claims 110-121 are rejected under 35 U.S.C. 112(a).
Claims 116-121 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention.
The written description requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement, the specification must reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention as of the filing date. Possession may be shown by a description of the complete structure of the claimed invention, a representative number of species falling within the scope of a claimed genus, or relevant identifying characteristics sufficient to show that the inventor had possession of the claimed subject matter.
Claims 116-121 recite an mRNA vaccine wherein the open reading frame encodes an “immunogenic fragment” of an RSV F glycoprotein comprising the S155C, S290C, S190F, and V207L substitutions. Claim 117 further requires that the immunogenic fragment comprise a deletion of C-terminal amino acid residues relative to a wild-type RSV F glycoprotein. The specification generally states that RSV RNA vaccines may encode an RSV antigenic polypeptide, “including immunogenic fragments thereof, e.g., immunogenic fragments capable of raising an immune response to RSV”(¶[0006]). Thus, the expression “immunogenic fragment” is described principally by the desired result of raising an immune response rather than by structural characteristics defining the fragments encompassed by the term. The specification also provides particular RSV F constructs; MRK-4 is identified as a “membrane-bound DS-CAV1 (stabilized prefusion F protein)” encoded by SEQ ID NO: 263 (¶[0849]), while MRK-11 is described as a “truncated RSV F protein (ectodomain only)” having an Ig secretion signal sequence, and MRK-12 is described as “DS-CAV1 (non-membrane bound form)” having an Ig secretion signal sequence (¶[0855-0856]). The specification additionally provides particular RSV F amino acid sequences, including SEQ ID NO: 291 (¶[0864]).
These disclosures reasonably convey possession of the particular RSV F constructs and truncated constructs that are actually identified. However, claim 116 is not limited to MRK-12, to a particular ectodomain construct, to SEQ ID NO: 291, or even to a specified degree of sequence identity to one of the disclosed sequences. Instead, claim 116 encompasses an immunogenic fragment of an RSV F glycoprotein of otherwise unspecified sequence and length so long as the fragment includes residues corresponding to S155C, S190F, V207L, and S290C and is immunogenic.
The specification does not describe a sufficient number of fragment species representative of that scope. In particular, the disclosure does not identify the permissible N-terminal or C-terminal boundaries of the claimed genus, identify which portions of RSV F may be removed while retaining the recited immunogenic property, or describe structural features common to the claimed fragments that distinguish members of the claimed genus from other RSV F fragments. The disclosure of MRK-12 provides a particular non-membrane-bound DS-CAV1 species, but one disclosed truncated DS-CAV1 construct does not reasonably describe the substantially broader genus of immunogenic fragments recited in claim 116.
The claimed fragments are defined, at least in part, by the recited function of being “immunogenic.” However, the specification does not establish a correlation between particular structural features of an RSV F fragment containing the four mutations and that recited function sufficient to identify the additional fragments falling within the scope of the claim. The specification states generally that an immunogenic fragment is capable of raising an immune response to RSV, but does not identify structural characteristics from which one skilled in the art could recognize the members of the claimed fragment genus. The disclosure of the desired immunogenic result, without a sufficient description of the structural genus that provides that result, does not demonstrate possession of the full scope of claim 116.
The disclosure also contains broad statements that RSV vaccines may encode fragments of disclosed antigenic polypeptide sequences (¶[0006][0843-0845]). Such generic statements do not provide structural identification of the particular genus now claimed. The question is not whether the specification mentions “fragments,” but whether the disclosure reasonably conveys possession of the claimed group of immunogenic fragments containing the four specified DS-CAV1 substitutions. The specification does not describe representative members distributed throughout that genus or identify common structural features that define which fragments belong to the genus.
Claim 117 does not cure this deficiency. Claim 117 limits the immunogenic fragment by requiring deletion of C-terminal amino acid residues relative to a wild-type RSV F glycoprotein, but does not specify the extent of the deletion or otherwise define the resulting fragment structurally. The specification provides particular truncated constructs, including the ectodomain-only MRK-11 construct and the non-membrane-bound MRK-12 DS-CAV1 construct at ¶[0855-0856]. However, the disclosure of these specific constructs does not reasonably convey possession of every C-terminally deleted RSV F fragment containing the four substitutions that also satisfies the functional requirement of immunogenicity. One skilled in the art would therefore be required to select additional C-terminal deletion boundaries not described in the specification and determine which resulting fragments retain the structural and antigenic characteristics necessary to satisfy claim 117. The specification does not identify a range of permissible termini, representative deletion variants across the scope, or structural characteristics sufficient to recognize those additional claimed fragments as having been possessed by the inventors at the time of filing.
