DETAILED ACTION
Disposition of Claims
Claims 1-44, 46-47, and 52-58 were pending. Claims 2-19, 25-27, 45, and 48-51 have been cancelled. Amendments to claims 1, 20, 22, 34-35, 37, 39, and 42 are acknowledged and entered. Claims 1, 20-24, 28-44, 46-47, and 52-58 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240238404A1, Published 07/18/2024.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Response to Arguments
Applicant's arguments filed 07/29/2026 regarding the previous Office action dated 04/30/2026 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Examiner Initiated Interview
On 09/18/2026, the Examiner contacted Applicants to propose claim amendments that would result in the allowance of the application. These amendments were not accepted. Please see attached interview summary.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/10/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Objections
(Objection withdrawn.) The objection to Claim 11 is withdrawn in light of the cancellation of said claim.
(New objection.) Claim 39 is objected to because of the following informalities: claim 39 was amended to recite ”…wherein the mRNA comprises a nucleotide sequence at least 90% sequence identity over the full length of a sequence selected from the group consisting of: (i) SEQ ID NO:2…”. It is suggested this be amended to read on “a nucleotide sequence having at least 90% sequence identity…”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 34-35 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claim 37 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
(Rejection withdrawn.) The rejection of Claim 39 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
(Rejection withdrawn.) The rejection of Claims 41 and 42 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claim 1 and dependent claims 20-24, 28-44, 46-47, and 52-58 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 1 has been amended to recite a particle comprising:
a nucleic acid wherein the nucleic acid is encapsulated by the particle and encodes a haemagglutinin (HA) protein of an influenza virus; and
a lipid comprising: a cationic lipid having the structure:
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disteraroyl phosphatidylcholine (DSPC); cholesterol; and 1,2-dimyristoyl-sn-glycero-3-methoxypolyethylene glycol (DMG-PEG). However, it is unclear whether the claim intends the term “lipid” to refer to a single lipid molecule comprising each of the subsequently recited components, or instead intends to recite a lipid particle or lipid composition comprising separate cationic lipid, DSPC, cholesterol, and DMG-PEG components. DSPC, cholesterol, the cationic lipid, and DMG-PEG are separately identifiable lipid components, and the present working therefore renders the scope of the claimed “lipid” unclear.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 1 is rejected on the grounds of being indefinite. Claims 20-24, 28-44, 46-47, and 52-58 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claim 37 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of the amendments to the claim.
(Rejection withdrawn.) The rejection of Claim 42 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of the amendments to the claim.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a particle comprising:
a nucleic acid wherein the nucleic acid is encapsulated by the particle and encodes a haemagglutinin (HA) protein of an influenza virus; and
a lipid composition comprising: a cationic lipid having the structure:
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disteraroyl phosphatidylcholine (DSPC); cholesterol; and 1,2-dimyristoyl-sn-glycero-3-methoxypolyethylene glycol (DMG-PEG).
