DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment filed 7/9/2026 has been entered. Claim 1-3, 5-7, 12-13, 17, 21, 29, 35, 36, 37, 38, 40 and 42-43 are now pending and under examination.
Election/Restrictions
Applicant’s election without traverse of Group I claims 1-3, 5-7, 12-13, 17, 21, 29, 35, 36, 37, 38, 40 and 42-43 in the reply filed on 7/9/2026 is acknowledged. The election of the following species is also acknowledged: Borrelia burgdorferi; Borrelia burgdorferi strain B31 (serotype 1); SEQ ID NO: 1; SEQ ID NO: 10 and SEQ ID NO: 16.
Claims 44 and 46 (Group II) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/9/2026.
Information Disclosure Statement
The information disclosure statements filed 10/9/2024 and 7/9/2026 have been considered and initialed copies are enclosed.
Claim Objections
Claim 29 and 42 are objected to because of the following informalities:
In claim 29 line 1 please replace “of any of claim 21” with “of claim 21”.
In claim 42 line 2, please correct the grammar of “at least of the following structural elements” which could be “at least one of following structural elements” or could be “at least the following structural elements”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 7 and 12-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 7 is drawn to a Lyme disease vaccine, comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia,
wherein: the at least one antigenic polypeptide or lipoprotein is OspA or a fragment or variant thereof; the OspA or a fragment or variant thereof comprises at least 5 amino acids; the OspA or a fragment or variant thereof is derived from OspA serotype (ST) 1 ;the OspA or a fragment or variant thereof is derived from Borrelia burgdorferi strain B31 of Serotype 1 and/or the at least one OspA polypeptide comprises an amino acid sequence with at least 85% identity to SEQ ID NOs: 1
Claims 12 is drawn to the Lyme disease vaccine of claim 1, wherein the mRNA comprises a nucleotide sequence that is at least 85% identical to any one of SEQ ID NOs: 10 and 16.
Claim 13 is drawn to the Lyme disease vaccine of claim 1, wherein: the mRNA encodes at least two different OspA serotypes or fragments or variants thereof; the OspA of one serotype or fragment or variant thereof, preferably comprising at least 5 amino acids, is fused to a OspA of a different serotype, or fragment or variant thereof, preferably comprising at least 5 amino acids; and/or the fused OspA of different serotypes or fragments or variants thereof are separated by a linker sequence, optionally wherein the linker sequence is derived from P66 or comprises an amino acid sequence with at least 85% identity to SEQ ID NO: 8 or to SEQ ID NO: 9.
The claims are drawn to a genus of mRNA comprising many member species having different structure. This is because all the different species are encoding different variants and different fragments of OspA.
For example, the species of mRNA encode variants and fragments comprising at minimum any 5 amino acids of OspA. The species of mRNA encode variant OspA proteins comprising an amino acid sequence that can vary by up to 15% from SEQ ID NO: 1. Such variant amino acid sequences can be generated by substitution, deletion and insertion mutations or a combination thereof. Thus, all the different variant OspA or different OspA fragments will each be encoded by mRNA of different structure.
The specification discloses that mRNA are formulated in a non-viral delivery vehicle such as lipid nanoparticles (LNP).
The specification reduces to practice mRNA encoding OspA ST1 or OspA ST2 formulated in LNP and the formulation was administered to mice. See example 1. The immunogenicity of the mRNA formulation was tested in mice by measuring IgG titers against OspA. In conclusion, the specification teaches that the mRNA coding for OspA ST1 and ST2 was immunogenic and induced strong anti-OspA IgG titers in mice both post-dose 1 and post-dose 2. See example 2 and figures 1-2.
The disclosure of the immunogenicity of the OspA ST1 and OspA ST2 mRNA+LNP formulation does not put Applicant in possession of the genus of mRNA encoding OspA variants and fragment that function as a Lyme disease vaccine.
The specification does not teach the common structure of the genus of mRNA that correlates with protection afforded as a Lyme disease vaccine.
Also, the disclosure of OspA proteins from different serotypes e.g. ST1-ST7 is insufficient to describe the genus of mRNA encoding the OspA variant and OspA fragments because they do not reflect the substantial variation in the genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
It is unpredictable without further testing that members of the genus of mRNA encoding the OspA variants and encoding the OspA fragments can protect against Lyme disease. Possession of a genus cannot be shown by merely describing how to obtain members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69USPQ2d at 1895. The written description provision of 35 U.S.C. § 112 are severable from its enablement provision Vas-Cath, Inc. v. Mahurkar, 1115.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. “Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement”. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
For these reasons, Applicants as of the effective filing date of the instant invention were not in possession of the genus of mRNA encoding OspA variants and encoding OspA fragments that protect against Lyme disease.