Claims 118-121 do not cure the written-description deficiency discussed above. Claims 118-120 further limit components or amounts within the lipid nanoparticle, and claim 121 limits the Formula (I) lipid to Compound 25. Those limitations concern the formulation surrounding the mRNA and do not further limit the structure of the “immunogenic fragment” encoded by the mRNA. Accordingly, each of claims 118-121 continues to encompass the unsupported genus of immunogenic RSV F fragments incorporated from claim 116. The specification describes particular RSV F proteins and particular truncated constructs, including MRK-4, MRK-11, and MRK-12. What the specification does not describe is the much broader genus recited in claim 116, namely structurally unspecified fragments of RSV F containing the four mutations and selected by the functional requirement that they be immunogenic. Likewise, the disclosure of particular truncated constructs does not reasonably convey possession of the broad range of C-terminally deleted immunogenic fragments encompassed by claim 117.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventors had possession of the full scope of the subject matter recited in claims 116-121 at the time the application was filed. Claims 117-121 do not cure the deficiency because each continues to incorporate the unsupported “immunogenic fragment” genus of claim 116.
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 110-113 and 116-119 are rejected under 35 U.S.C. 103 as being unpatentable over Tam et. al. (WO2016176330A1; Pub. 11/03/2016; Priority 04/27/2015; CITED ART OF RECORD IN 12/16/2024 IDS; hereafter “Tam”) in view of Mason et. al. (WO2015177312A1; Pub. 11/26/2015; CITED ART OF RECORD IN 12/16/2024 IDS; hereafter “Mason”).
The Prior Art
Tam teaches compositions and methods for inducing an adaptive immune response in a subject, namely through nucleoside-modified nucleic acids encoding antigens (entire document; see abstract.) Tam teaches the antigen may be a viral antigen (p. 2, ¶2; reference claims 1, 4) encoded by nucleoside-modified mRNA, wherein the RNA comprises 1-methyl-pseudouridine (p. 2, ¶1; p. 28, ¶3; p. 31, ¶2; reference claims 1-3). Tam teaches wherein the composition comprises a lipid nanoparticle (LNP)(reference claim 11) which encapsulates the RNA (reference claim 12). Tam teaches the antigen may be from respiratory syncytial virus (RSV)(p. 110, ¶1), such as an F protein antigen or fragment thereof in a prefusion form (pp. 111-112, ¶ bridging pages). Tam teaches that the LNP further comprises a PEG-modified lipid, a sterol, and a neutral lipid (p. 58, “Lipid Nanoparticle”, see e.g. p. 60, ¶2-3; p. 98, ¶1 to p. 99, ¶2; instant claims 112, 118), PEG-modified lipid is 1,2 dimyristoyl-sn-glycerol, methoxypolyethyleneglycol (PEG2000-DMG)(pp. 99-100, ¶ bridging pages), the sterol is cholesterol (p. 99, ¶1), and the neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)(p. 98, ¶4)(instant claim 113, 119). Tam teaches LNPs of molar ratio of approximately 50:10:38.5: 1.5 cationic lipid, DSPC, cholesterol, and PEG-lipid (Example 15, starting at p. 145). Tam also teaches that Formula III lipids, such as III-3 and III-7, may be used with nucleoside-modified RNA, that cationic lipids may be present at about 30-95%, including 40-60%, DSPC as a preferred neutral lipid, with a cationic lipid:neutral lipid ratio of about 2:1 to 8:1; cholesterol with a cationic lipid:cholesterol ratio of about 2:1 to 1:1; and PEG-DMG, with cationic lipid:PEG-lipid ratios of about 100:1 to 25:1 (reference claim 16; p. 98, ¶5; p. 99, ¶1; p. 100, ¶1). Tam teaches Compound III-3, which is ALC-0315 (Example 12) and structurally fits the recited formula (I) of instant claims 110 and 116.
However, Tam does not specifically teach an RSV F glycoprotein comprising the combination of S155C, S290C, S190F, and V207L substitutions required by instant claims 110 and 116. However, these substitutions in the RSV F glycoprotein were well-known in the art in the form of DS-Cav1, as evidenced by the teachings of Mason.
Mason teaches immunogenic complexes that contain RSV-F ectodomain polypeptides and methods for making the complexes, wherein the RSVF ectodomain polypeptides are in the prefusion form (entire document; see abstract.) The RSVF ectodomain polypeptides are C-terminally truncated to remove the transmembrane and cytoplasmic domains (p. 2, ¶2; instant claim 117). Mason teaches wherein the amino acid sequence of the RSV-F ectodomain polypeptides further comprises substitutions selected from the group consisting of S155C and S290C substitutions; S190F, and V207L substitutions; and S155C, S290C, S190F, and V207L substitutions (reference claim 12). Mason teaches polynucleotides which encode said RSV-F ectodomain proteins, and that said nucleic acids may be “provided with a variety of carrier systems, including…a lipid nanoparticle (LNP, e.g., in which the nucleic acid is enveloped in the LNP)”(p. 50-51; see esp. p. 51, ¶4). Mason teaches the A2 RSV F sequence as a reference sequence and expressly teaches RSV F variants having at least 85% identity thereto. The claimed SEQ ID NO: 291 is likewise a DS-CAV1 RSV F sequence based on the RSV A2 F backbone and containing the claimed stabilizing substitutions. Mason's A2-based stabilized RSV F constructs therefore fall within, or at minimum render obvious, the recited sequence-identity scope. SEQ ID NO:1 of Mason is also 95.5% identical to instant SEQ ID NO: 291 (see alignment below; “Qy” SEQ ID NO: 1; “Db” SEQ ID NO: 291.) Therefore, Mason provides the sequence of instant claim 111.