Further limitations on the particle of claim 1 are wherein the lipid composition of the amphipathic lipid, the sterol, the cationic lipid, and the PEG lipid is amphipathic lipid: 5 to 25%, sterol: 10 to 55%, cationic lipid: 40 to 65%, and PEG lipid: 1 to 5% on a molar amount basis (claim 20), wherein the proportion of the amphipathic lipid is 10 to 25% (claim 21); wherein the lipid composition of the amphipathic lipid, the sterol, the cationic lipid, and the PEG lipid is amphipathic lipid: 5 to 15%, sterol: 35 to 50%, cationic lipid: 40 to 55%, and PEG lipid: 1 to 3% on a molar amount basis (claim 22), wherein the proportions of the amphipathic lipid, the sterol, the cationic lipid, and the PEG lipid are 10 to 15%, 35 to 45%, 40 to 50%, and 1 to 2.5%, respectively (claim 23), wherein the proportion of the PEG lipid is 1 to 2% (claim 24), wherein the ratio of the total weight of lipids to the weight of the nucleic acid is from 15 to 30 (claim 28), wherein the ratio of the total weight of lipids to the weight of the nucleic acid is from 15 to 25 (claim 29), wherein the ratio of the total weight of lipids to the weight of the nucleic acid is from 17.5 to 22.5 (claim 30); wherein the HA protein of the influenza virus is a fusion protein comprising two or more different HA proteins bound to each other by a linker (claim 31), wherein the linker comprises a protease cleavage site (claim 32); wherein the influenza virus is a type A or type B influenza virus (claim 33); wherein the influenza virus is a type A or type B influenza virus, and the HA protein comprises an amino acid sequence having an identity of at least 85% (claim 34) or at least 90% (claim 35) over the full length of an amino acid sequence selected from the group consisting of SEQ ID NOS: 20 to 24, 50, 54, and 58 (claims 34-35); wherein the nucleic acid is mRNA comprising a cap structure (Cap), a 5' untranslated region (5'-UTR), a translated region encoding the HA protein, a 3' untranslated region (3'-UTR): and a poly A tail (polyA)(claim 36), wherein the mRNA comprises a nucleotide sequence having at least 90% sequence identity over the full length of a SEQ ID NO: selected from the group of SEQ ID NOS: 2, 7, 10, 13, 16, 19, 38 to 49, and 53 (claim 37); wherein the nucleic acid is mRNA comprising a cap structure (Cap), a 5' untranslated region (5'-UTR), a translated region encoding the HA protein, and a 3' untranslated region (3'-UTR)(claim 38), wherein the mRNA comprises a nucleotide sequence having at least 90% sequence identity over the full length of a sequence selected from the group consisting of: (i) SEQ ID NO:2, (ii) nucleotides 1 to 1900 of SEQ ID NO: 7, (iii) nucleotides 1 to 1903 of SEQ ID NO: 10, (iv) nucleotides 1 to 1903 of SEQ ID NO: 13, (v) nucleotides 1 to 1957 of SEQ ID NO: 16, (vi) nucleotides 1 to 1954 of SEQ ID NO: 19, (vii) nucleotides 1 to 1903 of SEQ ID NO:38, (viii) nucleotides 1 to 1957 of SEQ ID NO: 44, and (ix) nucleotides 1 to 1906 of SEQ ID NO: 53 (claim 39); wherein the nucleic acid comprises at least one modified nucleotide (claim 40), wherein the modified nucleotide comprises at least one of a pyrimidine nucleotide substituted at the 5-position, a pseudouridine, and a pseudouridine substituted at the 1-position (claim 41), wherein the modified nucleotide comprises at least one of 5-methylcytidine, 5- methoxyuridine, 5-methyluridine, and 1-alkylpseudouridine (claim 42); wherein the particle is 30 to 300 nm in size (claim 43), and comprising a second nucleic acid encoding a second HA protein (claim 44).
Claim 46 is drawn to a composition comprising; the particle of claim 1 and a carrier.
Claim 47 is drawn to a composition comprising;
a first particle comprising the particle of claim 1; and
a second particle comprising a second nucleic acid encoding a second HA protein, wherein the second nucleic acid and the second HA protein are different than the nucleic acid and HA proteins of the first particle.
Claim 52 is drawn to a method for expressing a HA protein of an influenza virus in vitro, comprising;
introducing the composition of claim 46 into a cell, wherein the cell is grown in vitro; and
allowing the cell to express the HA protein.
Claim 53 is drawn to a method for expressing a HA protein of an influenza virus in vivo, comprising:
administering the composition of claim 46 to a mammal;
allowing the lipid particle to contact at least one cell of the mammal and introduce the nucleic acid into the cell; and
allowing the cell of the mammal to express the HA protein; wherein the mammal is human (claim 56).
Claim 54 is drawn to a method for inducing an immune reaction against an influenza virus, comprising:
administering the composition of claim 46 to a mammal, wherein the composition is a medicament;
allowing at least one cell of the mammal to express the HA protein of the influenza virus, thereby inducing an immune reaction to the influenza virus; wherein the mammal is human (claim 57).
Claim 55 is drawn to a method for preventing and/or treating infection with an influenza virus, comprising:
administering the composition of claim 46 to a mammal, wherein the composition is a medicament and the mammal is infected with or at risk of being infected by the influenza virus; wherein the mammal is human (claim 58).
