DETAILED ACTION
Disposition of Claims
Claims 105-124 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250082748A1, Published 03/13/2025.
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.
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/27/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: the “Related Applications” section at ¶[0001] is missing applications in the continuity chain, namely the immediate parent of the instant application, which is 17/819,414, and is also missing 16/833,409.
Appropriate correction is required.
Claim Objections
Claim 105 is objected to because of the following informalities: the definition of the abbreviations “hCMV”, “gH”, “UTR”, and “gL” are 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. … human cytomegalovirus (hCMV)...).
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 107 and dependent claims 108-110 and 119 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 107 is drawn to the mRNA vaccine of claim 106, wherein the lipid nanoparticle comprises 20-60 mol % ionizable cationic lipid, 0.5-15 mol % PEG-modified lipid, 25-55 mol % sterol, and 5-25% neutral lipid. It is unclear how the “5-25% neutral lipid” relates to the overall composition, as the other components in the lipid nanoparticle (LNP) are recited at “mol %” while the neutral lipid is recited at simply “%”. For instance, under broadest reasonable interpretation, a “sterol” can be considered a “neutral lipid” because it lacks a charged or polar ionic group at physiological pH, even though it contains a polar hydroxyl group. Likewise, the “PEG-modified lipid” may also, under broadest reasonable interpretation, a “PEG-modified lipid” may also be a “neutral lipid”, depending on the base lipid attached to the polyethylene glycol (PEG) chain. Therefore, it is unclear from the wording of the claim what is encompassed by “neutral lipid” and what the percentage refers to (e.g. overall percentage of all non-charged lipids in the LNP or only a subset of specific lipids).
For at least these reasons, claim 107 is rejected on the grounds of being indefinite.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 122 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 122 is drawn to “the method of claim 123”, and, as per 35 USC 112d, a “claim in dependent form shall contain a reference to a claim previously set forth”. Therefore, claim 122 is rejected for depending on a subsequent claim, and not a claim which was previously set forth.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 105 is drawn to a messenger ribonucleic acid (mRNA) vaccine comprising:
(a) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an open reading frame (ORF) encoding an hCMV gH protein, a 3′ UTR, and a poly(A) tail;
(b) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an ORF encoding an hCMV gL protein, a 3′ UTR, and a poly(A) tail;
(c) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an ORF encoding an hCMV UL128 protein, a 3′ UTR, and a poly(A) tail;
(d) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an ORF encoding an hCMV UL130 protein, a 3′ UTR, and a poly(A) tail;
(e) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an ORF encoding an hCMV UL131 protein, a 3′ UTR, and a poly(A) tail; and
a lipid nanoparticle (LNP);
wherein 100% of uracil nucleosides in the ORF of the mRNA polynucleotides of (b) to (e) are N1-methylpseudouridine.
Further limitations on the mRNA vaccine of claim 105 are wherein the lipid nanoparticle comprises an ionizable cationic lipid, a PEG-modified lipid, a sterol, and a neutral lipid (claim 106), wherein the lipid nanoparticle comprises 20-60 mol % ionizable cationic lipid, 0.5-15 mol % PEG-modified lipid, 25-55 mol % sterol, and 5-25% neutral lipid (claim 107), wherein the PEG-modified lipid is PEG-DMG 2000, the sterol is cholesterol, and the neutral lipid is disteroylphosphatidyl choline (DSPC)(claim 108),
109. The mRNA vaccine of claim 108, wherein the lipid nanoparticle comprises a compound of Formula (I):
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or a salt thereof, 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, and n is selected from 1, 2, 3, 4, and 5;
R5 is H;
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 (claim 109), wherein the lipid nanoparticle comprises Compound 25:
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(claim 110), wherein:
(a) the hCMV gH protein comprises the amino acid sequence of SEQ ID NO: 59;
(b) the hCMV gL protein comprises the amino acid sequence of SEQ ID NO: 61;
(c) the hCMV UL128 protein comprises the amino acid sequence of SEQ ID NO: 63;
(d) the hCMV UL130 protein comprises the amino acid sequence of SEQ ID NO: 65; and
(e) the hCMV UL131 protein comprises the amino acid sequence of SEQ ID NO: 67 (claim 119); wherein the hCMV gH protein comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 59 (claim 111); wherein the hCMV gL protein comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 61 (claim 112); wherein the hCMV UL128 protein comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 63 (claim 113); wherein the hCMV UL130 protein comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 65 (claim 114); wherein the hCMV UL131 protein comprises an amino acid sequence that has at least 90% identity to the amino acid sequence of SEQ ID NO: 67(claim 115); further comprising:
(f) an mRNA polynucleotide having, from 5′ to 3′, a 5′ UTR, an ORF encoding an hCMV gB protein, a 3′ UTR, and a poly(A) tail, and wherein 100% of uracil nucleosides in the ORF of the mRNA polynucleotide of (f) are N1-methylpseudouridine (claim 116); wherein:
(a) the hCMV gH protein comprises the amino acid sequence of SEQ ID NO: 59;
(b) the hCMV gL protein comprises the amino acid sequence of SEQ ID NO: 61;
(c) the hCMV UL128 protein comprises the amino acid sequence of SEQ ID NO: 63;
(d) the hCMV UL130 protein comprises the amino acid sequence of SEQ ID NO: 65; and
(e) the hCMV UL131 protein comprises the amino acid sequence of SEQ ID NO: 67 (claim 117), wherein the mRNA vaccine further comprises:
(f) an mRNA polynucleotide having, from 5′ to 3′, a 5′ UTR, an ORF encoding an hCMV gB protein, a 3′ UTR, and a poly(A) tail, wherein an hCMV gB protein comprises the amino acid sequence of SEQ ID NO: 69 and wherein 100% of uracil nucleosides in the ORF of the mRNA polynucleotide of (f) are N1-methylpseudouridine (claim 118), and wherein the lipid nanoparticle comprises Compound 25:
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(claim 120).
Claim 121 is drawn to a method of inducing an immune response against hCMV in a subject comprising administering to the subject an mRNA vaccine comprising:
(a) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an open reading frame (ORF) encoding an hCMV gH protein, a 3′ UTR, and a poly(A) tail;
(b) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an ORF encoding an hCMV gL protein, a 3′ UTR, and a poly(A) tail;
(c) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an ORF encoding an hCMV UL128 protein, a 3′ UTR, and a poly(A) tail;
(d) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an ORF encoding an hCMV UL130 protein, a 3′ UTR, and a poly(A) tail;
(e) an mRNA polynucleotide having from 5′ to 3′ a 5′UTR, an ORF encoding an hCMV UL131 protein, a 3′ UTR, and a poly(A) tail; and
a lipid nanoparticle;
wherein 100% of uracil nucleosides in the ORF of the mRNA polynucleotides of (a) to (e) are N1-methylpseudouridine;
in an amount effective to produce an immune response against hCMV in the subject.