It would have been obvious to one of ordinary skill in the art to use the S155C, S290C, S190F, and V207L stabilized RSV F antigen taught by Mason as the RSV F antigen encoded by the nucleoside-modified mRNA vaccine of Tam. Tam expressly teaches mRNA vaccines encoding RSV F, including prefusion RSV F, while Mason identifies a particular prefusion-stabilized RSV F design containing the claimed four substitutions and demonstrates that stabilized RSV F antigens elicit RSV-neutralizing antibodies. Tam teaches the mRNA would comprise the use of modified nucleosides, namely N1-methyl-pseudouridine, and that said mRNA would be delivered in vaccine formulas with LNPs, wherein said LNP would comprise the ionizable cationic lipid ALC-0315, which falls within the formulation of Formula (I). Therefore, arriving at the limitations of instant claims 110-113 and 116-119 would have been obvious to a skilled artisan, given the teachings of Tam and Mason.
One would have been motivated to select Mason's stabilized RSV F antigen because Tam expressly identifies prefusion RSV F as a suitable RSV vaccine antigen, and Mason provides a specific antigen design intended to maintain the relevant RSV F conformation and induce neutralizing antibody responses. Encoding a known immunogenic RSV F antigen using Tam's antigen-encoding mRNA platform would have amounted to the predictable use of a known antigen in a known mRNA vaccine system for its established purpose. There would have been a reasonable expectation of success because Tam demonstrates that 1-methylpseudouridine-modified antigen-encoding mRNA formulated in an LNP induces adaptive immune responses and expressly teaches application of that platform to RSV F. Mason independently demonstrates that RSV F proteins containing the claimed stabilizing substitutions can be expressed and can elicit neutralizing antibodies. The skilled artisan therefore would have reasonably expected that expression of the stabilized RSV F antigen of Mason from the mRNA-LNP platform of Tam would present the same RSV F antigenic structure to the immune system and induce an RSV-directed immune response. 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.
Query Match 95.5%; Score 2775; DB 1; Length 553;
Best Local Similarity 98.7%;
Matches 546; Conservative 3; Mismatches 4; Indels 0; Gaps 0;
Qy 22 FASGQNITEEFYQSTCSAVSKGYLSALRTGWYTSVITIELSNIKENKCNGTDAKVKLIKQ 81
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 FASGQNITEEFYQSTCSAVSKGYLSALRTGWYTSVITIELSNIKENKCNGTDAKVKLIKQ 60
Qy 82 ELDKYKNAVTELQLLMQSTPPTNNRARRELPRFMNYTLNNAKKTNVTLSKKRKRRFLGFL 141
|||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||
Db 61 ELDKYKNAVTELQLLMQSTPATNNRARRELPRFMNYTLNNAKKTNVTLSKKRKRRFLGFL 120
Qy 142 LGVGSAIA SGVAVSKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTSKVLDLKNYIDK 201
||||||||||||| |||||||||||||||||||||||||||||||||| |||||||||||
Db 121 LGVGSAIA SGVAVCKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTFKVLDLKNYIDK 180
Qy 202 QLLPIVNKQSCSISNIETVIEFQQKNNRLLEITREFSVNAGVTTPVSTYMLTNSELLSLI 261
|||||:||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QLLPILNKQSCSISNIETVIEFQQKNNRLLEITREFSVNAGVTTPVSTYMLTNSELLSLI 240
Qy 262 NDMPITNDQKKLMSNNVQIVRQQSYSIMSIIKEEVLAYVVQLPLYGVIDTPCWKLHTSPL 321
|||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||
Db 241 NDMPITNDQKKLMSNNVQIVRQQSYSIMCIIKEEVLAYVVQLPLYGVIDTPCWKLHTSPL 300
Qy 322 CTTNTKEGSNICLTRTDRGWYCDNAGSVSFFPQAETCKVQSNRVFCDTMNSLTLPSEINL 381
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||:||
Db 301 CTTNTKEGSNICLTRTDRGWYCDNAGSVSFFPQAETCKVQSNRVFCDTMNSLTLPSEVNL 360
Qy 382 CNVDIFNPKYDCKIMTSKTDVSSSVITSLGAIVSCYGKTKCTASNKNRGIIKTFSNGCDY 441
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 CNVDIFNPKYDCKIMTSKTDVSSSVITSLGAIVSCYGKTKCTASNKNRGIIKTFSNGCDY 420
Qy 442 VSNKGMDTVSVGNTLYYVNKQEGKSLYVKGEPIINFYDPLVFPSDEFDASISQVNEKINQ 501
|||||:||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 VSNKGVDTVSVGNTLYYVNKQEGKSLYVKGEPIINFYDPLVFPSDEFDASISQVNEKINQ 480
Qy 502 SLAFIRKSDELLHNVNAGKSTTNIMITTIIIVIIVILLSLIAVGLLLYCKARSTPVTLSK 561
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 SLAFIRKSDELLHNVNAGKSTTNIMITTIIIVIIVILLSLIAVGLLLYCKARSTPVTLSK 540
Qy 562 DQLSGINNIAFSN 574
|||||||||||||
Db 541 DQLSGINNIAFSN 553
Claims 114 and 120 are rejected under 35 U.S.C. 103 as being unpatentable over Tam and Mason as applied to claims 110-113 and 116-119 above, and further in view of Brito et. al. (WO 2015/095340 A1; Pub. 06/25/2015, Priority 12/19/2013; CITED ART OF RECORD IN 12/16/2024 IDS; hereafter “Brito”).