Claim Rejections - 35 USC § 112(a); First Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection maintained in part- necessitated by amendment.) Claims 55 and 58 remain 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 certain prophylactic vaccination embodiments, does not reasonably provide enablement for the full scope of the claimed methods of treatment and prevention of any influenza virus infection using any of the compositions as claimed. Note the rejection is withdrawn with respect to claims 1-44, 46-47, 52-54, and 56-57 in light of the amendments to said 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 clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a method for preventing and/or treating infection with any influenza virus, comprising: administering the composition of claim 46 to a mammal, wherein the composition is a medicament and the mammal is infected with or at risk of being infected by the influenza virus; wherein the mammal is human. The composition of claim 46 is any composition comprising the particle of claim 1 and any carrier, wherein the particle of claim 1 is any particle comprising: any mRNA wherein the nucleic acid is encapsulated by the particle and encodes any haemagglutinin (HA) protein of any influenza virus; and any lipid composition comprising LP1, DSPC, cholesterol, and DMG-PEG in any amounts. The recitation of “preventing” any influenza virus infection in a subject is interpreted per the specification at ¶[0197], which interprets “prevention” as “reducing incidence of a disease caused by an infection with a virus, bacteria or the like. The prevention includes lowering the risk of progression of a disease caused by an infection with a virus, bacteria or the like, or reducing aggravation of such a disease.”
“Influenza virus” encompasses any influenza virus, of which there are four main species: Influenza A, B, C, and D virus. Influenza A and B viruses are those which mainly cause disease in humans, while influenza C can also infect humans, but usually only causes mild disease in the young or immunocompromised. Influenza A virus is further defined by its hemagglutinin (HA) and neuraminidase (NA) subtype, wherein there are 16 known HA subtypes and 11 known NA subtypes. Influenza B is mainly split into two main lineages, Victoria and Yamagata.
Any “HA protein” as of instant claim 1 is interpreted as full-length and fragments thereof of any influenza virus HA protein.
With respect to the breadth of the particle, said particle may be comprised of the four claimed lipid components at any concentration. The breadth of possible concentration ranges of each lipid within the LNP is large. Further dependent claims narrow the components of the particle down to a range, but do not identify specific species of components or smaller ranges for each particle component.
With respect to the methods of prevention/inhibition, the term “prevention” is interpreted per Applicant’s specification (¶[0197]), and is broadly drawn to inhibiting any influenza virus disease or infection through the broadly claimed administration of any type, dosage, or modality to the mammalian host. Said host is infected with or is at risk of infection from any influenza virus.
The state of the art and the predictability of the prior art, explanation of Working Examples, Guidance in the Specification, and Amount of Experimentation Necessary was set forth in a previous Office action, and will not be repeated herein.
Briefly, the specification provides evidence that administration of the disclosed mRNA-LNP compositions can induce immune responses and reduce viral burden and/or disease following subsequent influenza challenge; however, such results do not demonstrate prevention of infection itself, as distinguished from prevention or reduction of disease or symptoms resulting from infection. Indeed, the specification defines “prevention” in terms of reducing the incidence or progression of disease caused by infection rather than preventing establishment of the infection itself. The specification likewise does not demonstrate treatment of an established influenza infection by administration of the claimed mRNA-LNP composition. The relied upon studies administer the composition prophylactically or following recovery from a prior infection and therefore do not establish that the composition can prevent influenza infection or therapeutically treat an ongoing influenza infection across the scope of the claims. Accordingly, undue experimentation would be required to determine the compositions and conditions capable of achieving the claimed results, and the noted claims are not enabled across the full scope.
Response to Arguments
Applicant's arguments filed 07/29/2026 have been fully considered but they are not entirely persuasive. While the rejection is withdrawn with respect to the majority of the claims, it remains that those claims drawn to methods of treatment and/or prevention from any infection with any influenza virus remain outside the scope of what is reasonably enabled by the specification.
Applicant argues that the claims have been amended to recite a specific set of lipid constituents and to specify that the claimed particle encapsulates an mRNA encoding an HA of an influenza virus. However, these amendments define the composition being administered and do not address the lack of enablement for the full scope of the claimed functional result, namely preventing infection with any influenza virus and treating any existing influenza virus infection.
