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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 12, 2026 has been entered.
Summary
Claims 1, 3-4, 10, 15, 20-21, 24-25, 28-29, 33-34, 36, 38, 41, 47-48, and 54 are pending in this office action. Claims 2, 5-9, 11-14, 16-19, 22-23, 26-27, 30-32, 35, 37, 39-40, 42-46, 49-53, 55-59. All pending claims are under examination in this application.
Priority
The current application filed on October 19, 2022 is a 371 of PCT/US2021/028199 filed April 20, 2021, which in turn claims domestic priority to provisional patent application 63/012,796 all filed on April 20, 2020.
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 non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-4, 10, 15, 20-21, 24-25, 28-29, 33-34, 36, 38, 41, 47-48, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Hennessy et al. (WO2020/061284A1, published March 2020) in view of Karve et al. (US2020/0022921A1, published January 2020), Schariter et al. (WO2019/046809A1), and Muhrer et al. (WO2009/074666A1).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Hennessy et al.
Hennessy et al. is regarded as being the prior art closest to the subject-matter of the present application as it teaches PEG lipids and uses thereof (see title). Additionally, Hennessy et al. disclose PEG lipids which are useful in pharmaceutical compositions,
cosmetic compositions, and drug delivery systems, e.g, for use in lipid nanoparticle (LNP) formulations. The present disclosure also provides LNP formulations comprising PEG lipids described herein, and methods of using the same. For example, the LNPs provided herein are useful for the delivery of an agent (e.g, therapeutic agent) to a subject. The PEG lipids and LNPs provided herein, in certain embodiments, exhibit increased PEG shedding compared to existing PEG lipids and LNP formulations (see abstract).
2. Karve et al.
Karve et al. teach dry powder formulations for messenger RNA (see title). Additionally, Karve et al. disclose that the present invention provides, among other things, a dry powder (i.e., spray-dried) formulation of mRNA encapsulated with lipid- based nanoparticles for more efficient mRNA delivery and more efficacious mRNA therapy. Prior to the present invention, one of the challenges of spray-drying lipid nanoparticle-encapsulated mRNA arose from the fact that both mRNA and the lipid nanoparticle components are structurally labile at the high temperatures and/or pressures needed for adequate spray-drying. For example, an inlet temperature of a spray-dryer ranges between 80° C to 98° C. Lipids tend to melt and/or aggregate at the high inlet temperature at or near the spray nozzle. This causes hindrance to the flow of the formulation through the nozzle into the drying chamber, disrupts uniform dispersion of the spray and produces undesirable particle characteristics and poor yield. The present invention has unexpectedly solved this problem with the addition of a polymer to the mRNA and lipid nanoparticle mixture before subjecting the mixture to the spray-drying process. As described herein, the inventors observed that adding a polymer to an mRNA and lipid mixture effectively prevents aggregation of lipid nanoparticles and facilitates dry powder formation of fine particles containing mRNA-loaded lipid nanoparticles suitable for inhalation (see paragraph [0004] within Karve et al.).
3. Schariter et al.
Schariter et al. teach methods of making lipid nanoparticles (see title). In addition, Schariter et al. disclose a method of producing a nucleic acid
lipid nanoparticle composition, the method comprising: i) mixing a lipid solution comprising an ionizable lipid with a solution comprising a nucleic acid thereby forming a precursor nucleic acid lipid nanoparticle, ii) adding a lipid nanoparticle modifier comprising a modifying agent to the precursor nucleic acid lipid nanoparticle thereby forming a modified nucleic acid lipid nanoparticle, and iii) processing the precursor nucleic acid lipid nanoparticle, the modified nucleic acid lipid nanoparticle, or both thereby forming the nucleic acid lipid nanoparticle composition (see paragraph [0005] within Schariter et al.).
4. Muhrer et al.
Muhrer et al. teach organic compounds (see title). In addition, Muhrer et al. disclose a process of preparing a particulate and substantially crystalline drug substance. The process involves suspending a substantially crystalline drug substance in an anti-solvent to give a suspension, homogenizing the suspension at elevated pressure to give drug particles that have a mean particle size of less than 10 mm, and drying the drug particles to remove any residual ant-solvent (see abstract).