Further limitations on the method of claim 121 are wherein the lipid nanoparticle comprises Compound 25:
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(claim 123), wherein the mRNA vaccine further comprises:
(f) an mRNA polynucleotide having, from 5′ to 3′, a 5′ UTR, an ORF encoding an hCMV gB protein, a 3′ UTR, and a poly(A) tail, wherein an hCMV gB protein comprises the amino acid sequence of SEQ ID NO: 69 and wherein 100% of uracil nucleosides in the ORF of the mRNA polynucleotide of (f) are N1-methylpseudouridine (claim 122); and wherein the subject produces antibodies that neutralize hCMV (claim 124).
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 105-116 and 121-124 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 mRNA vaccines comprising the disclosed HCMV pentamer antigen sequences and specific tested lipid formulations for lipid nanoparticles (LNPs), does not reasonably provide enablement for the broader scope encompassing the HCMV gH, gL, UL128, UL130, and UL131 protein genera, including proteins having as little as 90% amino acid sequence identity to the claimed/disclosed sequences, in combination with the breadth of the LNP formulations encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to a messenger RNA (mRNA) and lipid nanoparticle (LNP) vaccine composition of the five HCMV glycoproteins which make up the pentameric complex, namely gH, gL, UL128, UL130, and UL131, wherein the mRNA encoding the glycoproteins use N1-methylpseudouridine instead of uracil for glycoproteins gL, UL128, UL130, and UL131 or for all glycoproteins. Each mRNA additionally comprises, from 5’ to 3’, a UTR, an open reading frame (ORF) encoding the glycoprotein, a 3’ UTR, and a poly A tail. The lipid nanoparticle comprises an ionizable cationic lipid, a PEG-modified lipid, a sterol, and a neutral lipid.
The specification describes mRNAs encoding the five pentamer components and identifies particular nucleic acid and protein sequences for these antigens. The specification further states that an RNA polynucleotide may encode an antigenic polypeptide having at least 90% identity to the disclosed HCMV protein sequences, including SEQ ID NOs: 32-52, 59, 61, 63, 65, 67, and 69 (¶[0027][0081-0082]). The specification provides experimental support for particular HCMV pentamer constructs, either monocistronic or multicistronic (Examples 12-17 starting at ¶[0770] for sequences for constructs and Examples 18-28 starting at ¶[0777] to ¶[0803]). Monocistronic and polycistronic constructs were generated and tested to determine the most efficient way to express all of the proteins and have them form the appropriate complex, and delivery of premixed mRNAs encoding individual pentamer subunits resulted in surface expression of the pentamer in HeLa cells (¶[0140][0148][0797]). The specification further reports that protein surface expression of any of the five proteins was detected at high levels only when all of the core subunits were expressed (¶[0141-0142]). Specific pentamer mRNA constructs also produced anti-pentamer antibodies in mice, and the specification reports neutralization of HCMV following immunization (¶[0144-0147]). Additional experiments were performed using first and second generation pentamer constructs, with the second generation sequences corresponding to disclosed SEQ ID NOs: 58-69 (¶[0148-0152]).
However, the claims are not limited to the disclosed embodiments, namely those tested protein sequences. The claims also encompass an HCMV gH protein, gL protein, UL128 protein, UL130 protein, and UL131 protein, without limiting the proteins to the specifically tested sequences, and even those claims which do have specific sequences claimed, namely instant claims 111-115, these claims encompass proteins having only 90% sequence identity to SEQ ID NOs: 59, 61, 63, 65, and 67. A 90% identity limitation permits numerous amino acid substitutions throughout each protein and does not identify residues that must be retained to preserve pentamer assembly, conformational antigenicity, or other properties relevant to use of the resulting composition as an HCMV vaccine.
The breadth is compounded because the five proteins operate as components of a multiprotein complex, and a sequence change in one member therefore need not affect only that protein in isolation. Said protein mutation may alter interaction with one or more pentamer components and change the structure presented to the immune system or prevent the complex from forming at all. The specification itself demonstrates this interdependence by reporting that high pentamer surface expression required expression of all core subunits (¶[0141]).
The LNP limitation introduces additional compositional breadth, although the LNP breadth is not relied upon, standing alone, for the basis of this rejection. Claim 105 merely requires any LNP, while claims 106-110 progressively narrow the species of lipid components. The specification acknowledges that an LNP formulation may be influenced by the selected cationic lipid, its degree of saturation, PEGylation, component ratios, and particle size (¶[0359-0362]).
The claimed scope therefore extends beyond the embodiments described in the specification.
State of the prior art and predictability of the art. At the time the application was filed, the HCMV pentamer structure and function was known to depend upon specific interactions among its subunit proteins. Ciferri et. al. (Ciferri C, et. al. PLoS Pathog. 2015 Oct 20;11(10):e1005230.) reported that gL residue C144 forms a disulfide bridge with UL128 residue C162 in the pentamer. Ciferri further reported that “mutation of gL-C144S was sufficient to prevent formation of covalent complexes between gH/gL and either gO or UL128 in gH/gL/gO and Pentamer, respectively. The same mutation resulted in formation of monomeric gH/gL heterodimers”. A single amino acid substitution could therefore materially alter an interaction necessary for the proper formation of the HCMV pentamer, even though the resulting protein would remain well within an “at least 90%” identity genus. Ciferri also noted and mapped multiple other interactions throughout the HCMV proteins, and identified regions of contact between UL128 and UL130 that were targeted by neutralizing antibodies and were specific to the pentamer, as well as neutralizing target sites on the individual proteins. These findings indicate that pentamer antigenicity and assembly were dependent on particular structural features rather than merely a high overall percentage of sequence identity. The art therefore did not provide a basis for assuming that amino acid substitutions distributed anywhere throughout the claimed at least 90% identity sequence space would be structurally or functionally equivalent to the disclosed reference sequence proteins and resulting HCMV pentameric complex.
Murrell et. al. (Murrell I, et. al. J Virol. 2013 Oct;87(19):10489-500. Epub 2013 Jul 24.) likewise demonstrated sensitivity to comparatively small sequence changes in the UL128 locus. Murrell reported that differential growth properties of two HCMV strains “were mapped to single-nucleotide substitutions in UL128L” and one substitution affected UL128 splicing, while another produced an amino acid substitution in UL130. Introducing these changes into other HCMV strain (Merlin) dramatically increased yields of cell-free virus and increased cell-to-cell spread in fibroblasts but reduced the abundance of pUL128 in the virion and the efficiency of epithelial cell infection. Murrell therefore supports that small sequence differences within the pentamer-associated proteins could produce substantial biological differences and that overall sequence identity alone would not reliably predict the relevant properties.