The rejection is not based on an inability of one of ordinary skill in the art to prepare the recited lipid particle, encapsulate an HA-encoding mRNA, or administer such a composition. Rather, the rejection is based on the absence of sufficient guidance demonstrating how the claimed composition may be used throughout the scope of the claims to prevent establishment of an influenza virus infection or to therapeutically treat an already established influenza virus infection. The specification demonstrates that particular HA mRNA-LNP compositions can induce immune response and can provide prophylactic protection against disease or reduce viral burden following subsequent influenza challenge. Such results do not establish prevention of infection itself, nor do they demonstrate therapeutic efficacy when the composition is administered to a subject having an ongoing influenza virus infection.
Applicant’s assertion that a skilled artisan could ascertain operable embodiments with reasonable experimentation is likewise not persuasive. The issue is not whether a skilled artisan could identify some embodiments that generate an immune response or protect against influenza-associated disease. The claims encompass preventing infection and treating established infection across the recited influenza HA embodiments, and the specification does not provide sufficient guidance regarding which HA antigens, viral strains or subtypes, doses, routes of administration, timing of administration, host conditions, or other treatment parameters would achieve these claimed results. Determining which combinations, if any, are capable of preventing establishment of any infection or therapeutically treating any ongoing influenza virus infection would require empirical screening and development beyond routine optimization of disclosed working embodiments.
Recitation of the specific lipid constituents therefore narrows one aspect of the claimed composition but does not supply the missing teaching concerning achievement of the claimed prevention and treatment results. Similarly, limiting the encapsulated nucleic acid to mRNA encoding an influenza HA does not establish that such compositions prevent infection itself or treat an already established infection throughout the scope of the claims. Accordingly, Applicant’s amendments and arguments do not overcome the scope of enablement rejection, and the rejection of claims 55 and 58 under 35 U.S.C. 112(a) is maintained.
(Rejection withdrawn.) The rejection of Claims 1-44, 46-47, and 52-58 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, is withdrawn in light of the amendments to the claims.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection maintained in part – necessitated by amendment.) Claims 1, 20-24, 28-36, 38, 40-44, 46-47, and 52-58 remain rejected under 35 U.S.C. 103 as being unpatentable over Koizumi et. al. (US20160257951A1, Pub. 09/08/2016; hereafter “Koizumi”) and
Ciaramella et. al. (US20180311336A1; Pub. 11/01/2018; hereafter “Ciaramella”) as evidenced by Liu (US20120107911A1, Pub. 05/03/2012; hereafter “Liu”.) Note the rejection of claims 2-19 and 25-27 is withdrawn in light of the cancellation of said claims.
The Prior Art
Koizumi teaches Formula Ia, which is 100% identical to Formula Ia of instant claim 1, and teaches that the R1, R2, L1, L2, and p groups may be the same as those of the cationic lipid of instant claim 1 (entire document; see abstract; reference claims 1-21). Koizumi teaches this cationic lipid may be used to encapsulate nucleic acid (¶[0005]), and teaches lipids in Examples 23 and 28 which are those LP1 ((7R,9Z,26Z,29R)-18-({[3-(Dimethylamino)propoxy]carbonyl}oxy)pentatriaconta-9,26-diene-7,29-diyl diacetate (exemplary compound 1-233)) and LP2 ((7R,9Z)-18-({[3-(Dimethylamino)propyloxy]carbonyl}oxy)octacos-9-en-7-yl acetate (exemplary compound 1-212)) of the instant application, respectively (see ¶[0318][0350] of instant PGPub). Koizumi teaches lipids with 100% structural identity to those of Formulas 2-4 (see Formula II at ¶[0052], Formula 4 at ¶[0045], and Formula 7 at ¶[0048]; ¶[0044-0054]; cationic lipid of instant claim 1). Koizumi teaches a lipid particle formulation