The Prior Art
The teachings of Tam and Mason have been set forth supra. While Mason teaches the RSV F mRNA vaccine and stabilized antigen substantially as discussed in the instant claims, and Tam also teaches RSV F protein antigens or fragments thereof encoded by nucleoside-modified mRNAs encapsulated in LNPs comprised of DSPC, cholesterol, and PEG-DMG, neither reference emphasizes the particular combination and component ranges presently recited in claims 114 and 120 in the context of an RSV F RNA vaccine. However, the differences in optimization of the LNP components would be obvious to the RSV mRNA-LNP composition, give the teachings of Brito.
Brito teaches lipid compositions for nucleic-acid delivery and expressly identifies PEG-dimyristylglycerol (PEG-DMG), as a PEG conjugate (p. 36, ¶2, p. 59, ¶3). Brito further teaches that useful LNP mixtures for immunization comprise an ionizable lipid, cholesterol, a PEGylated lipid such as PEG-DMG, and may additionally contain DSPC (p. 59, ¶3.) Brito teaches an RSV immunogenicity experiment in which an RNA replicon encoding RSV F was administered intramuscularly in lipid particles. Brito teaches that the particles contained 40 mole percent cationic lipid, 10 mole percent DSPC, 48 mole percent cholesterol, and 2 mole percent PEG-DMG, wherein the PEG was 2 kDa (“RSV Immunogenicity” at p. 172).
With respect to instant claims 114 and 120, Tam teaches ionizable lipid amounts of about 40-60 mole percent and PEG-lipid amounts within the presently claimed range. Tam teaches the m1Ψ antigen-encoding mRNA, a Formula (I)-qualifying ionizable lipid such as III-3, and an LNP containing DSPC, cholesterol, and PEG lipid. Tam's working ratio is 50:10:38.5:1.5, so Tam alone does not expressly exemplify claim 114 because DSPC is below 25 mol%. Brito teaches the same four classes of LNP components, expressly identifies DSPC/cholesterol/PEG-DMG, and teaches four-component ranges of 20-70% cationic lipid, 20-70% helper lipid, 0-30% neutral lipid, and 1-6% PEG lipid, which overlap the claimed ranges, including a 25-30% overlap for DSPC. Brito additionally expressly instructs the artisan to optimize the LNP by adjusting the lipid molar ratios (p. 40, ¶3). Selection of concentrations within the overlapping portions of these known LNP formulation ranges would have been prima facie obvious because the art recognized the relative amounts of these known LNP components as result-effective formulation variables that could be adjusted to obtain suitable RNA-containing particles. Therefore, the limitations of instant claims 114 and 120 would have been obvious, given the teachings of Tam, Mason, and Brito.
It would have been obvious to one of ordinary skill in the art to formulate the RSV F mRNA vaccine suggested by Tam and Mason using PEG2000-DMG, cholesterol, and DSPC as taught by Brito. One would have been motivated to do so because Brito teaches those components together in an LNP used for intramuscular delivery of RSV F-encoding RNA and demonstrates that the resulting formulations induce RSV F-specific immune responses. There would have been a reasonable expectation of success because both Tam and Brito teach lipid-particle delivery of RNA vaccines, and Brito specifically demonstrates the helper-lipid combination in an RSV F RNA vaccine. The selection of those known helper lipids for Tam's RSV F mRNA LNP therefore would have involved the use of a known RNA-vaccine formulation for the same purpose. 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 115 and 121 are rejected under 35 U.S.C. 103 as being unpatentable over Tam and Mason as applied to claims 110-113 and 116-119 above, and further in view of Benenato et al. (US20170224844A1; Priority 09/17/2015; hereafter “Benenato”.)
The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
The Prior Art
The teachings of Tam and Mason have been set forth supra. While Tam and Mason teach the RSV F mRNA vaccines substantially as discussed above, and Tam specifically teaches a cationic lipid that falls within the limits of Formula (I), neither reference alone or in combination specifically identifies instant Compound 25 as the ionizable lipid.