Claims 1-3, 5-7, 12-13, 17, 21, 29, 35-38, 40, 42 and 43 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 an immunogenic composition comprising mRNA comprising an open reading fame (ORF) encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia formulated in a lipid nanoparticle (LNP), does not reasonably provide enablement for a Lyme disease vaccine comprising mRNA comprising an ORF encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia with or without formulation in a LNP.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention
The claims are drawn to:
a Lyme disease vaccine, comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia.
Breadth of the Claims
The at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia can be any antigenic polypeptide derived from any Borrelia species.
Guidance in the Specification/The Existence of Working Examples
The specification discloses that mRNA are formulated in a non-viral delivery vehicle such as lipid nanoparticles (LNP).
The specification reduces to practice mRNA encoding OspA ST1 or OspA ST2 formulated in LNP and the formulation was administered to mice. See example 1. The immunogenicity of the mRNA formulation was tested in mice by measuring IgG titers against OspA. In conclusion, the specification teaches that the mRNA coding for OspA ST1 and ST2 was immunogenic and induced strong anti-OspA IgG titers in mice both post-dose 1 and post-dose 2. See example 2 and figures 1-2.
The specification does not correlate the immunogenicity of the OspA ST1 or ST2 mRNA+LNP formulation with protection from Lyme disease or protection from Borrelia.
The specification does not teach that the mRNA by itself without formulation in LNP is immunogenic and protects against Lyme disease or Borrelia.
State of the Art and Predictability of the Art and Amount of experimentation Necessary
The specification states that there is a dearth of effective Lyme disease vaccines available (paragraph 4).
Lyme borreliosis (i.e., Lyme disease) is a zoonotic disease caused by some bacterial species in the genus Borrelia and is transmitted to humans and other mammals by the bite of an infected Ixodes spp. tick. Outer surface protein A (OspA) is an abundant immunogenic lipoprotein of Borrelia. There are at least seven different serotypes (serotypes 1-7) of OspA that are found in Borrelia worldwide, and different genospecies of Borrelia that can cause Lyme borreliosis exist worldwide. Further, localized ranges of ticks that harbor Borrelia means that an OspA serotype that is associated with Lyme disease in patients in one geographic region might not be associated with Lyme disease in patients in another geographic region. See paragraph 3 of the specification.
The state of the art regarding recombinant OspA vaccine for human Lyme disease was well developed as of the effective filing date although complicated by molecular mimicry induced autoimmunity to native OspA and the need for continued booster doses to maintain sufficient titer of neutralizing antibodies amongst other issues. See Dattwyler et al. npj Vaccines 7, 10 (2022). https://doi.org/10.1038/s41541-022-00429-5 (5 pages).
The state of the art for a mRNA vaccine for Lyme disease was not well developed as of the effective filing date of the instant invention.
Thus, additional guidance is needed regarding the efficaciousness of mRNA encoding OspA or any other Borrelia antigen.
"The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art." "The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling" See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) and MPEP 2164.03.
For these reasons, the specification, while being enabling for an immunogenic composition comprising mRNA comprising an open reading fame (ORF) encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia formulated in a lipid nanoparticle (LNP), does not reasonably provide enablement for a Lyme disease vaccine comprising mRNA comprising an ORF encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia with or without formulation in a LNP.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13, 21, 29, 35-38 and 42 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 13 recites “prefarably”. The description of examples or preferences is properly set forth in the specification rather than in the claims because if stated in the claim it may lead to confusion over the intended scope of a claim. It is not clear whether the claim is drawn to the preferred embodiments rather than those embodiments that are not preferred.
Claim 13 recites a linker sequence derived from P66. “P66” is broadly recited and the metes and bounds of P66 is vague and indefinite.
In claim 21, please include the full formal names of the acronyms ML7/OF-02,
cKK-E10, GL-HEPES-E3-E10-DS-3-E18-1, GL-HEPES-E3-E12-DS-4-E10 and GL-HEPES-E3-E12-DS-3-E14.
In claim 29, the claim recites “The lyme disease vaccine of any one of claim 21”. Please clarify whether claim 29 is intended to be dependent on claim 21 and any other preceding claims. For the purposes of initial examination claim 29 is interpreted to depend on claim 21.
In claim 42, the claim recites, “wherein the mRNA comprises at least of the following structural elements”. It is not clear whether the mRNA comprises at least one of the structural elements listed or the mRNA comprises at least (all) the following structural elements listed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 5-7, 12, 13, 40 and 42 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
The claim(s) recite(s) a Lyme disease vaccine, comprising a messenger mRNA comprising an open reading frame encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia.