that comprises the cationic lipid, and teaches that the composition would further comprise a sterol, an amphipathic lipid, and a PEG-lipid (¶[0057][0246-0251]; reference claims 33-50). Koizumi teaches wherein the amphipathic (neutral) lipid may be DSPC (reference claim 48), wherein the sterol may be cholesterol (reference claim 45), and wherein the PEG-lipid is PEG-DMG or PEG-C-DPA (¶[0058]; additional lipids of instant claim 1). Koizumi teaches the lipid nanoparticle (LNP) comprises 15% or less of the amphipathic lipid, 32% or more of the sterol, 45% to 65% of the cationic lipid, and 1.5% to 3% of the PEG-lipid, in terms of molar quantity, preferably a lipid particle having any ratio selected from molar ratios of amphipathic lipid:sterol:cationic lipid:lipid reducing aggregation during lipid particle formation of 10:48:40:2, 10:38:50:2, 10:33:55:2, 10:28:60:2, 15:33:50:2, 10:48.5:40:1.5, and 10:47.5:40:2.5. (¶[0071-0072]; instant claims 20-24). Koizumi teaches the LNP encapsulates a nucleic acid (reference claim 51; Example 31 at ¶[0585]), wherein the w/w ratio of total lipid/nucleic acid is 15 (0.066 RNA/lipid) to 27 (0.037 RNA/lipid; see Table 24; instant claims 28-30). Koizumi teaches pharmaceutical compositions comprising the nucleic acid lipid particle and a carrier (¶[0019-0020][0364-0367]; instant claim 46). Koizumi teaches the LNP may be used to transfer a nucleic acid to a cell in vivo or in vitro (¶[0373]) and can be administered to a human in need thereof (¶[0376]; instant claims 56-58).
Ciaramella teaches Influenza virus ribonucleic acid (RNA) vaccines, as well as methods of using the vaccines and compositions comprising the vaccines, wherein the RNA is preferably mRNA and is encapsulated in a LNP (entire document; see abstract; reference claim 1; ¶[0005-0006].) Ciaramella teaches wherein the influenza polypeptide may be hemagglutinin (HA), such as the subunits HA1 and/or HA2 (reference claims 1-2). Ciaramella teaches that the antigenic mRNA may encode a fusion protein (¶[0301]) wherein the fusion protein is bound by a linker (¶[0302]). Full-length HA (HA0) is comprised of the HA1 and HA2 subunits joined by an amino acid linker that is a critical protease cleavage site; therefore Ciaramella teaches a “fusion protein” of at least “two different HA proteins” joined by a linker with a protease cleavage site (instant claims 31-32). Ciaramella teaches the HA may be from influenza A (reference claim 6) or influenza B (¶[0589]; instant claim 33).
Ciaramella teaches the HA may be from an H1 subtype, namely A/Puerto Rico/8/34 (¶[0021]). As evidenced by Liu, PR8 (A/Puerto Rico/8/34) is a well-known H1N1 influenza A virus, and the HA sequence of said virus is 100% identical to instant SEQ ID NO: 20 (reference SEQ ID NO: 22 of Liu aligns with 100% identity over the entire sequence of instant SEQ ID NO: 20; see ABSS alignment for 13/279,253 or attached NCBI BLAST alignment for SEQ ID NO: 20 and US Pat. No. 9,060,972; instant claims 34-35.)
Ciaramella teaches the mRNA encoding the HA may comprise additional structures, such as a 5’ cap, a 3’ polyA tail, and 3’/5’ UTRs (¶[0233][0290-0294][0335]; instant claims 36, 38). Ciaramella teaches the mRNA may have modified nucleotides (¶[0269-0272]; instant claim 40), such as pseudouridine or 5-methyluridine (¶[0038]; instant claims 41-42). Ciaramella teaches the LNP may have a mean diameter of 10-500 nm, 20-400 nm, 30-300 nm, or 40-200 nm (¶[0368]; instant claim 43). Ciaramella teaches the mRNA-HA-LNP composition may be multivalent (reference claim 14; ¶[0053]), wherein the composition can comprise two or more nucleic acids encoding different HA proteins (¶[0007][0079-0080][0257-0258]; instant claim 44). Ciaramella teaches pharmaceutical compositions which comprise the mRNA-HA-LNP and a pharmaceutically-acceptable carrier (¶[0082]; instant claim 46-47). Ciaramella teaches the HA may be encoded from the mRNA in vitro or in vivo (¶[0232]; instant claims 52-53). Ciaramella teaches the mRNA-HA-LNP compositions may be used to induce immune responses against influenza HA in a subject, including humans, such as in a prophylactic or therapeutic vaccine method (¶[0306-0317]; instant claims 54-58).
