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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Mar. 6, 2024. Claims 1-20 are pending and currently examined.
Claim Rejections - 35 USC § 112
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.
Claims 1-20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Base claim 1 recites “the composition comprising a combination of at least two lipid nanoparticle (LNPs) comprising a combination of nucleoside-modified RNA molecules encoding at least two influenza virus antigens, wherein the combination of at least two nucleoside-modified RNA molecules encode hemagglutinin (HA) antigens, or fragments thereof, are selected from the group consisting of influenza A virus H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, and influenza B virus Vic and Yam.” Base claim 10 recites “an effective amount of a composition comprising a combination of at least two lipid nanoparticle (LNPs) wherein each LNP comprises a nucleoside-modified RNA encoding at least one influenza virus antigen or a fragment thereof, and further wherein the combination of at least two LNPs together comprise at least two nucleoside-modified RNA molecule encoding hemagglutinin (HA) antigens, or fragments thereof selected from the group consisting of influenza A virus H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, and influenza B virus Vic and Yam.”
These two limitations render the claims unclear for at least the reasons below:
The claims do not specify if the “at least two lipid nanoparticle (LNPs)” or the “at least two nucleoside-modified RNA molecules encode hemagglutinin (HA) antigens, or fragments thereof” must be different. It is not clear how to interpret the term “at least two nucleoside-modified RNA molecules” (even a composition of RNA may comprise a plurality of RNA molecule). It is noticed that the claims specify that the combination of nucleoside-modified RNA molecules encode “at least two influenza virus antigens”. However, it is not clear if the HA antigens encoded by the RNA molecules must be different influenza H types. This is especially true when the claims recite the term “fragments thereof”. Any sequence of 2 or more consecutive amino acids in an influenza HA may be considered as a fragment of the HA. Therefore, a “fragment” of one influenza species may be identical to a “fragment” of a different influenza species.
Therefore, it is not clear if the claims require that the composition as claimed must comprise “at least two nucleoside-modified RNA molecules” encoding HA antigens of at least two different influenza H types (e.g., H1, H2, H3, H4 etc.). Indeed, the limitation “selected from the group consisting of influenza A virus H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, and influenza B virus Vic and Yam” does not require that two different H types must be selected.
Additionally, it is not clear what the metes and bounds are for the term “fragments thereof”. Any sequence of 2 or more consecutive amino acids in an influenza HA may be considered as a fragment of the HA. Therefore, a “fragment” of an HA antigen of one influenza species may be identical to a “fragment” of that of another different influenza species.
To expediate prosecution, the claims are broadly interpreted as not requiring that the influenza HA antigens or fragment thereof be different and from different H types.
Claim 9 is indefinite since neither the claim nor the specification defines the term “universal influenza vaccine”. It is not clear if the claimed composition must elicit immune protection against all possible influenza viruses.
To facilitate examination, the term “universal influenza vaccine” is considered as a designation of a vaccine that induces immune response to a plurality of influenza viruses.
Claim Rejections - 35 USC § 102/103
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.
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 of this title, 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.
Claims 1-2, 4, 7-11, 13 and 16-20 are rejected under 35 U.S.C. 102/103 as being unpatentable over Pardi et al. (Nat Commun 9, 3361 (2018); submitted in IDS filed on Jan. 10, 2025).
Base claim 1 is directed to a composition for inducing an immune response against one or more influenza viruses in a subject, the composition comprising a combination of at least two lipid nanoparticle (LNPs) comprising a combination of nucleoside-modified RNA molecules encoding at least two influenza virus antigens, wherein the combination of at least two nucleoside-modified RNA molecules encode hemagglutinin (HA) antigens, or fragments thereof, are selected from the group consisting of influenza A virus H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, and influenza B virus Vic and Yam.
Base claim 10 is directed to a method of inducing an immune response against multiple strains of influenza virus in a subject comprising administering to the subject an effective amount of a composition comprising a combination of at least two lipid nanoparticle (LNPs) wherein each LNP comprises a nucleoside-modified RNA encoding at least one influenza virus antigen or a fragment thereof, and further wherein the combination of at least two LNPs together comprise at least two nucleoside-modified RNA molecule encoding hemagglutinin (HA) antigens, or fragments thereof selected from the group consisting of influenza A virus H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, and influenza B virus Vic and Yam.