The claims encompass a product of nature. The product of nature is the Borrelia burgdorferi which comprises the mRNA and a mRNA transcript comprising an open reading frame encoding the lipoproteins OspA and OspB. Howe et al (Howe et al. Infection and Immunity, vol. 54, No. 1, p. 207-212, October 1986) discloses that total RNA extracted from Borrelia burgdorferi B31 comprises a single operon containing both the ospA and ospB genes and a single mRNA transcript hybridized with the individual DNA probes specific for ospA or ospB meaning that a single mRNA transcript derived from Borrelia burgdorferi B31 encodes the two antigenic polypeptides ospA and ospB. The ospB is regarded as a variant of OspA and vice-versa (see claim 13). The B31 ospA mRNA transcript encodes a protein that comprises an amino acid sequence with at least 85% identity to SEQ ID NO: 1. See Appendix A and Howe et al abstract, page 210 figure 4, page 210 under discussion, page 211 column 1 first two paragraphs.
In addition, the specification at paragraph 353-354 discloses that Borrelia species afzeii, garinii and bavariensis also possess the ospA mRNA transcript and that there are seven serotypes ST1-ST7 prevalent in the U.S. and Europe. The specification teaches that the ospA mRNA transcripts with amino acid sequence SEQ ID NO: 10-13 and 16-19 are native mRNA sequences. It appears that SEQ ID NO: 14 and 15 are the native 5’ untranslated region (UTR) and the native 3’ UTR sequences, respectively (see claim 40 and claim 42). See page 69-73. The native mRNA for Borrelia OspA necessarily comprises a 5’ cap, 5’ UTR, 3’ UTR and polyA sequence, absent other evidence to the contrary.
It is noted that not all of these claims are limited to mRNA encoding ospA. Claim 1 is broadly directed Borrelia which comprises many mRNA comprising ORF encoding at least one antigenic polypeptide (any) and also broadly directed to mRNA comprising ORF encoding at least one antigenic polypeptide (any) derived from Borrelia.
The mRNA of claims 1, 5-7, 12, 13, 40 and 42 including the Borrelia comprising mRNA (the claims do not recite the mRNA is isolated, thus the claims also read on Borrelia comprising mRNA) are products of nature and therefore these claims are directed to a judicial exception without significantly more.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 5, 17, 21, 29, 35-38, 40 and 42 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Casimiro et al. US 2022/0142923 5/12/2022.
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. 102(a)(2) 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) if the same invention is not being claimed; 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 in the reference 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.
Casimiro et al disclose the following:
Claim 1. A Lyme disease vaccine, comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia. See abstract, paragraph 4-9 and paragraph 118-119.
Claim 2. The Lyme disease vaccine of claim 1, wherein the mRNA is formulated in a lipid nanoparticle (LNP). See abstract, paragraph 4-9 and paragraph 118-119.
Claim 3. The Lyme disease vaccine of claim 1, wherein the mRNA is non- replicating mRNA i.e. Casimiro does not disclose that the mRNA includes additional sequences to induce self-amplification of the inserted mRNA sequence.
Claim 5: The Lyme disease vaccine of claim 1, wherein the bacteria of the genus Borrelia is selected from the species B. burgdorferi. See paragraph 118-119.
Claim 17: The Lyme disease vaccine of claim 1, wherein the mRNA comprises at least one chemical modification, optionally wherein the chemical modification is selected from the group consisting of pseudouridine, N1- methylpseudouridine, 2-thiouridine, 4'-thiouridine, 5- methylcytidine, 2-thio-l-methyl-1-deaza- pseudouridine, 2-thio-l-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy- pseudouridine, 4-thio-l-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methyluridine, 5-methoxyuridine, and 2'-0-methyl uridine;the chemical modification is selected from the group consisting of pseudouridine, N1- methylpseudouridine, 5-methylcytidine, 5- methoxyuridine, and a combination thereof; and/or the chemical modification is N1-methylpseudouridine.
See paragraphs 16-21.
Claim 21: The Lyme disease vaccine of claim 1, wherein the mRNA is formulated in a lipid nanoparticle (LNP) optionally wherein the LNP comprises at least one cationic lipid; the cationic lipid is selected from the group consisting of ML7/OF-02; cKK-E10; GL- HEPES-E3-E10-DS-3-E18-1; GL-HEPES-E3-E12-DS-4-E10; GL-HEPES-E3-E12-DS-3-E14; 9 and/or the cationic lipid is cKK-E10.