Given the teachings of Koizumi, one of skill in the art would be apprised as to LNP formulations for delivery of nucleic acids, namely LNPs which comprise LP1 and LP2 of the instant claims and methods. Given the teachings of Ciaramella, one of skill in the art would be apprised as to delivering mRNA via encapsulation in LNPs, especially wherein the mRNA encodes an influenza HA protein. It would be obvious to modify the related teachings of Koizumi and Ciaramella, making the limitations of instant claim 1 obvious to a skilled artisan.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Koizumi in order to deliver mRNA via their LNPs, thereby generating an effective immunogenic composition against influenza A and/or B virus(es). One would have been motivated to do so, given the suggestion by Ciaramella that the methods and compositions of delivering influenza HA proteins via mRNA-LNP platform was taught and successful in the art. There would have been a reasonable expectation of success, given the knowledge that the cationic lipids LP1 and LP2, as taught by Koizumi, could formulate LNPs that could deliver RNA, and also given the knowledge that the HA mRNA could successfully be delivered via LNP comprised of a cationic lipid and generate a therapeutic immune response in a host, as taught by Ciaramella. 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.
Response to Arguments
Applicant's arguments filed 07/29/2026 have been fully considered but they are not persuasive.
Applicant’s arguments regarding alleged surprising and unexpected results have been considered but are not persuasive. Evidence of unexpected results must be commensurate in scope with the claims, and the relied upon results must be shown to be unexpected relative to the closest prior art. See MPEP §716.02(b), 716.02(d), and 716.02(e). Applicant has not established that the results relied upon satisfy these requirements.
Applicant first argues that the presently claimed LNP-mRNA formulations exhibit a high degree of immunogenicity, referring to Figs. 1, 9-10, 11-14, and Test Examples 1 and 7. However, these experiments concern particular mRNAs encoding particular influenza HA antigens, particular lipid compositions and molar ratios, particular doses and administration schedules, and BALB/c mice. For example, the LP1-containing particles used in the relied upon examples employ specific DSPC/cholesterol/LP1/PEG-DMG formulations, including 10/43.5/45/1.5 or 12.5/41/45/1.5 molar ratios. The claims are not limited to the particular HA sequences, strains, doses, administration schedules, experimental conditions, or, except where specifically recited in a dependent claim, the particular lipid ratios responsible for the reported results. Applicant has not provided an adequate basis for concluding that the asserted degree of immunogenicity would be obtained throughout the considerably broader scope of the pending claims. Accordingly, the relied upon evidence is not commensurate in scope with the presently drafted claims.
Furthermore, the reported immunogenicity is principally compared with an inactivated split influenza vaccine rather than with the closest prior art mRNA-LNP vaccine. Ciaramella already teaches influenza mRNA vaccines formulated in lipid nanoparticles, and expressly teaches that such vaccines produce high antibody titers, including antibody titers greater than those obtained with traditional protein or inactivated vaccines. Ciaramella therefore provides an expectation that an influenza HA mRNA formulated in an LNP would exhibit strong immunogenicity and could produce antibody responses exceeding those of a conventional protein or inactivated influenza vaccine. Applicant has not provided comparative evidence demonstrating that use of the presently claimed LP1/DSPC/cholesterol/DMG-PEG formulation produces an unexpectedly superior response relative to the closest prior art mRNA-LNP formulation. For this additional reason, comparison of the claimed formulation only with an inactivated split vaccine does not establish that the asserted immunogenicity was unexpected over the applied prior art.