Benenato teaches ionizable lipids and nanoparticle compositions for intracellular delivery of therapeutic agents, including mRNA (entire document; see abstract; ¶[0118]). Benenato expressly identifies Compound 25 as heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate and provides its synthesis (¶[0600-0601]). Benenato further provides direct experimental evidence concerning use of Compound 25 to deliver mRNA. In Example 10, Compound 25-containing nanoparticle compositions were compared with MC3-containing compositions. Following intramuscular administration of mRNA, Benenato reports that the Compound 25 formulation produced a 7.1-fold increase in hEPO concentration relative to MC3 at the six-hour time point (starting at ¶[1022]). Table 30 reports a Compound 25 nanoparticle having a particle size of 98.8 nm and an encapsulation efficiency of 87.01% (Table 30). Benenato therefore teaches not merely that Compound 25 could theoretically form an mRNA nanoparticle, but that Compound 25 successfully formulated nanoparticles of a specific composition (e.g. DSPC as the neutral lipid, Cholesterol as the sterol, and PEG-DMG; Table 10), characterized said nanoparticles, and delivered an mRNA in vivo by an intramuscular route and produced substantial expression of the encoded protein.
It would have been obvious to one of ordinary skill in the art to use Compound 25 as the ionizable lipid for the RSV F mRNA vaccine suggested by Tam and Mason. One would have been motivated to do so because Benenato teaches Compound 25 specifically for mRNA delivery and demonstrates increased encoded-protein expression relative to MC3 following intramuscular administration. Further, the preferred neutral lipids, PEGylated lipids, and sterol used by Benenato were the same as those taught as preferable by Tam. For an mRNA vaccine, intracellular delivery and expression of the encoded antigen are necessary steps in producing the antigen that stimulates the immune response. A skilled artisan therefore would have had reason to select a lipid shown to provide efficient intramuscular mRNA expression when formulating an antigen-encoding mRNA vaccine, thereby rendering obvious the limitations of instant claims 115 and 121.
There would have been a reasonable expectation of success in using Compound 25 of Benenato in the formulation of Tam and Mason because Tam already teaches that antigen-encoding mRNA can be formulated in ionizable-lipid nanoparticles and administered as a vaccine, Mason supplies the known immunogenic RSV F antigen, and Benenato experimentally demonstrates that Compound 25 delivers an unrelated mRNA in vivo and produces the encoded protein following intramuscular administration. The expectation of success need not have been that Compound 25 would necessarily outperform every alternative lipid immunologically. Rather, the skilled artisan would reasonably have expected Compound 25 to perform its known function of delivering the mRNA and permitting intracellular expression of the encoded RSV F antigen. 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 110-121 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,464,848 in view of Tam and Mason (supra). Both the instant and ‘848 claims are drawn to a composition comprising an RNA encoding an RSV antigen and a LNP, wherein the LNP comprises 10-20 mol % neutral lipid, 35-45 mol % cholesterol, 1-5% PEG-modified lipid, and 40-50 mol % ionizable cationic lipid, wherein the ionizable cationic lipid is SM-102. Both claim the RSV antigen may be an F protein, such as prefusion stabilized F protein. Both claim the RNA may be chemically modified, such as with 1-methylpseudouridine. Both claim the sterol in the LNP is cholesterol. The main differences are the sequence claimed in the instant claim is not present in the ‘848 patent, and the instant claim requires the presence of substitution mutations. However, these differences would be obvious, given the teachings of Tam and Mason (detailed supra). Additionally, Tam teaches that the RSV antigens may additionally include the G protein, that the composition may comprise an adjuvant (abstract), and would comprise pharmaceutically acceptable carriers or ingredients. Therefore, given what was known by a skilled artisan and the teachings of Tam and Mason, the instant claims and the ‘848 claims are not patentably distinct.
Claims 110-121 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-40 of copending Application No. 19/345,347 in view of Joyce et. al. (Joyce MG, et. al. Nat Struct Mol Biol. 2016 Sep;23(9):811-820. Epub 2016 Aug 1.; hereafter “Joyce”.) Both sets of claims are drawn to RSV mRNA vaccine compositions, wherein the mRNA encodes an ORF comprising nucleosides consisting of N1-methyl-pseudouridine, adenosine, guanosine, and cytidine, wherein the ORF encodes a respiratory syncytial virus (RSV) fusion (F) glycoprotein comprising S155C, S290C, S190F, and V207L amino acid substitutions; and wherein the mRNA is formulated in a LNP comprising 20-60 mol % of an ionizable cationic lipid, 0.5-15 mol % PEG-modified lipid, 25-55 mol % sterol, and 25-55 mol % neutral lipid. Both claim the ionizable cationic lipid is of Formula (I), namely SM-102 (Compound 1/Compound 25). Both claim the sterol is cholesterol, both claim the PEG-modified lipid is PEG2000-DMG, both claim the neutral lipid is DSPC. The main difference between the two sets of claims is that the ‘347 claims require A149C and Y458C substitutions, as well as the F1 and F2 subunits of RSV F linked through a ser/gly linker, and the ‘347 claims are drawn to a method of administering to a subject the RSV vaccine in a therapeutically effective amount intramuscularly. However, these differences would be obvious given what was known in the art at the time of filing, especially as evidenced by the teachings of Joyce. Joyce teaches DS-Cav1 constructs that are single chain constructs (sc9-10 DS-Cav1) that comprise A149C/Y458C variants and a disulfide bridge between said residues, as well as flexible serine/glycine linkers to join the F1 and F2 protein subunits (entire document; see abstract; Tables 1-2). The sc9-10 construct has RSV F residues 104-144 deleted and a glycine/serine peptide linker joining residue 103 of F2 to residue 145 of F1, as well as maintaining the S155C, S290C, S190F, and V207L mutations. The A149C/Y458C disulfide bridge was introduced in order to form an interprotomer disulfide (p. 815). As these vaccine formulations were studied in mice and were injected intramuscularly (p. 815, rt. Col.), the differences between the instant claims and the ‘347 claims are not patentably distinct, especially in light of the teachings of Joyce.