Claim 29: The Lyme disease vaccine of claim 21, wherein the LNP further comprises: a polyethylene glycol (PEG) conjugated (PEGylated) lipid optionally wherein the PEGylated lipid comprises dimyristoyl-PEG2000 (DMG-PEG2000) ,DOPE. See paragraph 7.
Claim 35: The Lyme disease vaccine of claim 21, wherein the LNP comprises: a cationic lipid at a molar ratio of 35% to 45% or 38-42% or 42%; a polyethylene glycol (PEG) conjugated (PEGylated) lipid at a molar ratio of 0.25% to 2.75% e.g. 1-2% or 1.5%; ,a cholesterol-based lipid at a molar ratio of 20% to 35%, such as 27-30% or 35% and a helper lipid at a molar ratio of 25% to 35%, wherein all of the molar ratios are relative to the total lipid content of the LNP. See paragraph 114.
Claim 36: The Lyme disease vaccine of claim 35, wherein the LNP comprises: a cationic lipid at a molar ratio of 40%,a PEGylated lipid at a molar ratio of 1.5%,a cholesterol-based lipid at a molar ratio of 28.5%, and a helper lipid at a molar ratio of 30%. See paragraph 115.
Claim 37: The Lyme disease vaccine of claim 35, wherein the LNP comprises: cKK-E10 at a molar ratio of 40%, DMG-PEG2000 at a molar ratio of 1.5%, cholesterol at a molar ratio of 28.5%, and DOPE at a molar ratio of 30%. See paragraph 7 and 115
Claim 38: The Lyme disease vaccine of claim 21, wherein the LNP has an average diameter of 30-200 nm2 optionally wherein the LNP has an average diameter of 80-150 nm. See paragraph 30.
Claim 40: The Lyme disease vaccine of claim 1, wherein the mRNA comprises at least one 5' cap, at least one 5' untranslated region (5' UTR), at least one of 3' untranslated region (3' UTR), and/or at least one polyadenylation (polyA) sequence. See paragraph 15.
Claim 42: Casimiro et al disclose a Lyme disease vaccine, comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia or from bacteria or viruses (abstract, paragraph 4-9 and paragraph 117-119) and wherein the mRNA comprises at least one of the 5’ cap structure set forth in (i), and a poly A tail.
Claim(s) 1, 3, 5, 6, 7, 40 and 42 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gipson et al. Vaccine. 2003 Sep 8;21(25-26):3875-84, cited in IDS as evidenced by Accession Number G70208 PIR_80 Database 13 February, 1998 and as evidenced by Balasuriya et al. J Virol. 15 November 2000 Volume 74 Issue 22.
Claim 1: A Lyme disease vaccine (Venezuelan Equine Encephalitis (VEE) replicon-based outer surface protein A (OspA) vaccine, comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding OspA polypeptide derived from Borrelia - OspA and tpA-ospA gene products were inserted into pVR21, the VEE replicon expression vector downstream of the 26S promoter by overlapping extension PCR [25]. Tran scripts of pVR21-ospA and PVR21-tpA-ospA were generated in vitro using a mMessage mMachine T7 transcription kit. See abstract and p. 3876-3877 under section 2.3.
Claim 3: The Lyme disease vaccine of claim 1, wherein the mRNA is non- replicating mRNA: Gipson et al disclose the VEE replicons are only capable of a single round of infection, and the antigen of interest is only produced within host cells initially infected by the replicon particles. The vectors are also RNA based, which reduces the likelihood of integration into the host chromosome. See p. 3876 second paragraph column 1.
Claim 5: The Lyme disease vaccine of claim 1, wherein the bacteria of the genus Borrelia is selected from the species B. burgdorferi, strain N40. See p.3876 under section 2.2.
Claim 6: The Lyme disease vaccine of claim 1, wherein the antigenic polypeptide comprises at OspA lipoprotein of Borrelia.
Claim 7: The Lyme disease vaccine of claim 1, wherein the at least one antigenic polypeptide or lipoprotein is OspA or a fragment (expressed from a 850 bp fragment) or variant thereof (tpA signal sequence-OspA), wherein the OspA or a fragment or variant thereof comprises at least 5 amino acids and B. burgdorferis OspA is 98% identical to SEQ ID NO: 1 and Gipson et al disclose that B. burgdorferi N40 OspA are 99% similar. Thus, the OspA, fragment or variant thereof of Gipson et al comprises an amino acid sequence at least 85% identical to SEQ ID NO: 1. See p. 3878 figure 1 and figure 2, p. 3878 column 1.