Combination of Hennessy et al., Karve et al., and Schariter et al.
Regarding instant claim 1, Hennessy et al., Karve et al., Kontogiannopoulos et al., Kauffman et al., and Schariter et al. teach a composition comprising one or more biologically active polynucleotide molecules and lipid nanoparticles (LNPs). The necessary citations within Hennessy et al., Karve et al., Kontogiannopoulos et al., Kauffman et al., and Schariter et al. that correspond to instant claim 1 are compiled within Table I.
Table I
Instant Claim 1
Hennessy et al., Karve et al., and Schariter et al. Citations
A composition comprising one or more biologically active polynucleotide molecules and a lipid nanoparticles (LNPs),
Hennessy et al. disclose a composition comprising biologically active polynucleotide molecules and a lipid nanoparticles (LNPs) (LNPs… useful for the delivery of an agent… e.g. therapeutic agent…to a subject, see abstract within Hennessy et al.; the biologically active agent is an mRNA, see paragraph [00134] within Hennessy et al.).
wherein the LNPs comprises at least an ionizable lipid, at least a first phospholipid,
Furthermore, Hennessy et al. disclose that the LNPs comprise of at least an ionizable lipid, at least a first phospholipid (LNP formulations comprising PEG lipids, see paragraph [0005] within Hennessy et al.)….an LNP provided herein further comprises an ionizable amino lipid, a helper lipid, and/or a structural lipid (see paragraph [0024] within Hennessy et al.); the helper lipid is a phospholipid (see paragraph [00101] within Hennessy et al.).
wherein the phospholipid is 1,2-dioleoyl-sn-gilycerophosphoethanolamine (DOPE) or dipalmitoylphosphatidylcholine (DPPC) and the LNPs comprises a molar ratio of phospholipid from about 0.15 to about 0.2,
Hennessy et al. disclose the helper lipids DOPE and DPPC (see paragraph [00105] within Hennessy et al.). Furthermore, Hennessy et al. disclose the phospholipid (helper lipid) is present in a molar ratio of about 10-40% with respect to other lipids (see claims 60-62 within Hennessy et al.).
and at least a first poly-(ethylene) glycol PEG-lipid, wherein the PEG-lipid is 1,2-dimyristoyl-sn-gilycero-3-methoxypolyethylene glycol (DMG-PEG) or
Hennessy et al. disclose that the LNPs comprise at least a first PEG-lipid (LNP formulations comprising PEG lipids, see paragraph [0005] within Hennessy et al.); an LNP formulation described herein may comprise lipids other than PEG lipids (see paragraph [0024] within Hennessy et al.).
Hennessy et al. does not disclose the phospholipid DMG-PEG. However, Schariter et al. disclose the use of DMG-PEG (see paragraph [00204] within Scharitier et al.).
wherein the LNPs comprise a molar ratio from about 0.01 to about 0.02 of the PEG-lipid and the PEG-lipid is not DSPE-PEG,
Schariter et al. disclose that in some embodiments, the nucleic acid lipid nanoparticle comprises about 40-60 mol% ionizable lipid, about 5-15 mol% phospholipid,
about 35-45 mol% structural lipid, and about 0.01-20 mol% total amount of the first PEG lipid and the second PEG lipid (see paragraph [00120] within Schariter et al.). [overlapping region].
wherein the composition is formulated for inhalation.
Hennessy et al. does not disclose where the composition is formulated for inhalation. However, Karve et al. does disclose an inhalation formulation (see paragraph [0004] within Karve et al.).
Additionally, Karve et al. is analogous art and does disclose LNPs (see paragraph [0004] within Karve et al.) comprising mRNA (see paragraph [0004] within Karve et al.), a cationic lipid (see paragraphs [0025-0027] within Karve et al.), a PEG-modified lipid (see paragraph [0028] within Karve et al.), and a non-cationic lipid (phospholipid; see paragraphs [0030-0032] within Karve et al.). Furthermore, Karve et al. disclose the use of a dry powder material (see title and paragraph [0004] within Karve et al.).
Thus, a skilled artisan (POSITA; person of ordinary skill in the art) would combine the Hennessy et al., Karve et al., and Schariter et al. references teach all the instant claim 1 limitations.