As indicated in the 112(b) rejection above, it is not clear if the claims require that the influenza HA antigen or fragment thereof be different and from different H types. To expediate prosecution, the claims are broadly interpreted as not requiring that the influenza HA or fragment thereof be different and from different H types.
Pardi teaches a study on development of a nucleoside-modified mRNA-based vaccine for influenza virus. Pardi teaches that the authors evaluate a potent broadly protective influenza virus vaccine candidate that uses nucleoside-modified and purified mRNA encoding full-length influenza virus HA formulated in lipid nanoparticles (LNPs). They demonstrate that immunization with HA mRNA-LNPs induces antibody responses against the HA stalk domain of influenza virus in mice, rabbits, and ferrets. The HA stalk-specific antibody response is associated with protection from homologous, heterologous, and heterosubtypic influenza virus infection in mice. See Abstract.
Pardi teaches that to evaluate the immunogenicity of the nucleoside-modified HA mRNA-LNP vaccine, mice were immunized twice with 3, 10, or 30 μg of A/California/07/2009 (H1N1) (A/Cal09) HA-encoding mRNA-LNPs intradermally (i.d.) or 10, 30, or 90 μg of A/California/ 07/2009 HA mRNA-LNPs intramuscularly (i.m.) and antibody responses were assessed, and that the two immunizations were delivered 4 weeks apart. See page 2, left column, para 4.
For the production of nucleoside-modified HA mRNA, Pardi teaches that mRNAs were produced using T7 RNA polymerase on linearized plasmids encoding codon-optimized42 Puerto Rico/8/1934 influenza virus HA (pTEV-PR8 HA-A101), A/California/7/2009 influenza virus hemmaglutinin (pTEV-A/Cal09 HAA101), and firefly luciferase (pTEV-Luc-A101); that mRNAs were transcribed to contain 101 nucleotide-long poly(A) tails; that one-methylpseudouridine (m1Ψ)-5′-triphosphate (TriLink) instead of UTP was used to generate modified nucleoside-containing mRNA. RNAs were capped using the m7G capping kit with 2′-O-methyltransferase (ScriptCap, CellScript) to obtain cap1; and that mRNA was purified by FPLC (Akta Purifier, GE Healthcare). See page 9, para bridging left and right columns.
For the production of the LNP formulation of the mRNA, Pardi teaches that FPLC-purified m1Ψ-containing firefly luciferase and influenza virus HA-encoding mRNAs and poly(C) RNA (Sigma) were encapsulated in LNPs using a self-assembly process in which an aqueous solution of mRNA at pH = 4.0 is rapidly mixed with a solution of lipids dissolved in ethanol. LNPs used in this study contain an ionizable cationic lipid (proprietary to Acuitas)/phosphatidylcholine/cholesterol/PEG-lipid (50:10:38.5:1.5 mol/mol) and were encapsulated at an RNA to total lipid ratio of ~0.05 (wt/wt). They had a diameter of ~80 nm as measured by dynamic light scattering using a Zetasizer Nano ZS (Malvern Instruments Ltd., Malvern, UK) instrument. mRNA-LNP formulations were stored at −80 °C at a concentration of mRNA of ~1 μg/μl. See page 9, right column, para 2.
According, Pardi teaches a composition for inducing an immune response against one or more influenza viruses in a subject, comprising LNPs formulated to comprise nucleoside-modified mRNA molecules: PR8 HA mRNA-LNP (see Fig. 3) or A/Cal09 HA mRNA-LNP (see Fig. 4). Pardi also teaches a method of immunizing a subject comprising administering to the subject the LNP formulations.
Even though Pardi teaches LNPs that are formulated to comprise modified mRNA encoding HA of two different influenza strains (PR8 and A/Cal09), and that immunization with one of them induce protections to different strains, Pardi is silent in putting the LNPs comprising mRNAs encoding the two different HA antigens together in one “combination”, and using the “combination” in immunization of a subject.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine to LNP formulations separately containing the two different nucleoside-modified mRNAs (i.e., PR8 HA mRNA-LNP and A/Cal09 HA mRNA-LNP) together and to administer together to a subject so that immune responses induced by two difference HA antigens can be combined.