The LNP art likewise showed that mRNA delivery depended upon formulation parameters rather than merely the presence of an LNP. Kauffman et. al. (Kauffman KJ, et. al. Nano Lett. 2015 Nov 11;15(11):7300-6. Epub 2015 Oct 20.) explained that the relative ratios of the principal LNP components “can have profound effects on the formulation potency.” Kauffman varied both lipid structures and component ratios to optimize mRNA delivery and obtained an approximately seven-fold increase in potency for an optimized erythropoietin mRNA formulation. The same optimized formulation did not correspondingly improve siRNA delivery, indicating that formulation parameters were dependent on the nucleic acid payload and intended application rather than being universally interchangeable. This LNP evidence is consistent with the instant specification itself, which states that LNP 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, and the ratio of all components and biophysical parameters such as size (¶[0360]). At the same time, the specification provides meaningful LNP guidance and reports that different formulations of the disclosed pentamer mRNAs produced comparable antibody levels (¶[0144][0359-0673]). While the LNP issue alone is not reason for the scope of enablement issue, it is an added parameter that is another variable that needs to be optimized along with the substantially broader and untested pentamer protein sequence identity genus.
Accordingly, the results obtained using the disclosed antigen sequences and tested formulations would not have reasonably established that the broader claimed scope (sequence general and range of LNPs) could be practiced without further experimentation.
Level of skill in the art. One skilled in the art would have been familiar with recombinant nucleic acid methods, sequence alignment, in vitro transcription, mRNA isolation and modification, protein expression assays, LNP formulation, cell-surface expression assays, antibody-binding assays, and HCMV neutralization assays. However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further experimentation, which additional substitutions within each of the five pentamer glycoproteins could be made while retaining the properties required for the resulting composition to function as an HCMV vaccine in order to satisfy the claimed limitations.
Working examples. The specification provides multiple working examples directed to specific HCMV pentamer mRNA constructs, such as multicistronic mRNA and monocistronic mRNA encoding each individual pentameric protein. These studies include cell surface expression of the pentamer, immunization of mice, generation of anti-pentamer antibodies, HCMV neutralization, and evaluation of specifically disclosed first and second-generation constructs (¶[0140-0152]; Example 12 starting at¶[0770]). These data provide meaningful enablement for the disclosed sequences and closely related embodiments whose relevant structural and antigenic properties could reasonably be predicted from the disclosure.
The specification does not provide working examples directed to amino acid variants distributed across the at least 90% identity genera of gH, gL, UL128, UL130, and UL131. For example, the disclosure does not test substitutions at multiple positions throughout those proteins and establishes that the variants continue to assemble appropriately with the remaining pentamer components or maintained the antigenic properties underlying the reported immune responses. There likewise are not working examples demonstrating combinations in which substantia sequence variation is introduced independently into several pentamer components.
The disclosed examples therefore do not establish enablement across the full scope of claims 105-116 and 121-124.
Guidance in the specification. The specification provides substantial guidance regarding the identities of the HCMV pentamer components, particular mRNA sequences, particular protein sequences, mRNA preparation, nucleoside modification, and LNP formulation. The disclosure identifies at least 90% identity variants as contemplated embodiments. However, the specification does not provide sufficient guidance regarding actual teachings of which members of that sequence genus of “at least 90%” are suitable for the claimed vaccine. The specification does not identify conserved residues that may not be altered, tolerated substitution patterns, or a structural rule that permits a skilled artisan to select variants while preserving the relevant interactions amongst the five HCMV glycoproteins. The specification also fails to correlate particular amino acid changes with pentamer surface expression, maintenance of conformational neutralizing epitopes, or the ability of the resulting mRNA vaccine to produce the claimed HCMV-specific immune response.
The missing guidance is material in view of the prior art, as noted supra. Ciferri showed that alteration of a single residue in gL disrupted covalent interaction with UL128, while Murrelll showed that subtle changes in the UL128 loci materially change viral phenotypes. The specification does not provide a general sequence function principle that would permit those results to be distinguished prospectively from the many other substitutions allowed by the claims. With respect to the LNP, the specification provides considerably more concrete guidance, as it identifies relevant lipid classes, ranges, formulation parameters, and examples (¶[0359] “Nanoparticle Formulations”). The LNP disclosure therefore weighs against treating every untested LNP as independently non-enabled, but it does not cure the lack of guidance concerning which members of the broad pentamer sequence genera will provide a suitable antigenic vaccine when delivered from those formulations.
Quantity of experimentation necessary. To practice the full scope of claims 105-116 and 121-124, one skilled in the art would need to select amino acid substitutions within each claimed HCMV protein genus, prepare mRNAs encoding the different selected variants, express the variant combinations, and determine whether the encoded proteins retain the properties required of the vaccine. Where a variant affects pentamer formation or antigenic structure, additional variants would have to be prepared and tested. For the method claims, the selected compositions would further have to be evaluated in a relevant animal model to determine whether administration produces the recited HCMV immune response, and claim 124 further requires determining whether the antibodies produced would neutralize HCMV. Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test additional embodiments to determine whether they satisfy the claimed limitation of forming an antigenically relevant pentamer that would be useful in a vaccine composition. The formulation dimension adds further experimentation for claims that retain broad LNP scope. Kauffman (supra) showed before the filing date that changing LNP structures and ratios could materially alter mRNA delivery potency. The instant specification similarly acknowledges formulation dependence (¶[0360]), and while it was known how to make LNPs, a skilled artisan would have to determine whether a selected formulation adequately delivers a selected set of variant parameter mRNAs.
Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays; instead, the relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, one skilled in the art would need to prepare and test additional sequence identity species of each glycoprotein in the pentamer to determine which embodiments satisfy the ability to formulate HCMV pentamers in vivo.
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 specific HCMV pentamer mRNA sequences, demonstrates expression and immunogenicity using particular constructs, and provides considerable instruction concerning LNP formulations; However, the claims also encompass materially broader HCMV pentamer protein sequence space, including the at least 90% identity genera expressly recited in claims 111-115 and the unrestricted HCMV protein recitations of independent claims 105 and 121. The specification does not identify a general quality or provide sufficient guidance that would allow one skilled in the art to determine which substitutions throughout those genera preserve the relevant pentamer interactions and antigenic properties. Instead, a skilled artisan would have to generate and test additional members to determine which variants retain the properties required for use in the claimed vaccine. The problem is therefore not that the specification fails to individually exemplify every conceivable variant or LNP; the problem is that the disclosure does not provide sufficient guidance to move from the disclosed species to the materially broader claimed sequence genera without iterative selection and testing.