This is a provisional nonstatutory double patenting rejection.
Claims 110-121 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,453,766 in view of Joyce and Mason (supra). While the ‘766 independent claim is drawn to an RSV F protein with at least 95% sequence identity to SEQ ID NO: 5, an alignment of instant SEQ ID NO: 291 and reference SEQ ID NO:5 shows similarity in the sequence except for a N-terminal truncation of the signal peptide, an internal truncation, and A149C and Y458C substitutions. However, Mason teaches the RSV F protein has its N-terminal signal peptide naturally truncated (“Background of the Invention”), and Joyce teaches the sc9-10 construct, which has RSV F residues 104-144 deleted and a glycine/serine peptide linker joining residue 103 of F2 to residue 145 of F1, as well as maintaining the S155C, S290C, S190F, and V207L mutations along with further comprising the A149C and Y458C substitutions. All of these modifications result in a patentably indistinct RSV F protein between the instant claims and the patented claims, given the teachings of Joyce and Mason.
Qy 22 FASGQNITEEFYQSTCSAVSKGYLSALRTGWYTSVITIELSNIKENKCNGTDAKVKLIKQ 81
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 FASGQNITEEFYQSTCSAVSKGYLSALRTGWYTSVITIELSNIKENKCNGTDAKVKLIKQ 60
Qy 82 ELDKYKNAVTELQLLMQSTPAT-------------------------------------- 103
||||||||||||||||||||||
Db 61 ELDKYKNAVTELQLLMQSTPATNNRARRELPRFMNYTLNNAKKTNVTLSKKRKRRFLGFL 120
Qy 104 -GSGSAICSGVAVCKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTFKVLDLKNYIDK 162
| |||| ||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LGVGSAIA SGVAVCKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTFKVLDLKNYIDK 180
Qy 163 QLLPILNKQSCSISNIETVIEFQQKNNRLLEITREFSVNAGVTTPVSTYMLTNSELLSLI 222
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QLLPILNKQSCSISNIETVIEFQQKNNRLLEITREFSVNAGVTTPVSTYMLTNSELLSLI 240
Qy 223 NDMPITNDQKKLMSNNVQIVRQQSYSIMCIIKEEVLAYVVQLPLYGVIDTPCWKLHTSPL 282
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 NDMPITNDQKKLMSNNVQIVRQQSYSIMCIIKEEVLAYVVQLPLYGVIDTPCWKLHTSPL 300
Qy 283 CTTNTKEGSNICLTRTDRGWYCDNAGSVSFFPQAETCKVQSNRVFCDTMNSRTLPSEVNL 342
||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||
Db 301 CTTNTKEGSNICLTRTDRGWYCDNAGSVSFFPQAETCKVQSNRVFCDTMNSLTLPSEVNL 360
Qy 343 CNVDIFNPKYDCKIMTSKTDVSSSVITSLGAIVSCYGKTKCTASNKNRGIIKTFSNGCDY 402
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 CNVDIFNPKYDCKIMTSKTDVSSSVITSLGAIVSCYGKTKCTASNKNRGIIKTFSNGCDY 420
Qy 403 VSNKGVDTVSVGNTLYCVNKQEGKSLYVKGEPIINFYDPLVFPSDEFDASISQVNEKINQ 462
|||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||
Db 421 VSNKGVDTVSVGNTLYYVNKQEGKSLYVKGEPIINFYDPLVFPSDEFDASISQVNEKINQ 480
Qy 463 SLAFIRKSDELLHNVNAGKSTTNIMITTIIIVIIVILLSLIAVGLLLYCKARSTPVTLSK 522
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 SLAFIRKSDELLHNVNAGKSTTNIMITTIIIVIIVILLSLIAVGLLLYCKARSTPVTLSK 540
Qy 523 DQLSGINNIAFSN 535
|||||||||||||
Db 541 DQLSGINNIAFSN 553
Both the instant claims and the ‘766 claims are drawn to chemical modifications in the mRNA encoding the RSV F protein, namely a 1-methyl-pseudouridine. Both claim that the mRNA is within a LNP, wherein the lipid nanoparticle comprises 20-60 mol % ionizable cationic lipid, 5-25 mol % neutral lipid, 25-55 mol % sterol, and 0.5-15 mol % polyethylene glycol (PEG)-modified lipid. Both claim the neutral lipid is DSPC and the PEG-modified lipid is PEG2000-DMG. The sterol being cholesterol would be an obvious structural lipid to include in an LNP for a skilled artisan. Both claim the cationic lipid is SM-102. The main difference between the two sets of claims is that the ‘766 claims require not only the A149C and Y458C substitutions and sequence differences noted and discussed supra, but are also drawn to a method of administering to a subject the RSV vaccine in a therapeutically effective amount intramuscularly. However, these differences would be obvious given what was known in the art at the time of filing, especially as evidenced by the teachings of Joyce. As discussed supra, Joyce teaches DS-Cav1 constructs that are single chain constructs (sc9-10 DS-Cav1) that comprise A149C/Y458C variants and a disulfide bridge between said residues, as well as flexible serine/glycine linkers to join the F1 and F2 protein subunits (entire document; see abstract; Tables 1-2). The sc9-10 construct has RSV F residues 104-144 deleted and a glycine/serine peptide linker joining residue 103 of F2 to residue 145 of F1, as well as maintaining the S155C, S290C, S190F, and V207L mutations. The A149C/Y458C disulfide bridge was introduced in order to form an interprotomer disulfide (p. 815). As these vaccine formulations were studied in mice and were injected intramuscularly (p. 815, rt. Col.), the differences between the instant claims and the ‘766 claims are not patentably distinct, especially in light of the teachings of Joyce and Mason.