Applicant additionally argues that the claimed LNP-mRNA formulations exhibit surprising cross efficacy against antigenically drifted influenza strains. The relied upon evidence, however, is limited to particular H3 vaccine and antigen-drift strains under particular experimental conditions. Test example 8 evaluates antibody binding using HA from particular H3 strains, and Test Example 9 evaluates challenge with the particular H3 antigen-drift strain A/Guizhou/54/89 following vaccination with a particular H3 LNP-mRNA formulation. These limited results do not establish that mRNAs encoding HA proteins generally, including HA proteins from the numerous influenza A subtypes and influenza B lineages encompassed by the claims, will provide a comparable degree of cross-reactivity or cross-protection against antigenically drifted viruses. Applicant has therefore not shown that the alleged cross-efficacy is commensurate in scope with the pending claims. Moreover, Ciaramella teaches influenza mRNA vaccines capable of inducing antibodies binding a diverse panel of HA proteins and specifically addresses the desirability of broader protection against antigenically diverse influenza strains. Accordingly, some degree of broader HA reactivity was already contemplated by the prior art, and Applicant has not established that the reported degree of cross-reactivity represents an unexpected result attributable to the claimed distinction over the prior art.
Applicant further argues that the LNP-mRNA formulations exhibit an unexpected degree of resistance to vaccine interference in multivalent formulations. The relied upon experiments tested a particular quadrivalent combination comprising selected H1, H3, B/Yamagata, and B/Victoria HA mRNAs formulated and administered under particular conditions. The pending claims, to the extent they encompass multivalent embodiments, are not limited to this particular combination of HA antigens, the tested relative amounts, or the tested formulation and administration conditions. The results obtained from this single defined quadrivalent combination therefore do not establish that the absence of interference extends across the full scope of multivalent embodiments encompassed by the claims. In addition, Ciaramella expressly reports that combining mRNAs encoding influenza H1 and H3 HA-derived antigens did not result in interference in the immune response to either HA. The absence of interference upon combining influenza mRNA antigens was therefore already demonstrated in the prior art and has not been shown to constitute an unexpected property of the presently claimed formulation.
Applicant also argues that the claimed LNP-mRNA formulations unexpectedly induce both humoral and cellular immunity. The cellular immune response relied upon in the present application was demonstrated using the particular A/Puerto Rico/8/34 HA mRNA formulation of Example 13, wherein HA-specific cytokine production and predominantly CD4-positive T-cell responses were observed. Applicant has not established that these results are representative of the full range of HA mRNAs and influenza antigens encompassed by the claims. More importantly, Ciaramella expressly teaches that influenza mRNA-LNP vaccines are capable of inducing a balanced immune response comprising both humoral and cellular immunity and reports antigen-specific T-cell responses following mRNA vaccination. Accordingly, induction of both antibody-mediated and cellular immune responses would have been expected from the prior art and does not establish an unexpected property sufficient to overcome the prima facie case of obviousness.
Additionally, Applicant has not adequately demonstrated that the alleged advantageous results are attributable to the feature alleged to distinguish the claims from the prior art, namely the presently recited lipid formulation comprising the claimed cationic lipid together with DSPC, cholesterol, and DMG-PEG. The cited experiments do not provide a comparative study in which the claimed formulation is compared under otherwise equivalent conditions with the closest prior art influenza mRNA-LNP formulation so as to establish that the claimed lipid composition is responsible for the asserted increase in immunogenicity, cross-reactivity, absence of interference, or cellular immune response. The evidence therefore fails to establish the required nexus between the alleged unexpected results and the claimed subject matter as distinguished from the prior art.
Applicant’s argument that one of ordinary skill in the art would not have combined the lipid of Koizumi Example 23 (LP1 of instant invention) with the influenza mRNA-LNP system of Ciaramella has been considered and is not persuasive. Contrary to Applicant’s implication, the compound of Koizumi Example 23 is not merely one untested compound selected from a large genus. Koizumi specifically prepares a nucleic acid lipid particle containing the compound of Example 23 together with DSPC, cholesterol, and a PEG lipid. Koizumi reports 99% encapsulation of siFVII using the Example 23 lipid and further demonstrates in vivo biological activity following administration to mice, wherein the resulting particle substantially inhibited Factor VII expression. Koizumi therefore provides direct evidence that the Example 23 lipid is functional as the cationic lipid of a nucleic acid lipid particle and is capable of delivering an encapsulated nucleic acid in vivo. Although Koizumi’s specific Example 23 experiment employs siRNA rather than mRNA, this does not establish that one of ordinary skill would have lacked a reasonable expectation of successfully using the lipid with mRNA. Koizumi expressly identifies mRNA as a nucleic acid suitable for its nucleic acid lipid particles and separately demonstrates successful encapsulation and expression of mRNA using the same general four component lipid particle platform comprising DSPC, cholesterol, a disclosed cationic lipid, and a PEG lipid. Accordingly, Koizumi teaches both that the presently recited Example 23 lipid functions as a nucleic acid delivery lipid and that the disclosed lipid particle technology is applicable to mRNA.