Claim 40: The Lyme disease vaccine of claim 1, wherein the mRNA replicon RNA of VEE comprises a 5' cap, 3’ untranslated region and a polyadenylation (polyA) sequence as evidenced by figure 1 and under construction of recombinant plasmids of Balasuriya et al. J Virol. 15 November 2000 Volume 74 Issue 22.
Claim 42: A Lyme disease vaccine (Venezuelan Equine Encephalitis (VEE) replicon-based outer surface protein A (OspA) vaccine, comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding OspA polypeptide derived from Borrelia - OspA and tpA-ospA gene products were inserted into pVR21, the VEE replicon expression vector downstream of the 26S promoter by overlapping extension PCR [25]. Tran scripts of pVR21-ospA and PVR21-tpA-ospA were generated in vitro using a mMessage mMachine T7 transcription kit. See abstract and p. 3876-3877 under section 2.3 and the mRNA replicon RNA of VEE comprises a 5' cap, 3’ untranslated region and a polyadenylation (polyA) sequence as evidenced by figure 1 and under construction of recombinant plasmids of Balasuriya et al. J Virol. 15 November 2000 Volume 74 Issue 22.
Claim(s) 1, 5, 6, 7, 12, 13, 40 and 42 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Howe et al. Infection and Immunity, vol. 54, No. 1, p. 207-212, October 1986.
Claim 1, 5, 6, 7: Howe et al disclose a Lyme disease vaccine corresponding to the Borrelia burgdorferi which comprises the mRNA comprising an open reading frame encoding at least one antigen polypeptide derived from said Borrelia, wherein one of the antigens is OspA and OspB and a Lyme disease vaccine comprising an isolated mRNA transcript comprising an open reading frame encoding the lipoproteins OspA and OspB.
The OspA protein or variant thereof (OspB) comprises at least 5 amino acids derived from and the OspA protein or variant thereof is derived from Borrelia burgdorferi strain B31 Serotype 1; and the B31 ospA mRNA transcript encodes a protein that comprises an amino acid sequence with at least 85% identity to SEQ ID NO: 1. See Appendix A.
See Howe et al abstract, page 210 figure 4, page 210 under discussion, page 211 column 1 first two paragraphs.
Claim 12: The instant specification discloses that SEQ ID NO: 10 is the native mRNA for OspA ST1 (B. burgdorferi B31 serotype 1) and SEQ ID NO: 16 is the coding sequence for OspA ST1 native (ORF only). Therefore, absent evidence to the contrary B. burgdorferi B31 serotype 1 comprises the mRNA of OspA of B. burgdorferi B31 serotype 1, wherein the mRNA comprises a nucleotide sequence that is at least 85% identical to SEQ ID NO: 10 or SEQ ID NO: 16 and the mRNA comprises a nucleotide sequence that is at least 85% identical to SEQ ID NO: 10 or SEQ ID NO: 16.
Claim 13: Howe et al discloses that total RNA extracted from Borrelia burgdorferi B31 comprises a single operon containing both the ospA and ospB genes and a single mRNA transcript hybridized with the individual DNA probes specific for ospA or ospB meaning that a single mRNA transcript derived from Borrelia burgdorferi B31 encodes the two antigenic polypeptides ospA and ospB which comprise at least 5 amino acids. The ospB is regarded as a variant of OspA and vice-versa.
Claim 40: the mRNA of Howe et al necessarily comprises at least one a 5’ cap, 5’ UTR, 3’ UTR and polyA sequence, absent other evidence to the contrary which are all structural elements of mRNA.
Claim 42: Howe et al disclose a Lyme disease vaccine corresponding to the Borrelia burgdorferi which comprises a mRNA comprising an open reading frame encoding at least one antigen polypeptide derived from said Borrelia, wherein one of the antigens is OspA and OspB and a Lyme disease vaccine comprising an isolated mRNA transcript comprising an open reading frame encoding the lipoproteins OspA and OspB.
See Howe et al abstract, page 210 figure 4, page 210 under discussion, page 211 column 1 first two paragraphs.
The mRNA comprises at least one of a poly A Tail, at least one OspA open reading frame having SEQ ID NO: 16 (the instant specification discloses that SEQ ID NO: 10 is the native mRNA for OspA ST1 (B. burgdorferi B31 serotype 1) and SEQ ID NO: 16 is the coding sequence for OspA ST1 native (ORF only) and absent other evidence to the contrary SEQ ID N: 14 and SEQ ID NO: 15 appear to be the native 5’UTR sequence and the 3’ UTR sequence respectively.
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.