Regarding claims 4 and 13, the PR8 HA and A/Cal09 HA of Pardi can be considered as an additional antigen to each other.
Regarding claim 9, neither the claim nor the specification defines the term “universal influenza vaccine”. Pardi teaches that the HA stalk-specific antibody response is associated with protection from homologous, heterologous, and heterosubtypic influenza virus infection in mice (see Abstract), suggesting that the LNP-mRNA vaccine formulations of Pardi can elicit protection against multiple different influenza viruses.
Therefore, Pardi anticipates or makes obvious claims 1-2, 4, 7-11, 13 and 16-20.
Claims 1-2, 4, 7-11, 13 and 16-20 are rejected under 35 U.S.C. 102/103 as being unpatentable over Freyn et al. (Molecular Therapy Vol. 28 No 7 July 2020, pages 1569-1584); submitted in IDS filed on Jan. 10, 2025).
These claims are described above.
Freyn teaches that seasonal influenza virus vaccines are employed to prevent
disease, but with limited effectiveness. Development of a universal influenza virus vaccine with the potential to elicit long-lasting, broadly cross-reactive immune responses is necessary for reducing influenza virus prevalence. In this study, the authors have utilized lipid nanoparticle-encapsulated, nucleoside-modified mRNA vaccines to intradermally deliver a combination of conserved influenza virus antigens (hemagglutinin stalk, neuraminidase, matrix-2 ion channel, and nucleoprotein) and induce strong immune responses with substantial breadth and potency in a murine model. The immunity conferred by nucleoside-modified mRNA-lipid nanoparticle
vaccines provided protection from challenge with pandemic H1N1 virus at 500 times the median lethal dose after administration of a single immunization, and the combination vaccine protected from morbidity at a dose of 50 ng per antigen. The broad protective potential of a single dose of combination vaccine was confirmed by challenge with a panel of group 1 influenza A viruses. These findings support the advancement of nucleoside-modified mRNA-lipid nanoparticle vaccines expressing multiple conserved antigens as universal influenza virus vaccine candidates. See Abstract.
Figure 1 of Freyn (see below) shows the mRNA-LNP nanoparticle vaccine platform utilized for the delivery of a combination of conserved influenza virus antigens. It shows that the mRNA-lipid nanoparticle incorporates a 1-methylpseudouridine-modified mRNA molecule into an 80 lipid nanometer vesicle for efficient delivery into host cells upon vaccination.
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Freyn teaches that to determine the extent of the variation in influenza virus proteins proposed as antigens for a combination universal influenza virus vaccine, conservative diagrams were produced, that sequences were acquired for viruses spanning influenza HA group 1 viruses (H1, H2, H5, H6, H8, H9, H11, H12, H13, and H16) as well as NA group 1 viruses (N1, N4, N5, and N8) not limited by species tropism, that differences in M2 and NP are mostly found between species, and therefore sequences were selected from human, avian, and swine strains to model the breadth of influenza viruses of seasonal and pandemic concern, that both M2 and NP proteins show high levels of conservation compared to the more exposed glycoproteins and were both previously studied as antigens for influenza virus vaccines. See page 1570, right column, para 2.
Freyn teaches that to elicit antibodies against the conserved HA stalk domain, a “Mini HA” construct based on the A/Brisbane/59/2007 H1N1 HA and designed to lack the highly variable globular head domain of HA was used.8 The wild-type, membrane-bound NA from A/Michigan/45/2015 H1N1pdm (Mich15) was used to match the currently circulating seasonal influenza virus strain. Similarly, the wild-type NP from Mich15 was used, which matches the currently circulating H1N1 viruses and is overall highly conserved. To elicit immune responses against M2, a construct (based on Mich15) with the amino acid residues 29–31 deleted was used. See page 1570, right column, para 3.
According, Freyn teaches a composition for inducing a “universal” immune response against one or more influenza viruses in a subject, comprising LNPs formulated to comprise nucleoside-modified mRNA molecules encoding a HA antigen: the “Mini HA” construct based on the A/Brisbane/59/2007 H1N1 HA and designed to lack the highly variable globular head domain of HA, as well as LNPs formulated to comprise mRNA encoding other influenza virus antigens (NA, M2 or NP etc.). Freyn also teaches a method of immunizing a subject comprising administering to the subject the LNP formulations.