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 105-116 and 121-124 without undue experimentation.
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 105-108, 111-118, 121, and 124 are rejected under 35 U.S.C. 103 as being unpatentable over Bancel et. al. (WO2013151666A2, Pub. 10/10/2013; CITED ART OF RECORD IN IDS DATED 11/27/2024; hereafter “Bancel”) in view of Geall et. al. (US20140227346A1, Pub. 08/14/2014; CITED ART OF RECORD IN IDS DATED 11/27/2024; hereafter “Geall”.)
The Prior Art
Bancel teaches the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and modified mRNA (mmRNA) molecules (entire document; see abstract.) Bancel teaches the mmRNA may encode at least one antigen and be used as a vaccine composition (¶[000616]). Bancel teaches the polynucleotides, primary constructs or mmRNA may be self-replicating mRNA may encode at least one antigen (¶[000922-00924]), or may include one or more messenger RNAs that comprise one or more modified nucleosides (¶[000310]). Bancel teaches mmRNA which is fully modified with N1-methyl-pseudouridine (¶[00021]), wherein the natural nucleotide may be fully or partially substituted with the modified nucleotide (¶[000533]). Bancel teaches that, traditionally, the basic components of an mRNA molecule include at least a coding region, a 5'UTR, a 3'UTR, a 5' cap and a poly-A tail (¶[00095]). Bancel teaches the viral antigens may be from cytomegalovirus (¶[000887]). Bancel teaches lipid nanoparticles (LNPs) may encapsulate the mmRNA for delivery, and that said lipid nanoparticle comprises an ionizable cationic lipid, a PEG-modified lipid, a sterol, and a neutral lipid (¶[000544][000557-000563]; Example 14 at ¶[0001277]; instant claim 106), wherein the LNP comprises 20-60 mol % ionizable cationic lipid, 0.5-15 mol % PEG-modified lipid, 25-55 mol % sterol, and 5-25% neutral lipid (¶[000562]; instant claim 107), and wherein the PEG-modified lipid is PEG-DMG 2000, the sterol is cholesterol, and the neutral lipid is disteroylphosphatidyl choline (DSPC)(¶[000562][000575], See Example 61 at ¶[0001451]; instant claim 108). Bancel teaches the mmRNA may be within pharmaceutical compositions (“IV. Pharmaceutical Compositions” starting at ¶[000538]) and includes vaccines (¶[000165][000581]).
While Bancel teaches the majority of the instant independent claims, including teaching delivery of CMV antigens, Bancel fails to explicitly teach human CMV (HCMV) antigens, especially HCMV pentamer antigens, as the antigens delivered in the mRNA-LNP platform. However, the delivery of HCMV pentameric proteins using RNA was taught and actively being investigated in the art, as evidenced by the teachings of Geall.
Geall teaches immunogenic compositions that comprise an RNA component encoding multiple antigens from a pathogen to induce an immune response to said antigens (entire document; see abstract; ¶[0053]). Geall teaches that said antigens encoded by RNA may be cytomegalovirus (CMV) antigens, such as one or more of gH, gL, UL128, UL130, and UL131 (¶[0034][0053-0054]). Geall teaches that two or more CMV antigens encoded by the RNA may be co-delivered so that they form a complex in vivo (e.g., gH/gL complex, gM/gN complex, gH/gL/UL128/UL130/UL131 pentameric complex)(¶[0086-0087]). Geall teaches the CMV antigens may be human CMV (HCMV) antigens, and teaches gH, gL, UL128, UL130, and UL131 HCMV sequences (Table 1). Geall teaches that the RNA may comprise modifications to increase the efficacy of expression or replication of the RNA, or to provide additional stability or resistance to degradation, such as the use of 3’ poly A tails, 5’ caps (¶[0106]), and modified nucleosides, such as pseudouridine (¶[0107-0108][0127]). Geall teaches the RNA may be delivered via nanoparticles (¶[0259]). Geall teaches these RNA may be present in immunogenic compositions, such as vaccines (¶[0130]), and would include pharmaceutically acceptable components (“5. Immunogenic Compositions” starting at ¶[0258]). Geall teaches the RNA delivering RNA encoding CMV antigens produces a neutralizing antibody response in the host (Tables 1-2; ¶[0313-0316]; instant claim 124).
Geall teaches SEQ ID NO: 8, which is 100% identical to instant SEQ ID NO: 59; Geall teaches SEQ ID NO: 12, which is 100% identical to instant SEQ ID NO: 61; Geall teaches SEQ ID NO: 20, which is 99.6% identical to instant SEQ ID NO: 63; Geall teaches SEQ DI NO: 22, which is 100% identical to instant SEQ ID NO: 65, Geall teaches SEQ ID NO: 24, which is 100% identical to instant SEQ ID NO: 67; and Geall teaches SEQ ID NO: 2, which is a glycoprotein B (gB) protein sequence that is 100% identical to instant SEQ ID NO: 69 (Table 1; See attached ABSS sequence alignment results against 14-130-899 in “.rapbm” files; instant claims 111-112, 114-116). Geall teaches a UL128 antigen comprising an amino acid sequence that is at least 75% identical to SEQ ID NO: 20 (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20); Geall also teaches the CMV proteins may be from different CMV strains (¶[0055]). While SEQ ID NO: 20 is only 99.6% identical to instant SEQ ID NO: 63, Geall would render obvious this sequence at 100% identity, given the teachings and motivation provided therein (instant claims 113, 117).
