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 .
Application Status
The preliminary amendments filed 04 April 2024 are acknowledged and have been entered. Claims 3-4, 6-8, 10-15, and 18 are amended. Claims 1-20 are pending and being examined on the merits.
Information Disclosure Statement
The information disclosure statement filed 9/16/2024 has been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 90-91. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term Thermo Scientific and Malvern, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because of the following informalities:
Paragraphs [0260]–[0262] and [0265]–[0267] describe lipid quantities as a “molar amount” while also expressing those quantities as “% w/w relative to the total weight.” Molar percentages and weight percentages are different measures. The express weight basis in claims 6, 9, and 11 is used for the present examination; it is not silently replaced with a molar basis.
Paragraph [0532] lists lipid masses and solvent volumes that do not readily reconcile with its stated 20 mg/mL concentration.
Appropriate correction is required.
Claim Objections
Claims 2, 4, 7, 11, and 13–15 and 20 are objected to because of the following informalities:
Claim 2: Replace “a ultrasonic spray nozzle” with “an ultrasonic spray nozzle.”
Claim 4: Replace “said method comprises” with “said method comprising” or “wherein said method comprises.”
Claim 7: Clarify “the sterol, or an ester thereof” by using terminology consistent with “a steroid alcohol, or an ester thereof” in claim 1.
Claim 11: Insert “or” between the 46.3/9.4/42.7/1.6 formulation and the following 47.4/10/40.9/1.7 formulation.
Claim 13: Replace “an messenger RNA” with “a messenger RNA” and “interference RNA” with “interfering RNA.” Revise the introductory language to identify the listed RNAs and combinations thereof as alternatives.
Claims 14 and 20: Replace “an hormone” with “a hormone.”
Claim 15: Replace “the liquid composition comprising said LNPs comprise a cryoprotectant” with “the liquid composition comprising said LNPs comprises a cryoprotectant.”
Appropriate correction is required.
Claim Interpretation
Claims 1–17 are interpreted to require freezing, or where expressly recited freeze-drying, of the specified nucleic-acid-containing lipid nanoparticles. The claims do not require a specified improvement in storage stability, a minimum retained encapsulation percentage, a particular duration of storage, or a minimum level of expression after reconstitution. Such results described in the specification are not imported into the claims. Claim 1 does not require PEG-lipid or a cryoprotectant; those limitations first appear in claims 8 and 15, respectively. The “and/or” language in claim 6 permits satisfaction of one or more of its three lipid-percentage alternatives, consistently with the definition in paragraph [0094]. The percentages in claims 6, 9, and 11 are interpreted as weight percentages of total lipid components, as expressly stated in those claims.
Claim 18 is a product-by-process claim to freeze-dried LNPs obtainable by the method of claim 4. Patentability is evaluated on the claimed product, including any structural characteristics imparted by the recited process. Claim 19 additionally requires a micropellet form. Paragraph [0108] describes micropellets as generally spherical or round particles in the micrometer range and gives optional diameter embodiments.
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 7 and 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.
Regarding claim 7. the phrases “the ionizable cationic lipid is selected from the group comprising” and “the neutral lipid is selected from the group comprising” define open-ended Markush groups, rendering unclear which additional alternatives are encompassed. Applicant should replace “comprising” with “consisting of” in each selection group or otherwise clearly define the intended alternatives.
Regarding claim 7, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 20 recites “Freeze-dried LNPs according to claim 15.” However, claim 15 is directed to a method of freezing the liquid droplets of claim 1 in which the liquid composition comprises a cryoprotectant; it does not define freeze-dried LNPs or require a drying step. It is therefore unclear whether claim 20 is intended to define a product by the freezing process and cryoprotectant limitation of claim 15, followed by an additional drying operation, or instead to depend from one of the freeze-dried-product claims, such as claim 18 or claim 19. These readings impose different limitations, including whether the cryoprotectant limitation and/or the micropellet limitation is required. Applicant is required to clarify the intended relationship to the referenced claim so that the scope of claim 20 can be determined.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1–4, 7, 8, 10, 12, 13, 15, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suzhou (CN 112843019 A).
Regarding claim 1, Suzhou discloses preparing mRNA-containing LNPs using DLin-MC3-DMA, DSPC, cholesterol, and PEG-DSPE. DLin-MC3-DMA provides the claimed cationic ionizable lipid, DSPC provides the neutral lipid, cholesterol provides the steroid alcohol, and mRNA provides the nucleic acid. The lipids are dissolved in ethanol, mixed with mRNA in an aqueous citrate buffer using microfluidics, and subjected to tangential-flow removal of ethanol to obtain an mRNA-containing LNP solution. This solution is combined with an aqueous excipient solution, sprayed through a three-fluid spray device into a freezing spray tower operated at −60°C, and freeze-dried to form nucleic-acid LNP dry powder. [Example 9; p. 7].