Ciaramella further teaches the specific use of mRNA encoding influenza HA in LNPs comprising an ionizable cationic lipid, DSPC, cholesterol, and a PEG lipid, including PEG-DMG. One of ordinary skill seeking to formulate Ciaramella’s influenza HA mRNA vaccine would therefore have had reason to employ other known functional ionizable lipids suitable for nucleic acid delivery, including the Example 23 lipid expressly demonstrated by Koizumi to function in a nucleic acid lipid particle. Such modification constitutes the use of a known functional cationic lipid in the same role performed by the cationic lipid of Ciaramella’s LNP.
The fact that Koizumi does not expressly exemplify the precise combination of Example 23 lipid and influenza HA mRNA does not render the proposed modification nonobvious. Obviousness does not require that the prior art have actually prepared the claimed combination, nor does reasonable expectation of success require absolute predictability. Here, Koizumi demonstrates that the Example 23 lipid successfully forms biologically active ribonucleic acid lipid particles, Koizumi further demonstrates that its lipid particle platform can encapsulate and express mRNA, and Ciaramella demonstrates that influenza HA mRNA can be successfully delivered using the same type of four component LNP system. Applicant has not identified a teaching in either reference that would have discouraged the use of the lipid of Example 23 of Koizumi for delivery of the influenza HA mRNA of Ciaramella or otherwise shown that such substitution would have been beyond the ordinary skill in the art. Therefore, this line of argument is not persuasive.
Accordingly, when the evidence is considered as a whole, Applicant’s showing is limited to particular exemplified formulations and experimental conditions, is not commensurate in scope with the pending claims, does not provide an appropriate comparison with the closest prior art, and relies in substantial part on properties already taught or reasonably expected from Ciaramella’s influenza mRNA-LNP vaccines. Applicant’s evidence of alleged unexpected results therefore does not outweigh the evidence supporting the prima facie conclusion of obviousness, and the rejection under 35 U.S.C. 103 is maintained.
Double Patenting
The text regarding nonstatutory double patenting was presented in a previous Office action.
(Rejection maintained in part – necessitated by amendment.) Claims 1, 20-24, 28-36, 38, 40-44, 46-47, and 52-58 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 and 25-29 of U.S. Patent No. 9,803,199 in view of Koizumi and Ciaramella (supra). Note the rejection of claims 2-19 and 25-27 is withdrawn in light of the cancellation of said claims. The rationale behind this rejection was set forth in a previous Office action and will not be repeated herein.
(Rejection maintained in part – necessitated by amendment.) Claims 1, 20-24, 28-36, 38, 40-44, 46-47, and 52-58 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 and 36-41 of U.S. Patent No. 10,533,176 in view of Koizumi and Ciaramella (supra). Note the rejection of claims 2-19 and 25-27 is withdrawn in light of the cancellation of said claims. The rationale behind this rejection was set forth in a previous Office action and will not be repeated herein.
Response to Arguments
Applicant's arguments filed 07/29/2026 have been fully considered but they are not persuasive.
Applicant has requested that the non-statutory obviousness-type double patenting rejection be held in abeyance until allowable subject matter is indicated in the present application. However, said rejection must be maintained as a matter of record until the appropriate terminal disclaimers have been filed, or until the claims have been amended in such a way as to not claim patently identical subject matter.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: SEQ ID NOs: 2, 7, 10, 13, 16, 19, 38, 44, and 53 appear to be novel and nonobvious.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