Therefore, based on the claims interpretation in the 112(b) rejection above, Freyn anticipates or makes obvious claims 1-2, 4, 7-11, 13 and 16-20.
Claim Rejections - 35 USC § 103
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 of this title, 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.
Claims 6 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Pardi et al. (Nat Commun 9, 3361 (2018); submitted in IDS filed on Jan. 10, 2025) and Freyn et al. (Molecular Therapy Vol. 28 No 7 July 2020, pages 1569-1584); submitted in IDS filed on Jan. 10, 2025), as applied above, in view of Zhuang et al. (Vaccines 2020, 8, 123).
These claims specify that the composition further comprises an adjuvant.
Relevance of Pardi and Freyn is described above. However, they are silent on the inclusion of an adjuvant.
Zhuang teaches a study on mRNA vaccines encoding the HA protein of Influenza A H1N1 virus delivered by cationic LNPs. Zhuang teaches that many factors can affect the efficacy of mRNA vaccines, including optimization of target genes, incorporation of UTRs, selection of delivery vectors, modification of ligands, and addition of vaccine adjuvants. See page 2, para 4.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Pardi, Freyn and Zhuang to arrive the invention as claimed. One would have been motivated to do so to evaluate how the addition of different vaccine adjuvants affects the efficacy of the vaccines of Pardi and Freyn.
Claims 3 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Pardi et al. (Nat Commun 9, 3361 (2018); submitted in IDS filed on Jan. 10, 2025) and Freyn et al. (Molecular Therapy Vol. 28 No 7 July 2020, pages 1569-1584); submitted in IDS filed on Jan. 10, 2025), as applied above, in view of Wu et al. (Cold Spring Harb Perspect Med 2020; 10: a038778) and Virk et al. (PNAS, 2020, 117(1): 619-628).
Claims 3 and 12 further specify that the nucleoside-modified RNA molecules encoding HA antigens from each of influenza A virus H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, and influenza B virus Vic and Yam.
Relevance of Pardi and Freyn is described above. However, they are silent on HA antigens from each of influenza A virus H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, and H18, and influenza B virus Vic and Yam.
Wu teaches that Influenza viruses are classified based on their antigenicity, which is determined by their surface glycoproteins. Four types of influenza viruses, A, B, C, and D, have been isolated and characterized. Based on the antigenicity of HA and NA, influenza A viruses are further classified into subtypes. There are 18 known HA subtypes (H1–H18) and 11 known NA subtypes (N1–N11). HA subtypes are further divided into two groups. Group 1 HA includes H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18, whereas group 2 HA includes H3, H4, H7, H10, H14, and H15. Both influenza A and B viruses infect humans and can cause severe illness or death. In contrast, influenza C virus only causes mild symptoms in most cases. Human infection with influenza D virus has not been observed. Therefore, most influenza research has been focused on influenza A and B viruses. See page 1.
Virk teaches that two influenza B viruses (Victoria and Yamagata) cocirculate in humans and contribute to the estimated 290,000–650,000 annual influenza-attributed deaths. The authors analysed influenza B genomic data to understand the causes of a recent surge in human influenza B infections. They found that evolution is acting differently on Yamagata and Victoria viruses and that this has led to the cocirculation of a diverse group of influenza B viruses. If this phenomenon continues, they could potentially witness the emergence of 3 or more distinct influenza B viruses that could require their own vaccine component, thereby complicating influenza vaccine formulation and highlighting the urgency of developing universal influenza vaccines. See Significance on page 619.
Accordingly, teachings of Wu and Virk indicate that influenza A viruses of type H1-18 and influenza B viruses of Victoria (Vic) and Yamagata (Yam) lineages are circulating and causing human diseases.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Pardi, Freyn, Wu and Virk to arrive the invention as claimed. One would have been motivated to do so to combine LNP-mRNA vaccine formulations against each of influenza virus types that potentially cause disease in humans.
Conclusion
No claims are allowed.
Claims 5 and 14 are objected to for depending from a rejected claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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