Therefore, the mRNA LNPs disclosed by Hennessy et al., along with the supported claim limitations by Karve et al., and Schariter et al. would allow a skilled artisan (POSITA) to arrive at the present invention without the addition of inventive skill.
[The remainder of the instant claims that are either directly or indirectly dependent on instant claim 1 are taught in full by the combination of Hennessy et al., Karve et al., and Schariter et al.]
Regarding instant claims 3 and 4, Hennessy et al., Karve et al., and Schariter et al. teach wherein the biologically active polynucleotide molecules comprises RNA (or mRNA). Hennessy et al. disclose that such agents may be, without limitation, nucleic acids, proteins or peptide, small organic compounds, carbohydrates and/or polysaccharides, and the like (see paragraph [00158] within Hennessy et al.). Furthermore, Hennessy et al. disclose that nucleic acids include any compound and/or substance that comprises a polymer of nucleotides. These polymers are referred to as polynucleotides. Nucleic acids may be or may include, for example, ribonucleic acids (RNAs) … (see paragraph [00161] within Hennessy et al.). Additionally, Hennessy et al. disclose where the biologically active agent is an mRNA (see paragraph [00134] within Hennessy et al.).
Regarding instant claim 10, Hennessy et al., Karve et al., and Schariter et al. teach wherein the biologically active polynucleotide molecules are encapsulated in the LNPs. For the
nanoparticle compositions described herein, the encapsulation efficiency of a therapeutic agent (nucleic acid; see instant claim 3 discussion and citations) may be at least 50%, for example 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency may be at least 80%. In certain embodiments, the encapsulation efficiency may be at least 90%. Each possibility represents a separate embodiment of the present invention (see paragraph [00153] within Hennessy et al.).
Regarding instant claim 15, Hennessy et al., Karve et al., and Schariter et al. teach wherein the LNPs comprise a molar ratio of ionizable lipid of from about 0.4 to about 0.6. Hennessy et al. disclose the following molar ratios with respect to the other lipids:
Ionizable amino lipid 25-65% (see claim 51 within Hennessay et al.)
Helper lipid (phospholipid) 10-40% (see claim 60 within Hennessay et al.)
Structural lipid (cholesterol) 30-50% (see claim 66 within Hennessay et al.)
Regarding instant claim 20, Hennessy et al., Karve et al., and Schariter et al. teach further comprising a pH buffering agent. Karve et al. disclose the use of a pH buffering agent (see paragraphs [0034], [0269-0270], and [0193]) within Karve et al.).
Regarding instant claim 21, Hennessy et al., Karve et al., and Schariter et al. teach wherein the LNPs comprise ionizable lipids, phospholipids, cholesterol, lecithin and/or poly-(ethylene) glycol (PEG)-lipid. Hennessy et al., Karve et al., Kontogiannopoulos et al., Kauffman et al., and Schariter et al. support the use of ionizable lipids, phospholipids, cholesterol, and poly-(ethylene) glycol (PEG)-lipids (see instant claims 1 and 15). Schariter et al. further disclose lipid nanoparticles may include any substance useful in pharmaceutical compositions, such as the surface-active agent and/or emulsifier (see paragraph [00426] within Schariter et al.). Schariter et al. disclose the use of surface-active agents and/or emulsifiers may include, but are not limited to, natural emulsifiers (e. g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin)… (see paragraph [00428] within Schariter et al.).
Regarding instant claim 24, Hennessy et al., Karve et al., and Schariter et al. teach wherein the composition further comprises at least a first excipient. Karve et al. disclose the use of pharmaceutically acceptable excipient (see paragraphs [0034] and [0036] within Karve et al.).
Regarding instant claims 25 and 34, Hennessy et al., Karve et al., and Schariter et al. teach wherein the first excipient comprises a sugar or sugar alcohol. Hennessy et al. disclose that in certain embodiments, the helper lipid (the phospholipid) comprises a sugar moeity (e.g., saccharide, disaccharide, polysaccharide) (see paragraph [00107] within Hennessy et al.).
Regarding instant claim 28, Hennessy et al., Karve et al., and Schariter et al. teach a nebulized composition in accordance with the composition of instant claim 1. Please see the discussion and citations within instant claim 1. Karve et al. disclose the use of a nebulized composition (see paragraphs [0047] and [0213] within Karve et al.).