Claim(s) 1-2, 21, 29, 35-36 and 38, is/are rejected under 35 U.S.C. 103 as being unpatentable over Gipson et al. Vaccine. 2003 Sep 8;21(25-26):3875-84, cited in IDS in view of Navarro et al. WO 2021/123332 6/24/2021 cited in IDS.
Claim 1: Gipson et al disclose a Lyme disease vaccine (Venezuelan Equine Encephalitis (VEE) replicon-based outer surface protein A (OspA) vaccine, comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding OspA polypeptide derived from Borrelia - OspA and tpA-ospA gene products were inserted into pVR21, the VEE replicon expression vector downstream of the 26S promoter by overlapping extension PCR [25]. Tran scripts of pVR21-ospA and PVR21-tpA-ospA were generated in vitro using a mMessage mMachine T7 transcription kit. See abstract and p. 3876-3877 under section 2.3.
Gipson et al does not disclose the Borrelia mRNA is delivered in a lipid nanoparticle, does not disclose the mRNA is formulated in a lipid nanoparticle (LNP) wherein the LNP comprises at least one cationic lipid and does not disclose the LBP further comprises a PEGylated lipid, cholesterol based lipid, and helper lipid.
Navarro et al relates to cationic lipids useful for the delivery of nucleic acids into living cells. See abstract. Navarro et al disclose the cationic LNP are used for mRNA e.g. antigen-providing mRNA based vaccines. See page 1 lines 1-5, p. 12 lines 34-39 and p. 26.
See also p. 13 lines 25-45 to p. 14 lines 1-14 describing the structure of mRNA which comprises 3’ UTR, polyA tail, 5’ UTR, and 5’ cap, wherein these features serve to stabilize the mRNA (p. 16 lines 1-7)
Navarro et al disclose RNA is considered rather unstable which may be readily degraded by ubiquitous RNAses. See p. 2. Navarro et al disclose that lipid nanoparticles formed from cationic lipids with other components, such as neutral lipids, cholesterol, PEG, PEGylated lipids have been used to block degradation of the RNA in plasma and facilitate the cellular uptake of the oligonucleotide. See p. 2 lines 20-32
Navarro et al discloses various cationic lipids (p. 26-55) which can comprise PEGylated lipids which comprise a hydrophilic moiety such as PEG 2000 (p. 55) and a lipid moiety such as DMG (i.e. DMG-PEG2000. p. 56-57); or helper lipids (neutral lipids) such as DOPE and DSPC (p. 58-59).
Navarro et al disclose that the average diameter of the LNPs are 30-200 nm or 80-150 nm exemplified by average diameter disclosures from about 30 nm to about 150 nm, from about 50 nm to about 200 nm, from about 60 nm to about 200 nm, from about 70 nm to about 200 nm, from about 80 nm to about 200 nm, from about 90 nm to about 200 nm, from about 90 nm to about 190 nm, from about 90 nm to about 180 nm, from about 90 nm to about 170 nm, from about 90 nm to about 160 nm, from about 90 nm to about 150 nm, from about 90 nm to about 140 nm, from about 90 nm to about 130 nm, from about 90 nm to about 120 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, or 200 nm. See p. 62.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have modified Gipson et al by substituting the VEE vector with the LNP of Navarro et al for the delivery of the Borrelia mRNA, thus resulting in the instant invention with a reasonable expectation of success.
The rationale for the substitution is that both delivery vehicles were known and studied extensively in the prior art for their function as delivery vehicles for mRNA as of the effective filing date and one of ordinary skill in the art could have substituted the VEE for the LNP and the results of the substitution would have been predictable, for example, LNP can deliver mRNA comprising cationic lipids are useful for the delivery of nucleic acids into living cells and that lipid nanoparticles formed from cationic lipids with other components, such as neutral lipids, cholesterol, PEG, PEGylated lipids have been used to block degradation of the RNA in plasma and facilitate the cellular uptake of the oligonucleotide.
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007): Simple Substitution of one known element for another to obtain predictable results. MPEP 2143.
Regarding claims 35-36, Navarro et al disclose that the lipid nanoparticles according to one of the preferred embodiments comprise a cationic lipid, a neutral lipid helper lipid, a steroid which may be cholesterol, and a polymer conjugated lipid. See p. 63.
Navarro et al disclose that the amount of the cationic lipid in the composition (and thus in the lipid nanoparticles) relative to the total molar amount of all lipidic excipients in the composition (or nanoparticles) is about 30, 35, 40, 45, 50, 55, 60, 65, or 70 mol%, or from about 40 mol% to about 60 mol%, respectively; such as about 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59 or 60 mol%, respectively.