Claims 110-121 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,911,453 in view of Joyce and Mason (supra). While the ‘453 independent claim is drawn to an RSV F protein with at least 95% sequence identity to SEQ ID NO: 5, an alignment of instant SEQ ID NO: 291 and reference SEQ ID NO:5 shows similarity in the sequence except for a N-terminal truncation of the signal peptide, an internal truncation, and A149C and Y458C substitutions. However, Mason teaches the RSV F protein has its N-terminal signal peptide naturally truncated (“Background of the Invention”), and Joyce teaches the sc9-10 construct, which has RSV F residues 104-144 deleted and a glycine/serine peptide linker joining residue 103 of F2 to residue 145 of F1, as well as maintaining the S155C, S290C, S190F, and V207L mutations along with further comprising the A149C and Y458C substitutions. All of these modifications result in a patentably indistinct RSV F protein between the instant claims and the patented claims, given the teachings of Joyce and Mason.
Qy 22 FASGQNITEEFYQSTCSAVSKGYLSALRTGWYTSVITIELSNIKENKCNGTDAKVKLIKQ 81
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 FASGQNITEEFYQSTCSAVSKGYLSALRTGWYTSVITIELSNIKENKCNGTDAKVKLIKQ 60
Qy 82 ELDKYKNAVTELQLLMQSTPAT-------------------------------------- 103
||||||||||||||||||||||
Db 61 ELDKYKNAVTELQLLMQSTPATNNRARRELPRFMNYTLNNAKKTNVTLSKKRKRRFLGFL 120
Qy 104 -GSGSAICSGVAVCKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTFKVLDLKNYIDK 162
| |||| ||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LGVGSAIA SGVAVCKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTFKVLDLKNYIDK 180
Qy 163 QLLPILNKQSCSISNIETVIEFQQKNNRLLEITREFSVNAGVTTPVSTYMLTNSELLSLI 222
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QLLPILNKQSCSISNIETVIEFQQKNNRLLEITREFSVNAGVTTPVSTYMLTNSELLSLI 240
Qy 223 NDMPITNDQKKLMSNNVQIVRQQSYSIMCIIKEEVLAYVVQLPLYGVIDTPCWKLHTSPL 282
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 NDMPITNDQKKLMSNNVQIVRQQSYSIMCIIKEEVLAYVVQLPLYGVIDTPCWKLHTSPL 300
Qy 283 CTTNTKEGSNICLTRTDRGWYCDNAGSVSFFPQAETCKVQSNRVFCDTMNSRTLPSEVNL 342
||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||
Db 301 CTTNTKEGSNICLTRTDRGWYCDNAGSVSFFPQAETCKVQSNRVFCDTMNSLTLPSEVNL 360
Qy 343 CNVDIFNPKYDCKIMTSKTDVSSSVITSLGAIVSCYGKTKCTASNKNRGIIKTFSNGCDY 402
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 CNVDIFNPKYDCKIMTSKTDVSSSVITSLGAIVSCYGKTKCTASNKNRGIIKTFSNGCDY 420
Qy 403 VSNKGVDTVSVGNTLYCVNKQEGKSLYVKGEPIINFYDPLVFPSDEFDASISQVNEKINQ 462
|||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||
Db 421 VSNKGVDTVSVGNTLYYVNKQEGKSLYVKGEPIINFYDPLVFPSDEFDASISQVNEKINQ 480
Qy 463 SLAFIRKSDELLHNVNAGKSTTNIMITTIIIVIIVILLSLIAVGLLLYCKARSTPVTLSK 522
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 SLAFIRKSDELLHNVNAGKSTTNIMITTIIIVIIVILLSLIAVGLLLYCKARSTPVTLSK 540
Qy 523 DQLSGINNIAFSN 535
|||||||||||||
Db 541 DQLSGINNIAFSN 553
Both the instant claims and the ‘453 claims are drawn to chemical modifications in the mRNA encoding the RSV F protein, namely a 1-methyl-pseudouridine. Both claim that the mRNA is within a LNP, wherein the lipid nanoparticle comprises 20-60 mol % ionizable cationic lipid, 5-25 mol % neutral lipid, 25-55 mol % sterol, and 0.5-15 mol % polyethylene glycol (PEG)-modified lipid. Both claim the neutral lipid is DSPC, the sterol is cholesterol, and the PEG-modified lipid is PEG2000-DMG. Both claim the cationic lipid is SM-102. The main difference between the two sets of claims is that the ‘453 claims require not only the A149C and Y458C substitutions and sequence differences noted and discussed supra, but are also drawn to a method of administering to a subject the RSV vaccine in a therapeutically effective amount intramuscularly. However, these