Regarding instant claim 29, Hennessy et al., Karve et al., and Schariter et al. teach wherein said dry powder comprising at least a first excipient, said dry powder having been produced by spray drying, spray freeze drying, or freeze drying. Karve et al. disclose the production of dry powders via spray drying (see paragraph [0004] within Karve et al.). Instant claims 20 and 24-25 support the use of an excipient within the composition.
Regarding instant claim 36, Hennessy et al., Karve et al., and Schariter et al. teach wherein first excipient comprises lactose, trehalose, sucrose, mannitol or sorbitol. Karve et al. disclose that a suitable sugar is lactose and/or mannitol. In some embodiments, a suitable sugar is mannitol. In some embodiments, the mannitol is added at a concentration of about 1-10%. In some embodiments, the mannitol is added at a concentration of about 2-10%. In some embodiments, the mannitol is added at a concentration of about 3-10%. In some embodiments, the mannitol is added at a concentration of about 4-10%. In some embodiments, the mannitol is added at a concentration of about 5-10% (see paragraph [0170] within Karve et al.).
Regarding instant claims 38 and 41, Hennessy et al., Karve et al., and Schariter et al. teach the dry powder of instant claim 29, wherein the first excipient comprises about 50%-99.5% of the powder by weight. Both Hennessy et al. and Karve et al. add additional components (excipients) to their LNPs (see instant claims 20, 24-25, 29, and 36). However, Schariter et al. disclose that one or more excipients or accessory ingredients may make up greater than 50% of the total mass or volume of a pharmaceutical composition including an LNP. For example, the one or more excipients or accessory ingredients may make up 50%, 60%, 70%, 80%, 90%, or more of a pharmaceutical convention (see paragraphs [00426] and [00450] within Schariter et al.).
Regarding instant claim 47, Hennessy et al., Karve et al., and Schariter et al. teach an inhaler comprising the composition of instant claim 1. Please see the discussion and citations within instant claim 1 (Table I). Karve et al. disclose the use of their dry powder for inhalation purposes (see paragraph [0004]; supports manufacture of an inhaler; within Karve et al.).
Regarding instant claim 48, Hennessy et al., Karve et al., and Schariter et al. teach wherein the inhaler is a fixed dose combination inhaler, a single dose dry powder inhaler, a multi-dose dry powder inhaler, multi-unit dose dry powder inhaler, a metered dose inhaler, or a pressurized metered dose inhaler. Karve et al. disclose the use of a metered dose inhaler within the Background Section (see paragraph [0003] within Karve et al.). Therefore, a skilled artisan (POSITA) synthesizing mRNA-loaded nanoparticles suitable for inhalation (see paragraph [0004] within Karve et al.) would prepare either a fixed dose combination inhaler, a single dose dry powder inhaler, a multi-dose dry powder inhaler, multi-unit dose dry powder inhaler, a metered dose inhaler, or a pressurized metered dose inhaler or combination thereof (all known in the art).
Regarding instant claim 54, Hennessy et al., Karve et al., and Schariter et al. teach a method treating a lung disease, lung injury or lung infection comprising administering an effective amount of a composition instant claim 1 to a subject. Karve et al. disclose the method of treating a disease or disorder by administration of the mRNA-loaded nanoparticles selected from cystic fibrosis; asthma; COPD; emphysema; primary ciliary dyskinesia (CILD1) with or without situs inversus, or Kartagener syndrome; pulmonary fibrosis; Birt-Hogg-Dube syndrome; hereditary hemorrhagic telangiectasia; alpha-1 antitrypsin deficiency; Cytochrome b positive granulomatous diseases (CGD, X-lined); Cytochrome b positive granulomatous diseases, autosomal recessive; surfactant deficiency diseases, Pulmonary Surfactant Metabolism Dysfunction 1, Pulmonary Surfactant Metabolism Dysfunction 2, Pulmonary Surfactant Metabolism Dysfunction 3; Respiratory distress syndrome of prematurity; tuberculous tuberculosis, lung viral diseases, including influenza, Respiratory Syncytial Virus (RSV) (see paragraph [0049] within Karve et al.).