While Geall expressly distinguishes its self-replicating RNA molecules from conventional mRNA, noting that self-replicating RNA molecules are larger than other types of RNA, including mRNA, Geall explains that this distinction is from the self-replicating RNA having an additional replicase and replication-control elements present in the nucleic acid. This distinction does not teach away from the expression of the same HCMV antigens using conventional mRNA. Rather, it establishes that the self-replicating RNA and mRNA were recognized alternative RNA architectures for expressing an encoded polypeptide. Geall does not attribute the identity, structure, or antigenic properties of the disclosed HCMV glycoproteins to these additional components within the self-replicating RNA. Bancel provides an alternate RNA delivery platform, and provides an independent reason to express those known HCMV antigen coding sequences using conventional, modified mRNA rather than retaining the self-replicating RNA of Geall. Bancel is directed to polynucleotides and mmRNA designed for production of selected polypeptides, and teaches that a plurality of polypeptides may be independently encoded by a plurality of nucleic acids (¶[000121]). Bancel further teaches its modified mmRNAs may encode vaccine antigens and expressly contemplates encoding vaccines already in development or being marketed (¶[000157]). One of ordinary skill, considering a CMV vaccine, would be motivated to utilize the HCMV antigens already identified by Geall and the mmRNA system of Bancel to provide an alternative platform for those same selected vaccine antigens. Bancel provides further motivation to make the substitution, in that he teaches mmRNA constructs are designed to improve properties relevant to in vivo protein production, including improving one or more of the stability and/or clearance in tissues, receptor uptake and/or kinetics, cellular access by the compositions, engagement with translational machinery, mRNA half-life, translation efficiency, immune evasion, protein production capacity, secretion efficiency (when applicable), accessibility to circulation, protein half-life and/or modulation of a cell's status, function and/or activity (¶[00092]). Therefore, Geall teaches the HCMV antigens may be delivered and expressed via RNA to elicit an immunogenic response, and Bancel teaches an alternate RNA platform for the expression of CMV antigens already in development, and Geall, in view of Bancel, renders obvious the limitations of instant claims 105, 118, and 121.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Bancel in order to deliver known viral antigens from established or actively investigated viral vaccine platforms, and since Bancel teaches that CMV antigens may be delivered using their mmRNA-LNP platform, it would be obvious to look for what CMV antigens would be useful or were actively being used or investigated to be delivered as vaccines. One would have been motivated to do so, given the suggestion from Geall that the HCMV pentameric proteins and the further inclusion of gB would be useful to elicit a protective immune response against HCMV infection. There would have been a reasonable expectation of success, given the knowledge from Geall that the HCMV antigens could be expressed from RNA in vivo and form the correct HCMV pentamer, and also given the knowledge that applying the platform of Bancel to a known platform would not require discovering a new HCMV antigen or predicting the behavior of unidentified members of a broad sequence genus, as Geall provides specific HCMV antigen sequences and Bancel teaches using its mmRNA constructs to encode selected vaccine proteins. 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 109-110, 119, and 122-123 are rejected under 35 U.S.C. 103 as being unpatentable over Bancel and Geall as applied to claims 105-108, 111-118, 121, and 124 above, and further in view of Benenato et. al. (US20170210697A1; Priority 09/17/2015; CITED ART OF RECORD IN IDS DATED 11/27/2024; hereafter “Benenato”.)
The applied reference (Benenato) has a common assignee (ModernaTx) 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 Bancel and Geall have been set forth supra. While Bancel teaches that the LNP may comprise a ionizable cationic lipid, Bancel fails to teach a lipid of Formula (I), namely that of Compound 25. However, LNPs comprising the ionizable lipid of Compound 25 were known in the art at the time of filing, as evidenced by Benenato.
Benenato teaches LNP composition comprising mRNA together with a phospholipid, PEGylated lipid, structural lipid, and a compound of Formula (I)(entire document; see ¶[0007-0061]; reference claims 1-14). Benenato teaches nanoparticle formulations containing a Formula (I) ionizable cationic lipid, DSPC, cholesterol, and PEG-DMG at 50:10:38.5:1.5 mol% for delivery of mRNA (¶[1436]; instant claim 109). Benenato expressly discloses Compound 25, heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate, and provides its synthesis and characterization (¶[0648-0652]; instant claims 110, 123).
It would have been obvious to substitute the Formula (I) ionizable lipids taught by Benenato, including Compound 25, for the ionizable lipid in the RNA LNP formulation of Bancel and Geall because Benenato expressly teaches these compounds for the intracellular delivery of mRNA in LNPs and demonstrates their effectiveness (¶[0004-0005][1479]; Tables 30-32). Bancel teaches the cationic lipid may be selected from any of those known in the art (¶[000568]) and provides motivation to look beyond the use of DLinDMA, DLin-KC2-DMA, and DLin-MC3-DMA in LNPs, as these ionizable cationic lipids have been shown to accumulate in plasma and tissues over time and may be a potential source of toxicity (¶[000579]). Therefore, arriving at the limitations of instant claims 109-110, 119, and 122-123 would be obvious to a skilled artisan, given the combined teachings of Bancel, Geall, and Benenato.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Bancel and Geall in order to utilize a less toxic ionizable lipid in LNPs for viral vaccine antigen delivery, thereby selecting the safest possible cationic lipid to deliver the mRNA encoding the HCMV antigens. One would have been motivated to do so, given the suggestion by Bancel that the commonly used cationic lipids in LNPs could accumulate in tissues and potentially be toxic. There would have been a reasonable expectation of success, given the knowledge that the LNP formulations using Compound 25 were tolerated similarly to MC3 formulations and produced efficacious immune responses, as taught by Benenato. 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 105-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21, 26-27, and 29-30 of U.S. Patent No. 11,406,703 in view of Geall and Bancel (both supra) and Heartlein et. al. (WO2014152774A1, Pub. 09/25/2014; hereafter “Heartlein”).
Both the instant claims and the ‘703 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to methods of using said composition to elicit a HCMV-specific immune response. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘703 claims are drawn to HCMV pentameric proteins and glycoprotein B (gB) being within the composition.
The main differences between the two is that the ‘703 claims are drawn to specific ratios of the HCMV glycoproteins within the composition, and the ‘703 claims also identify the stability and different formulations of the vaccine (such as lyophilized forms) and further structural limitations to the mRNA, such as a 5’ cap. However, given the teachings of Heartlein and Bancel, these differences would be obvious optimizations of the ‘703 claims.
Bancel teaches the mRNA may have a 5’ cap (¶[00095][000220-000230]) and that the sequence may be codon optimized (¶[000244]). Bancel teaches the mRNA compositions may be lyophilized (¶[000611]). Heartlein teaches that delivery of mRNA in liposomes encoding different protein subunits of a complex needs to have its ratios optimized to one another, such as 1:1 or 2:1 (reference claims 1-7; ¶[0007-0008]). Heartlein teaches it to be advantageous to deliver different mRNAs encoding different aspects of a protein complex at varying ratios in order to optimize production of fully assembled functional protein complexes (¶[0066]).
As the instant claims and the ‘703 claims are drawn to subject matter that comprises the same structural steps in its method, in view of the obvious nature of the claims in view of Heartlein and Bancel, the functional limitations claimed would be inherent to each claim set as the claims are structurally identical and would inherently result in or comprise the same functional limitations. Additionally, the instant claims are drawn to compositions which “comprise” the HCMV antigens, which allows for the inclusion of additional, unrecited antigens into the composition.
For at least these reasons, the instant claims and the ‘703 claims are obvious variants of one another, especially in light of the teachings of Heartlein and Bancel.
Claims 105-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 10,695,419 in view of Geall and Bancel (both supra).