Navarro et disclose that the amount of the steroid (cholesterol) in the composition may optionally at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mol%, respectively relative the total molar amount of all lipidic excipients in the composition.
Navarro et al disclose that the neutral lipid (helper lipid) may optionally be present at an amount of at least about 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, 15 mol%, 16 mol%, 17 mol%, 18 mol%, 19 mol%, 20 mol%, 21 mol%, 22 mol%, 23 mol%, 24 mol% or 25 mol%, respectively, relative the total molar amount of all lipidic excipients in the composition.
Navarro et al disclose that the amount of the polymer conjugated lipid e.g. PEGylated lipid in the lipid nanoparticles may relative the total molar amount of all lipidic excipients in the composition, for example, be selected is about 0.5 mol% to about 5 mol%, or from about 1 mol% to about 3 mol%, such as about 0.3, 0.5, 1 , 2, 3, mol% respectively or 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7 mol%.
See p. 63 lines 38-45 and p. 64-66.
Thus, the combination of Gipson et al and Navarro et al further renders claims 35-36 prima facie obvious.
Claim(s) 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gipson et al. Vaccine. 2003 Sep 8;21(25-26):3875-84, cited in IDS in and Navarro et al. WO 2021/123332 6/24/2021 cited in IDS as applied to claims 1-2, 21, 29, 35-36 and 38, above further in view of Kuwae et al. WO 2019131770 07/04/2019.
The combination of Gipson et al and Navarro et al does not disclose the cationic lipid is cKK-E10.
Kuwae et al disclose cKK-E10 amongst other that can be used as a cationic lipid that can be incorporated into a LNP for nucleic acid delivery. See abstract and under technical field and:
“In another embodiment, cationic lipids K-E12, H-A12, Y synthesized according to the following scheme described in Dong et al. (Proc Natl Acad Sci USA: 2014 Apr. 15; 111 (15): 5753). -E12, G-O12, K-A12, R-A12, cKK-E12, cPK-E12, PK1K-E12, PK500-E12, cQK-E12, cKK-A12, KK-A12, PK-4K-E12, cWK -E12, PK500-O12, PK1K-O12, cYK-E12, cDK-E12, cSK-E12, cEK-E12, cMK-E12, cKK-O12, cIK-E12, cKK-E10, cKK-E14, and cKK- E16 is mentioned.”
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention that cKK-E10 could be used as a cationic lipid for the LNP of the combination of Gipson et al and Navarro et al as taught by Kuwae et al, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Kuwae et al disclose cKK-E10 amongst other cationic lipids that can be used as a cationic lipid that can be incorporated into a LNP for nucleic acid delivery.
Claim(s) 17, 21 and 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gipson et al. Vaccine. 2003 Sep 8;21(25-26):3875-84, cited in IDS and Navarro et al. WO 2021/123332 6/24/2021 cited in IDS as applied to claims 1-2, 21,29, 35-36 and 38, further in view of Casimiro et al. US 2022/0142923 5/12/2022, cited in IDS.
The combination of Gipson et al and Navarro et al does not disclose the cationic lipid is OF-02, cKK-E1O, GL-HEPES-E3-E10-DS-3-E18-1, GL-HEPES-E3-E12-DS-4-E10, or GL-HEPES-E3-E12-DS-3-E14 and does not disclose the mRNA comprises at least one chemical modification.
Casimiro et al disclose OF-02, cKK-E1O, GL-HEPES-E3-E10-DS-3-E18-1, GL-HEPES-E3-E12-DS-4-E10, or GL-HEPES-E3-E12-DS-3-E14 can be used as a cationic lipid that can be incorporated into a LNP for mRNA delivery. See paragraph 3-8. Casimiro disclose that the mRNA can comprise chemical modification selected from the group consisting of pseudouridine, N1 -methylpseudouridine, 2-thiouridine, 4 ’-thiouridine, 5 -methylcytosine, 2- thio-l-methyl- 1 -deaza-pseudouridine, 2-thio-l-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-l-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5 -methyluridine, 5-methyluridine, 5-methoxyuridine, and 2’-O-methyl uridine or , the chemical modification is selected from the group consisting of pseudouridine, N1 -methylpseudouridine, 5 -methyl cytosine, 5-methoxyuridine, and a combination thereof. See paragraphs 19-20. Casimiro et al disclose that the chemical modifications enhance the stability of the mRNA. See paragraph 161-163.
Regarding claim 17, it would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have chemically modified the mRNA of the combination of Gipson et al and Navarro et al as taught by Casimiro et al, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Casimiro et al disclose that the chemical modifications enhance the stability of the mRNA.
