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 .
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-9, 11-14, and 18-20 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.
The claims recite “in accordance with” a previous claim. The metes and bounds of “in accordance with” are not definite. It is unclear whether the claim language is intended to require all of the limitations of the base claim or if a different requirement is intended. For claim 2, for example, recitation of “The suspension formulation of claim 1, wherein…”, is suggested.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-14 and 18-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Pharmaceutics, 12(11), 1-16, 1042, 2020), further in view of Yan et al. (Biomaterials 118 (2017) 84-93), Sanchez-Arribas et al. (Pharmaceutics 2020, 12, 791, 1-22), Dohmen et al. (WO 2014/207231 A1), and Freag et al. (International Journal of Nanomedicine, 11, 4799-4818, 2016).
The Yan et al. reference is of record and cited on the IDS filed on 8/18/23.
Zhang et al. teach: The development of a stable and efficacious mRNA pulmonary delivery system would enable high therapeutic concentrations locally in the lungs to improve efficacy and limit potential toxicities. In this study, we employed a Design of Experiments (DOE) strategy to screen a library of lipid nanoparticle compositions to identify formulations possessing high potency both before and after aerosolization. Lipid nanoparticles (LNPs) showed stable physicochemical properties for at least 14 days of storage at 4 ◦C, and most formulations exhibited high encapsulation efficiencies greater than 80%. Generally, upon nebulization, LNP formulations showed increased particle size and decreased encapsulation efficiencies. An increasing molar ratio of poly-(ethylene) glycol (PEG)-lipid significantly decreased size but also intracellular protein expression of mRNA. We identified four formulations possessing higher intracellular protein expression ability in vitro even after aerosolization which were then assessed in in vivo studies. It was found that luciferase protein was predominately expressed in the mouse lung for the four lead formulations before and after nebulization. This study demonstrated that LNPs hold promise to be applied for aerosolization-mediated pulmonary mRNA delivery (abstract).
Zhang et al. teach an aqueous suspension for aerosol formulation comprising lipid nanoparticles comprising mRNA (page 3, 2.2.1; and page 4, 2.2.5). wherein the lipid nanoparticle comprises an ionizable lipid, Dlin-MC3-DMA, phospholipid, cholesterol, and PEG-lipid, wherein the prepared lipid nanoparticles were dialyzed into an aqueous PBS solution (2.1, 2.2.1, and 3.1) (instant claims 1 and 4).
Zhang et al. teach that the LNP composition comprises 50% Dlin-MC3-DMA, 10% DSPC, 38.5% cholesterol, and 1.5% PEG-DMG, which meets the limitations of instant claim 5.
Zhang et al. does not teach the concentration of claim 8. However, Freag et al. teach aqueous lipid-based nanoparticle dispersions comprising Pluronic F-127 (poloxamer 407), a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, at a concentration of .5% w/v (Materials and Methods). Freag et al. teach that a concentration of .5% w/v provided satisfactory nanoparticle dispersibility and was selected as the preferred concentration for subsequent experimentation. It would have been obvious to employ this concentration of Pluronic F-127 in the formulation of Zhang et al. , modified by Yan et al., because Freag et al. demonstrate that is concentration is effective for stabilizing aqueous lipid-based nanoparticle dispersions. The selection would have represented the application of a known stabilizer at a concentration demonstrated to provide dispersibility, with a reasonable expectation of success of obtaining a stable aqueous solution (instant claim 8).
Zhang et al. teach aerosolizing the lipid nanoparticle formulations using a nebulizer and demonstrate than certain formulations retain intracellular protein expression activity following nebulization (2.2.5, 3.2, and 3.3) (instant claims 9, 13, and 14).
Zhang et al. teaches nebulizing the lipid nanoparticle formulations and delivery to lungs of mice (instant claim 14). Additionally, claim 14 recites intended use of the composition rather than an additional structural requirement.
Zhang et al. teach aerosolization of aqueous suspensions comprising lipid nanoparticles containing mRNA and an ionizable lipid, Dlin-MC3-DMA. The nebulization of such aerosol suspensions produces aerosol droplets dispersed in a gas phase (instant claim 10).
Zhang et al. teaches that before nebulization the lipid nanoparticle formulations had a particle diameter ranging from 35.7-120.9 nm (3.2 and Figure S2a) and post-nebulization ranges from 100.9 to 1480.7 nm across different formulations (instant claim 12).
Zhang et al. does not teach that the aqueous vehicle solution comprising a triblock copolymer which contains one poly(propylene oxide) block and two poly(ethylene oxide) blocks.