Both the instant claims and the ‘419 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to using said composition to elicit a HCMV-specific immune response, which renders the methods of the instant claims obvious. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘419 claims are drawn to HCMV pentameric proteins and glycoprotein B (gB) being within the composition.
The main differences between the two is that the ‘419 claims are drawn to also having pp65 (UL83) encoded by the mRNA. The ‘419 claims also identify specific responses to the vaccine, specific doses of the vaccine, and further structural limitations to the mRNA, such as a 5’ cap or codon optimization. However, given the teachings of Geall and Bancel, these differences would be obvious optimizations of the ‘419 claims.
Geall teaches the delivery of HCMV antigens via an RNA platform to elicit an immune response against HCMV, and notes that in addition to the HCMV glycoproteins, other notable antigens from HCMV may be included, such as gB or pp65 (¶[0053-0054]). Geall teaches the CMV antigens may be sequences from any known strains, and provides examples of known clinical, low-passage, and laboratory strains (¶[0055]). Bancel teaches the mRNA may have a 5’ cap (¶[00095][000220-000230]) and that the sequence may be codon optimized (¶[000244]). The specific dosages of the identically claimed vaccines would be obvious optimization steps for a skilled artisan.
As the instant claims and the ‘419 claims are drawn to subject matter that comprises the same structural steps in its method, in view of the obvious nature of the claims in view of Geall and Bancel, the functional limitations claimed would be inherent to each claim set as the claims are structurally identical and would inherently result in or comprise the same functional limitations. Additionally, the instant claims are drawn to compositions which “comprise” the HCMV antigens, which allows for the inclusion of additional, unrecited antigens into the composition.
For at least these reasons, the instant claims and the ‘419 claims are obvious variants of one another, especially in light of the teachings of Geall and Bancel.
Claims 105-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11,197,927 in view of Geall and Bancel (both supra).
Both the instant claims and the ‘927 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to a method of using said composition to elicit a HCMV-specific immune response. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘927 claims are drawn to HCMV pentameric proteins and glycoprotein B (gB) being within the composition.
The main differences between the two is that the ‘927 claims are drawn to also having pp65 (UL83) encoded by the mRNA. The ‘927 claims also identify specific responses to the vaccine, specific doses of the vaccine, and further structural limitations to the mRNA, such as a 5’ cap or codon optimization. However, given the teachings of Geall and Bancel, these differences would be obvious optimizations of the ‘927 claims.
Geall teaches the delivery of HCMV antigens via an RNA platform to elicit an immune response against HCMV, and notes that in addition to the HCMV glycoproteins, other notable antigens from HCMV may be included, such as gB or pp65 (¶[0053-0054]). Geall teaches the CMV antigens may be sequences from any known strains, and provides examples of known clinical, low-passage, and laboratory strains (¶[0055]). Bancel teaches the mRNA may have a 5’ cap (¶[00095][000220-000230]) and that the sequence may be codon optimized (¶[000244]). The specific dosages of the identically claimed vaccines would be obvious optimization steps for a skilled artisan.
As the instant claims and the ‘927 claims are drawn to subject matter that comprises the same structural steps in its method, in view of the obvious nature of the claims in view of Geall and Bancel, the functional limitations claimed would be inherent to each claim set as the claims are structurally identical and would inherently result in or comprise the same functional limitations. Additionally, the instant claims are drawn to compositions which “comprise” the HCMV antigens, which allows for the inclusion of additional, unrecited antigens into the composition.
For at least these reasons, the instant claims and the ‘927 claims are obvious variants of one another, especially in light of the teachings of Geall and Bancel.
Claims 105-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,541,113 in view of Geall and Bancel (both supra).
Both the instant claims and the ‘113 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to a method of using said composition to elicit a HCMV-specific immune response. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘113 claims are drawn to HCMV pentameric proteins being within the composition.
The main differences between the two is that the ‘113 claims are drawn to also having pp65 (UL83) encoded by the mRNA. The ‘113 claims also identify the specific patient populations receiving the vaccine, and further structural limitations to the mRNA, such as a 5’ cap or codon optimization. However, given the teachings of Geall and Bancel, these differences would be obvious optimizations of the ‘113 claims.
Geall teaches the delivery of HCMV antigens via an RNA platform to elicit an immune response against HCMV, and notes that in addition to the HCMV glycoproteins, other notable antigens from HCMV may be included, such as gB or pp65 (¶[0053-0054]). Geall teaches the CMV antigens may be sequences from any known strains, and provides examples of known clinical, low-passage, and laboratory strains (¶[0055]). Bancel teaches the mRNA may have a 5’ cap (¶[00095][000220-000230]) and that the sequence may be codon optimized (¶[000244]). The target patient populations for a HCMV vaccine, such as persons capable of gestating or persons with immunocompromising conditions, including hematopoietic stem cell transplant recipients, would be obvious patient populations to target for a skilled artisan.
As the instant claims and the ‘113 claims are drawn to subject matter that comprises the same structural steps in its method, in view of the obvious nature of the claims in view of Geall and Bancel, the functional limitations claimed would be inherent to each claim set as the claims are structurally identical and would inherently result in or comprise the same functional limitations.
For at least these reasons, the instant claims and the ‘113 claims are obvious variants of one another, especially in light of the teachings of Geall and Bancel.
Claims 105-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,064,935.
Both the instant claims and the ‘934 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to the composition being a vaccine to elicit a HCMV-specific immune response, rendering the methods of the instant claims an obvious use of the vaccine of the ‘935 claims. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘935 claims are drawn to HCMV pentameric proteins and gB being within the composition. Both the instant claims and the ‘935 claims are drawn to Compound 25 as the ionizable lipid.
The main differences between the two is that the ‘935 claims provide further structural limitations on the mRNA, such as a 5’ cap. The ‘935 claims also provide for specific functional limitations after delivery of the vaccine to a subject. However, all of these would be obvious optimizations to a skilled artisan, and do not render the claims patentably distinct over one another. Both sets of claims are drawn to the same compositions, and the instant claims recite the method of administration at a high level, and neither require specific administration steps or dosages in order to elicit the functional results. Since the compositions are patentably indistinct, the functional results would be obvious variants given both are administering the same vaccine compositions. While the instant claims are drawn to the protein sequences, knowing the protein sequences and having said sequences be identical between claims minimally renders obvious nucleotide sequences which may encode for the proteins. For at least these reasons, the instant claims and the ‘935 claims are obvious variants of one another.
Claims 105-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,383,937.