differences would be obvious given what was known in the art at the time of filing, especially as evidenced by the teachings of Joyce. As discussed supra, Joyce teaches DS-Cav1 constructs that are single chain constructs (sc9-10 DS-Cav1) that comprise A149C/Y458C variants and a disulfide bridge between said residues, as well as flexible serine/glycine linkers to join the F1 and F2 protein subunits (entire document; see abstract; Tables 1-2). The sc9-10 construct has RSV F residues 104-144 deleted and a glycine/serine peptide linker joining residue 103 of F2 to residue 145 of F1, as well as maintaining the S155C, S290C, S190F, and V207L mutations. The A149C/Y458C disulfide bridge was introduced in order to form an interprotomer disulfide (p. 815). As these vaccine formulations were studied in mice and were injected intramuscularly (p. 815, rt. Col.), the differences between the instant claims and the ‘453 claims are not patentably distinct, especially in light of the teachings of Joyce and Mason.
Claims 110-121 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-40 of copending Application No. 18/314,980. Both sets of claims are drawn to RSV mRNA vaccine compositions, wherein the mRNA encodes an ORF comprising nucleosides consisting of N1-methyl-pseudouridine, adenosine, guanosine, and cytidine, wherein the ORF encodes a respiratory syncytial virus (RSV) fusion (F) glycoprotein comprising S155C, S290C, S190F, and V207L amino acid substitutions; and wherein the mRNA is formulated in a LNP comprising 20-60 mol % of an ionizable cationic lipid, 0.5-15 mol % PEG-modified lipid, 25-55 mol % sterol, and 25-55 mol % neutral lipid. Both claim the sterol is cholesterol. The main difference between the two sets of claims is that the ‘980 claims do not require the ionizable cationic lipid to be SM-102. Compound 25 is a species of the ionizable cationic lipid genus already claimed in 18/314,980. The instant claims do not recite an unexpected property or a different function resulting from selection of Compound 25, but instead use Compound 25 for the same purpose for which the ionizable cationic lipid is claimed in the reference application, namely formulation and delivery of the RSV antigen-encoding mRNA. Therefore, selection of Compound 25 represents an obvious species within the broadly claimed genus in ‘980, and the copending claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
Claims 110-121 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,872,278 in view of Mason (supra).
Both the instant claims and the ‘278 claims are drawn to chemical modifications in the mRNA encoding the RSV F protein, namely a 1-methyl-pseudouridine. Both claim that the mRNA is within a LNP, wherein the lipid nanoparticle comprises 20-60 mol % ionizable cationic lipid, 5-25 mol % neutral lipid, 25-55 mol % sterol, and 0.5-15 mol % polyethylene glycol (PEG)-modified lipid. Both claim the neutral lipid is DSPC, the sterol is cholesterol, and the PEG-modified lipid is PEG2000-DMG. Both claim the cationic lipid is SM-102. While the ‘278 claims further require the presence of a human metapneumovirus (HMPV) F protein, the instant claims are drawn to compositions “comprising” the RSV F protein and an LNP, and this is not outside the scope of the ‘278 claims.
The main difference between the two sets of claims is that the instant claims require S155C, S290C, S190F, and V207L amino acid substitutions. However, these differences would be obvious given what was known in the art at the time of filing, especially as evidenced by the teachings of Mason, as discussed supra. Further, Mason teaches that HMPV F protein antigens may be within the vaccine (reference claim 6). Therefore, the differences between the instant claims and the ‘278 claims are not patentably distinct, especially in light of the teachings of Mason.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Espeseth AS, et. al. NPJ Vaccines. 2020 Feb 14;5(1):16. Applicant-related post-filing art that teaches aspects of the instant claims.
Sabnis S, et. al. Mol Ther. 2018 Jun 6;26(6):1509-1519. Epub 2018 Mar 14. Applicant-related post-filing art that teaches aspects of the instant claims.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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