However, it would have been obvious to incorporate a triblock copolymer which contains one poly(propylene oxide) block and two poly(ethylene oxide) blocks because Yan et al. teach aerosol delivery of nucleic acid containing nanoparticles stabilized with Pluronic F-127, an amphiphilic copolymer which contains one poly(propylene oxide) block and two poly(ethylene oxide) blocks (2.2 and 3.4). Yan et al. teach incorporating Pluronic F-127 during preparation of the nanoparticles to reduce surface charge and improve nanoparticle stability. Yan et al. demonstrate the suitability of the stabilized nanoparticle formulations for administration of nucleic acids to the lungs (instant claims 1 and 10).
Yan et al. tech the structure PEO101-PPO56-PEO101 (2.1, materials) (instant claim 7). Yan et al. teach using Pluronic F-127 as a stabilizing agent for nucleic acid containing nanoparticles at amounts of 5 or 10% by weight relative to the polymer carrier (3.4 and 5).
Yan et al. teach a method of treating orthotopic lung tumors in mice via delivery of the F-127 nanoparticle composition comprising a siRNA targeted to Cy5.5 via aerosol mist using a nebulizer.
It would have been obvious to one of ordinary skill in the art to incorporate Pluronic F-127, as taught by Yan et al., into the aqueous aerosol formulation of ionizable lipid nanoparticles taught by Zhang et al. with the motivation of improving nanoparticle instability associated with aerosolization, including increased particle size and reduced nucleic acid encapsulation efficiency following nebulization because Yan et al. demonstrate that Pluronic F-127 can be employed as a stabilizing agent for nucleic acid containing nanoparticles intended for aerosol delivery.
There would have been a reasonable expectation of success that Pluronic F-127 could provide a stabilizing effect to the composition of Zhang et al. because each were utilized for enhanced nucleic acid delivery via aerosol and the benefits are taught by Yan et al.
Additionally, Sanchez-Arribas et al. teach incorporation of Pluronic-F127 into a lipoplex preparation for delivery of nucleic acids. Therefore, it was known to incorporation Pluronic-F127 specifically into a lipid formulation.
Zhang et al. teach preparing the LNP formulation using mRNA concentration of 10 ng/uL, which converts to .01 mg/mL (instant claim 2).
Zhang et al. teaches characterization of the particle size of the aerosolizable nucleic acid containing lipid nanoparticles before and after nebulization (sections 2.2 and 3.2). Zhang et al. teach measuring the nanoparticle hydrodynamic size using a Zetasizer Nano Zs (2.2) (instant claims 3 and 20). These claims recite an outcome of a test rather than a specific structural requirement. In absence of the patent office performing the test, the particles of Zhang et al. appear to meet the structural requirements of the claims.
Zhang et al. does not teach the specific structure of instant claim 6. However, it would have been obvious to incorporate the ionizable lipidoid of instant claim 6 because Dohmen et al. teach ionizable lipidoids comprising oligo(alkylene amine) backbones having the structure of formula IV including preferred embodiments IVa-IVc, wherein the nitrogen atoms can be protonated to provide positively charged lipidoids capable of complexing and protecting RNA.
Dohmen et al. teaches formulating these lipidoids with mRNA and additional lipid components, including phospholipids, cholesterol, and PEG-conjugated lipids, to form nanoparticles for intracellular delivery of RNA (Examples 12 and 16-20, C12-(2-3-2) lipidoids in RNA delivery formulations).
It would have been obvious to one of ordinary skill in the art to employ the ionizable lipidoid of Dohmen et al. into the formulation of Zhang et al., modified with Pluronic F-127 of Yan et al., with the motivation of successful nucleic acid delivery and effective facilitation of intracellular nucleic acid delivery, as taught by Dohmen et al. It would have been a matter of design choice to utilize the lipid of Zhang et al. or the lipidoid of Dohmen et al. given that each were known to successfully delivery nucleic acids.
Dohmen et al.t each administration by aerosolization or nebulization or oral administration. Dohmen et al. teach: The experiment shows that mRNA is effectively expressed in the lung cells of mice upon pulmonary aerosol delivery as a combination with PAA20k-(2-3-2), indicating that the polymer is able to efficiently transport the mRNA into lung cells in vivo (cf. figure 7) (Example 5).
The specific triblock copolymer of Yan et al. (PEO101-PPO56-PEO101) does not meet the limitations of instant claims 18 and 19). However, the claims are directed to a range for each component wherein each component can vary substantially. The amount of each component is considered to be a result effective variable subject to routine optimization.
It would have been obvious as a matter of design choice to select the number of PEO blocks to be between 50-100 or 60-90 as recited in instant claims 18 and 19 because Yan et al. teaches that F-127 comprising PEO subunits (PEO101-PPO56-PEO101; Pluronic F-127, Mw=12,600,PDI=1.05) reduced the surface charge of the NPs resulting in an increase in serum stability (abstract) (instant claims 18 and 19). F-127 has PEO repeats of approximately 101 and PPO repeats of approximately 56. Selection of the quantity of each type of the blocks is considered to be a matter of design choice given that the combination was known and the benefits of the combination were known.
Conclusion
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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