Both the instant claims and the ‘937 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to the composition being a vaccine to elicit a HCMV-specific immune response, and both claim methods of administering the composition to a subject. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘937 claims are drawn to HCMV pentameric proteins and gB being within the composition. Both the instant claims and the ‘937 claims are drawn to Compound 25 as the ionizable lipid.
The main differences between the two is that the ‘937 claims provide further structural limitations on the mRNA, such as a 5’ cap. The ‘937 claims also provide for specific functional limitations after performing the method of administration. However, all of these would be obvious optimizations to a skilled artisan, and do not render the claims patentably distinct over one another. Both sets of claims are generically drawn to methods of administration and do not require specific administration steps or dosages in order to elicit the functional results, and therefore the functional results would be obvious variants given both are administering the same vaccine compositions. While the instant claims are drawn to the protein sequences, knowing the protein sequences and having said sequences be identical between claims minimally renders obvious nucleotide sequences which may encode for the proteins. For at least these reasons, the instant claims and the ‘937 claims are obvious variants of one another.
Claims 105-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11,484,590.
Both the instant claims and the ‘590 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to the composition being a vaccine to elicit a HCMV-specific immune response, and both claim methods of administering the composition to a subject. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘590 claims are drawn to HCMV pentameric proteins and gB being within the composition. Both the instant claims and the ‘590 claims are drawn to Compound 25 as the ionizable lipid.
The main differences between the two is that the ‘590 claims provide further structural limitations on the mRNA, such as a 5’ cap. The ‘590 claims are also drawn to specifying the patient population receiving the vaccine. However, all of these would be obvious optimizations to a skilled artisan, and do not render the claims patentably distinct over one another. While the instant claims are drawn to the protein sequences, knowing the protein sequences and having them be identical between claims minimally renders obvious nucleotide sequences which may encode for the proteins. For at least these reasons, the instant claims and the ‘590 claims are obvious variants of one another.
Claims 105-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 10,022,435 in view of Geall, Bancel, and Benenato (all supra).
The applied reference (Benenato) has a common assignee (ModernaTx, Inc.) 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.
Both the instant claims and the ‘435 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode an infectious antigen, wherein said mRNA is within LNPs. The instant claims are also drawn to a method of using said composition to elicit a HCMV-specific immune response, which is similar in scope to the ‘435 claimed method of using said composition for vaccination of a subject. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine.
The main difference between the two is that the ‘435 claims are drawn generically to the antigenic polypeptides being from an infectious agent, while the instant claims are drawn to the mRNA encoding HCMV pentamer and gB antigens. The instant claims are also drawn to a method of using said composition to elicit a HCMV-specific immune response, which is similar in scope to the ‘435 claimed method of using said composition for vaccination of a subject. The instant claims also specify the species of ionizable cationic lipid within the LNP, namely that of Formula I and Compound 25. However, these differences would be obvious in light of the prior art, as evidenced by the teachings of Geall, Bancel, and Benenato.
The teachings of Geall, Bancel, and Benenato have been detailed supra, and render obvious the instant claims with regards to delivery of HCMV pentameric proteins using an LNP-mRNA delivery platform as a vaccine. As the instant claims and the ‘435 claims are drawn to identical or obvious subject matter that comprises the same structural steps in its method, the functional limitations claimed (such as accumulation at 100-fold higher level in local lymph node) would be inherent to each claim set as the claims are structurally identical and would inherently result in or comprise the same functional limitations. Therefore, the claimed differences in the composition would be obvious, as would the claimed method of using said composition, especially in light of the teachings of Geall, Bancel, and Benenato.
Further, delivery of mRNA using LNPs comprising amino lipids of Formula I was known in the art, as evidenced by Benenato. Benenato teaches lipids of Formula I, including Compound 25 (¶[0438][0517][0649-0652]), and that said lipid may be in a LNP comprising said amino lipid, neutral lipid, cholesterol, and PEG-modified lipid (reference claims 3-14) wherein said LNP comprises therapeutic mRNA (reference claims 20-21). Benenato teaches wherein the lipid nanoparticle comprises 20-60 mol% cationic lipid, 0.5- 15 mol% PEG-modified lipid, 25-55 mol% sterol, and 5-25 mol% neutral lipid (reference claims 12-14). Benenato teaches the mRNA may comprise a 5’ cap and a 3’ poly A tail, and modified nucleosides such as 5-methoxyuridine or 1-substituted pseudouridine (e.g., 1-methyl-pseudouridine or 1-ethyl-pseudouridine)(¶[0319]). The broader disclosure of the ‘435 claims encompasses the species of the instant claims with respect to the ionizable cationic lipid.
For at least these reasons, the instant claims and the ‘435 claims are obvious variants of one another, especially in light of the teachings of Geall, Bancel, and Benenato.
Claims 105-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,709,779 in view of Geall, Bancel, and Benenato (all supra).
The applied reference (Benenato) has a common assignee (ModernaTx, Inc.) 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.
Both the instant claims and the ‘779 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode an infectious antigen, wherein said mRNA is within LNPs. The instant claims are also drawn to a method of using said composition to elicit a HCMV-specific immune response, which is similar in scope to the ‘779 claimed method of using said composition for vaccination of a subject. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine.
The main difference between the two is that the ‘779 claims are drawn generically to the antigenic polypeptides being from an infectious agent, while the instant claims are drawn to the mRNA encoding HCMV pentamer and gB antigens. The instant claims also specify the identity of the ionizable cationic lipid, while the ‘779 claims are generically drawn to any ionizable cationic lipid. However, given the teachings of Geall, Bancel, and Benenato, these differences would be obvious optimizations of the ‘779 claims.
The teachings of Geall, Bancel, and Benenato have been detailed supra, and render obvious the instant claims with regards to delivery of HCMV pentameric proteins using an LNP-mRNA delivery platform as a vaccine. Geall teaches HCMV antigens delivered via an RNA platform, namely HCMV pentameric antigens. Bancel teaches the delivery of mRNA-LNP vaccines and provides motivation to look for existing platforms, such as those of Bancel, and adjust them to the mRNA-LNP delivery platform. Delivery of mRNA using LNPs comprising amino lipids of Formula I was known in the art, as evidenced by Benenato. Finally, the broader disclosure of the ‘779 claims encompasses the species of the instant claims with respect to the ionizable cationic lipid.
For at least these reasons, the instant claims and the ‘779 claims are obvious variants of one another, especially in light of the teachings of Geall, Bancel, and Benenato.
Claims 105-124 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Pat. No. 10,716,846.
Both the instant claims and the ‘846 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to the composition being a vaccine to elicit a HCMV-specific immune response, rendering the methods of the instant claims an obvious use of the vaccine of the ‘846 claims. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘846 claims are drawn to HCMV pentameric proteins and gB being within the composition. Both the instant claims and the ‘846 claims are drawn to Compound 25 as the ionizable lipid.