Regarding claim 21 and 37, it would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention that cationic lipids of Casimiro et al could be used as a cationic lipid for the LNP of the combination of Gipson et al and Navarro et al as taught by Casimiro et al, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Casimiro et al disclose that said cationic lipids can be used as a cationic lipid that can be incorporated into a LNP for nucleic acid delivery.
Claim(s) 42 and 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Casimiro et al. US 2022/0142923 5/12/2022, cited in IDS in view of Howe et al. Infection and Immunity, vol. 54, No. 1, p. 207-212, October 1986.
Claim 42: Casimiro et al disclose a Lyme disease vaccine, comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia or from bacteria (abstract, paragraph 4-9 and paragraph 117-119) and wherein the mRNA comprises at least one of the 5’ cap structure set forth in (i); (ii) a 5’ UTR having the sequence of SEQ ID NO: 14 i.e. SEQ ID NO: 19 of Casimiro et al (see alignment in Appendix B) ; a 3 UTR having the sequence of SEQ ID NO: 15 i.e. SEQ ID NO: 20 of Casimiro (see alignment in Appendix C) and a poly A tail. See paragraph 25-29. See abstract, paragraph 4-9 and paragraph 118-119.
Claim 43: Casimiro et al disclose a Lyme disease vaccine, comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding at least one antigenic polypeptide derived from at least one bacteria of the genus Borrelia or from bacteria or viruses (abstract, paragraph 4-9 and paragraph 117-119) and wherein the mRNA comprises at least one of the 5’ cap structure set forth in (i); (ii) a 5’ UTR having the sequence of SEQ ID NO: 14 i.e. SEQ ID NO: 19 of Casimiro et al (see alignment in Appendix B) ; a 3 UTR having the sequence of SEQ ID NO: 15 i.e. SEQ ID NO: 20 of Casimiro (see alignment in Appendix C) and a poly A tail. See paragraph 25-29. See abstract, paragraph 4-9 and paragraph 118-119;
Wherein the mRNA is formulated in a LNP comprising:
A cationic lipid such as cKK-E10 at a molar ratio of 40% (paragraph 114-115);
A PEGylated lipid such as DMG-PEG200 at a molar ratio of 1.5% (paragraph 112-114);
Cholesterol at a molar ratio of 28.5% (paragraph 112-114); and
DOPE at a molar ratio of 30% (paragraph 112-114).
Casimiro et al does not disclose that one of the structural element is at least one OspA open reading frame having one of the nucleic acid sequences of SEQ ID NO: 16.
Howe et al disclose a Borrelia burgdorferi B31 serotype 1 (ST1) mRNA comprising an open reading frame encoding at least one antigen polypeptide derived from said Borrelia, wherein one of the antigens is OspA and OspB and a Lyme disease vaccine comprising an isolated mRNA transcript comprising an open reading frame encoding the lipoproteins OspA and OspB. See Howe et al abstract, page 210 figure 4, page 210 under discussion, page 211 column 1 first two paragraphs.
The instant specification discloses that SEQ ID NO: 16 is the coding sequence for OspA ST1 native (ORF only). Therefore, absent evidence the mRNA of OspA of B. burgdorferi B31 serotype 1, wherein the mRNA comprises a OspA ORF having any one the nucleic acid sequence of SEQ ID NO: 16.
Howe et al discloses that total RNA extracted from Borrelia burgdorferi B31 comprises a single operon containing both the ospA and ospB genes and a single mRNA transcript hybridized with the individual DNA probes specific for ospA or ospB meaning that a single mRNA transcript derived from Borrelia burgdorferi B31 encodes the two antigenic polypeptides ospA and ospB which comprise at least 5 amino acids. The ospB is regarded as a variant of OspA and vice-versa. See Howe et al abstract, page 210 figure 4, page 210 under discussion, page 211 column 1 first two paragraphs.
Howe et al disclose that Osp proteins are abundant, immunogenic and surface exposed on the bacteria and make them potential candidates for vaccine studies. See p. 211 column 1 2nd to the last paragraph.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have used the OspA mRNA of B. burgdorferi B31 serotype as the Borrelia mRNA in the LNP of Casimiro et al, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Casmiro et al disclose Borrelia mRNA can be delivered by LNP and Howe et al disclose OspA mRNA from B. burgdorferi B31 and that because Osp proteins are abundant, immunogenic and surface exposed makes them potential candidates for vaccine studies.
Status of Claims
Claims 1-3, 5-7, 12-13, 17, 21, 29, 35-38, 40, 42 and 43 are rejected.
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/OLUWATOSIN A OGUNBIYI/ Primary Examiner, Art Unit 1645
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