Combination of Hennessy et al., Karve et al., Schariter et al. and Muhrer et al.
Regarding instant claim 33, Hennessy et al., Karve et al., Schariter et al. and Muhrer et al. teach the dry powder of instant claim 29, wherein the powder has a surface area of about 2.0 to 8.5 m2/g. While Karve et al. does disclose a dry powder and they do discuss surface area (see paragraph [0181] within Karve et al.), Karve et al. does not disclose a specific surface area of the LNP defined in m2/g.
However, Muhrer et al. does disclose that nanoparticles are produced on a large scale with the help of high-pressure homogenization (HPH) technology (see page 4, paragraph 3 within Muhrer et al.). Furthermore, Muhrer et al. disclose the size of the substantially crystalline drug substance (glycopyrrolate) is less than 10 mm (see page 4, paragraph 2 within Muhrer et al.). Moreover, Muhrer et al. disclose that the spray dried glycopyrrolate is examined by scanning electron microscopy (SEM), and laser light diffraction (LLD) and does not reveal any significant change in particle size and shape upon spray drying compared to the material in suspension directly after high pressure homogenization. Particles still appear as rectangularly shaped fragments with smoothed edges and an average size around or slightly above 1 μm. The specific surface area of the dried suspension (analysed by adsorption analysis, BET surface measurement) is determined to be 4.0 m2/g (see page 12, paragraph 2 within Muhrer et al.).
The Examiner acknowledges that the glycopyrrolate is not a nanoparticle, but the diameter is similar. Therefore, the surface area defined within Muhrer et al. is analogous art, based on the size. Therefore, a skilled artisan (POSITA) following the protocol outlined within the teachings of Hennessy et al. and Karve et al. would obtain within the desired claim limitation range (surface area) using the Muhrer et al. disclosure.
Analogous Art
The Hennessy et al., Karve et al., Schariter et al. and Muhrer et al. disclosures are all relevant for the rejection of instant claims 1, 3-4, 10, 15, 20-21, 24-25, 28-29, 33-34, 36, 38, 41, 47-48, and 54 due to their direct application to the present invention.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the mRNA LNP for inhalation purposes disclosed by Hennessy et al., using the teachings of Karve et al., Schariter et al. and Muhrer et al. to incorporate the necessary claim limitations. Starting with Hennessy et al., the skilled person only had to try the addition of the necessary claim limitations disclosed by Karve et al., Schariter et al. and Muhrer et al. The combination of Hennessy et al., Karve et al., Schariter et al. and Muhrer et al. would allow one to arrive at the present application without employing inventive skill. This combination of the mRNA LNP for inhalation purposes taught by Hennessy et al. along with the use of the necessary claim limitations taught by Karve et al., Schariter et al. and Muhrer et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the mRNA LNP for inhalation purposes disclosed by Hennessy et al. with the use of the claim limitations taught by Karve et al., Schariter et al. and Muhrer et al. This combined modification would have led to an enhanced mRNA LNP for inhalation purposes that would be beneficial for patients.
Response to Arguments
Applicant's arguments filed February 12, 2026 have been fully considered but they are not persuasive.
The Applicant’s claim amendments were sufficient to address the claim objections.
Therefore, the claim objections from the Final office action dated September 12, 2025 are withdrawn.
The Applicant’s claim amendments did prompt the Examiner to necessitate a new ground of rejection.
Applicant Argument: The Applicant argues that the instant claim 1 amendments have significantly limited the phospholipids.
Examiner’s Rebuttal: The references of record, namely, Hennessy et al., Karve et al., Schariter et al. and Muhrer et al., teach both the phospholipids and the molar ratio range relative to the other lipids within the LNP. Despite the fact that no specific examples within Hennessy et al. disclose the molar ratio cited within instant claim 1, the specification does teach a range which encompasses the molar ratios (see Table I). This disclosure makes the instant claim 1 limitations obvious to a skilled artisan (POSITA).
Therefore, the 35 U.S.C. 103 rejection is maintained for instant claims 1, 3-4, 10, 15, 20-21, 24-25, 28-29, 33-34, 36, 38, 41, 47-48, and 54.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615