The main differences between the two is that the ‘846 claims comprise further limitations regarding the HCMV glycoproteins being truncated, such as to generate soluble glycoproteins that appear to lack the native signal peptide, and provide further structural limitations on the mRNA, such as a 5’ cap. The ‘846 claims are also drawn to further functional limitations that present upon administration to a subject, further rendering obvious the instant methods of delivery of the vaccine composition. However, all of these would be obvious optimizations to a skilled artisan, and do not render the claims patentably distinct over one another. Additionally, the claims require that the mRNA “comprises” the sequences which encode the glycoproteins, which allows for additional, unrecited elements to be present in the coding regions for the HCMV proteins claimed. While the instant claims are drawn to the protein sequences, knowing the protein sequences minimally renders obvious nucleotide sequences which may encode for the proteins. For at least these reasons, the instant claims and the ‘846 claims are obvious variants of one another.
Claims 105-124 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 181-190 of copending Application No. 18/926,517 in view of Geall, Bancel, and Benenato (all supra).
The applied reference (Benenato) has a common assignee (ModernaTx, Inc.) 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.
Both the instant claims and the ‘517 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to a method of using said composition to elicit a HCMV-specific immune response. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘517 claims are drawn to HCMV pentameric proteins being within the composition.
The main differences between the two is that the ‘517 claims are drawn to also having pp65 (UL83) encoded by the mRNA. The instant claims also specify the identity of the ionizable cationic lipid, while the ‘517 claims are generically drawn to any ionizable cationic lipid. However, given the teachings of Geall, Bancel, and Benenato, these differences would be obvious optimizations of the ‘517 claims.
Geall teaches the delivery of HCMV antigens via an RNA platform to elicit an immune response against HCMV, and notes that in addition to the HCMV glycoproteins, other notable antigens from HCMV may be included, such as gB or pp65 (¶[0053-0054]). Geall teaches the CMV antigens may be sequences from any known strains, and provides examples of known clinical, low-passage, and laboratory strains (¶[0055]).
Further, delivery of mRNA using LNPs comprising amino lipids of Formula I was known in the art, as evidenced by Benenato. Benenato teaches lipids of Formula I, including Compound 25 (¶[0438][0517][0649-0652]), and that said lipid may be in a LNP comprising said amino lipid, neutral lipid, cholesterol, and PEG-modified lipid (reference claims 3-14) wherein said LNP comprises therapeutic mRNA (reference claims 20-21). Benenato teaches wherein the lipid nanoparticle comprises 20-60 mol% cationic lipid, 0.5- 15 mol% PEG-modified lipid, 25-55 mol% sterol, and 5-25 mol% neutral lipid (reference claims 12-14). Benenato teaches the mRNA may comprise a 5’ cap and a 3’ poly A tail, and modified nucleosides such as 5-methoxyuridine or 1-substituted pseudouridine (e.g., 1-methyl-pseudouridine or 1-ethyl-pseudouridine)(¶[0319]). The broader disclosure of the ‘517 claims encompasses the species of the instant claims with respect to the ionizable cationic lipid.
As the instant claims and the ‘517 claims are drawn to subject matter that comprises the same structural steps in its method, in view of the obvious nature of the claims in view of Geall, Bancel, and Benenato, the functional limitations claimed would be inherent to each claim set as the claims are structurally identical and would inherently result in or comprise the same functional limitations.
For at least these reasons, the instant claims and the ‘517 claims are obvious variants of one another, especially in light of the teachings of Geall, Bancel, and Benenato.
This is a provisional nonstatutory double patenting rejection.
Claims 105-124 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 19/382,559 in view of Heartlein (supra).
Both the instant claims and the ‘559 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to a method of using said composition to elicit a HCMV-specific immune response. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘559 claims are drawn to HCMV pentameric proteins and gB being within the composition. Both the instant claims and the ‘559 claims are drawn to Compound 1/Compound 25 as the ionizable lipid.
The main differences between the two is that the ‘559 claims comprise further limitations about the molar ratio of each mRNA encoding each glycoprotein, and provide further structural limitations on the mRNA, such as a 5’ cap. However, these would be obvious optimizations to a skilled artisan, especially in light of the teachings of Heartlein, and do not render the claims patentably distinct over one another. Heartlein teaches that delivery of mRNA in liposomes encoding different protein subunits of a complex needs to have its ratios optimized to one another, such as 1:1 or 2:1 (reference claims 1-7; ¶[0007-0008]). Heartlein teaches it to be advantageous to deliver different mRNAs encoding different aspects of a protein complex at varying ratios in order to optimize production of fully assembled functional protein complexes (¶[0066]). For at least these reasons, the instant claims and the ‘559 claims are obvious variants of one another in view of Heartlein.
This is a provisional nonstatutory double patenting rejection.
Claims 105-124 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 19/738,943 in view of Heartlein (supra).
Both the instant claims and the ‘943 claims are drawn to a composition comprising one or more mRNA polynucleotides comprising at least one chemical modification, wherein said mRNA encode a viral surface antigen, wherein said mRNA is within LNPs. Both sets of claims are also drawn to a method of using said composition to elicit a HCMV-specific immune response. Both sets of claims are drawn to the compositions formulated in LNPs that comprises a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid, wherein the polynucleotides comprise chemical modifications such as 1-methyl-pseudouridine. Both the instant claims and the ‘943 claims are drawn to HCMV pentameric proteins and gB being within the composition. Both the instant claims and the ‘943 claims are drawn to Compound 1/Compound 25 as the ionizable lipid.
The main differences between the two is that the ‘943 claims comprise further limitations about the molar ratio of each mRNA encoding each glycoprotein, and provide further structural limitations on the mRNA, such as a 5’ cap. However, these would be obvious optimizations to a skilled artisan, especially in light of the teachings of Heartlein, and do not render the claims patentably distinct over one another. Heartlein teaches that delivery of mRNA in liposomes encoding different protein subunits of a complex needs to have its ratios optimized to one another, such as 1:1 or 2:1 (reference claims 1-7; ¶[0007-0008]). Heartlein teaches it to be advantageous to deliver different mRNAs encoding different aspects of a protein complex at varying ratios in order to optimize production of fully assembled functional protein complexes (¶[0066]). For at least these reasons, the instant claims and the ‘943 claims are obvious variants of one another in view of Heartlein.
This is a provisional nonstatutory double patenting rejection.
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.
Ciferri C, et. al. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1767-72. Epub 2015 Jan 26. Teaches different antigenic regions of the HCMV pentamer. Not utilized as rejection would be redundant to those set forth supra.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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