Regarding claim 2, Suzhou discloses using a three-fluid spray device with compressed air at 0.3 MPa for that same formulation and process. This is pneumatic atomization and satisfies the pneumatic-nozzle alternative of claim 2 [Example 9, p. 7].
Regarding claim 3, the liquid composition is sprayed into a freezing spray tower operated at −60°C, thereby freezing the droplets in the cold gaseous environment of the tower and satisfying the cryogenic-atmosphere alternative. [Example 9; p. 7].
Regarding claim 4, Suzhou additionally freeze-dries the sprayed formulation to obtain nucleic-acid LNP dry powder. The method therefore includes the freezing method of claim 1 and the subsequent drying of the frozen droplets to obtain freeze-dried LNPs [Example 9; p. 7].
Regarding claim 7, the disclosed DLin-MC3-DMA, DSPC, and cholesterol correspond to expressly listed alternatives for the ionizable cationic lipid, neutral lipid, and sterol, respectively [Example 9; p. 7].
Regarding claim 8, the same LNP formulation contains PEG-DSPE, which is a PEG-lipid [Example 9; p. 7].
Regarding claim 10, PEG-DSPE is a PEGylated phosphatidylethanolamine and therefore falls within the expressly recited PEG-PE alternative [Example 9; p. 7].
Regarding claims 12 and 13, the nucleic acid in Example 9 is mRNA [Example 9; p. 7].
Regarding claim 15, Example 8 discloses DLin-MC3-DMA/DSPC/cholesterol/PEG-c-DMA LNPs containing RNA, with lactose and mannitol added to the aqueous LNP composition before spraying through a two-fluid device into a −85°C freezing spray tower and freeze-drying. Lactose and mannitol provide the cryoprotectant limitation [Example 8; p. 6].
Regarding claim 18, the freeze-dried mRNA-containing LNP product obtained in Example 9 is produced by the method mapped above to claim 4 and contains the required ionizable lipid, neutral lipid, sterol, and nucleic acid [Example 9; p. 7].
Claims 1, 4, 6-9, 12, 14-15, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rauch (WO 2021/156267 A1, published August 12, 2021).
Regarding claim 1, 4, 7-8 12, and 15, Rauch discloses RNA-containing LNPs comprising the ionizable cationic lipid ALC-0315, the neutral lipid DSPC, cholesterol, and the PEG-lipid ALC-0159, including a formulation with a lipid molar ratio of approximately 50:10:38.5:1.5 [p. 101, lines 1–28]. Rauch provides an aqueous preparation procedure in which an ethanolic lipid solution is mixed with an aqueous mRNA solution, followed by removal of ethanol and buffer exchange [p. 187, section 1.4; p. 188, first full paragraph]. Rauch expressly teaches spray-freeze drying compositions comprising these LNPs to obtain temperature-stable dried compositions and identifies trehalose as a preferred lyoprotectant (i.e., cryoprotectant as it protects biomolecular structures) [p. 106, lines 13–30]. Spray-freeze drying entails atomizing the liquid feed into droplets, freezing the droplets, and drying the frozen material. Thus, the spray-freeze-drying embodiment directly supplies the liquid LNP composition, spraying, and freezing required by claim 1; the additional drying is permitted by the open-ended claim.
Regarding claim 6, the disclosed molar composition also falls within the claimed broad weight-percentage alternatives when converted on the proper basis. Weight percentage is calculated as 100(nᵢMᵢ)/Σ(nⱼMⱼ), where n is relative molar amount and M is molecular weight. For ALC-0315/DSPC/cholesterol/ALC-0159 at 50:10:38.5:1.5, using approximately 766.3, 790.15, and 386.65 g/mol for the first three components and Rauch’s disclosed approximately 2,000–3,000 g/mol PEG-lipid molecular-weight range, the respective weight percentages are approximately 58.4–59.8%, 12.0–12.3%, 22.7–23.2%, and 4.7–6.9%. Consequently, the first three components satisfy, respectively, the 20–60%, 5–50%, and 20–55% alternatives of claim 6 [p. 99, lines 1–4; p. 101, lines 18–28; p. 188, Table A, structures and mass information].
Regarding claim 9, the same calculation establishes approximately 4.7–6.9% PEG-lipid by weight of total lipid, within the expressly recited 0.5–15% alternative [p. 99, lines 1–4; p. 101, lines 18–28].
Regarding claim 14, Rauch’s mRNA encodes coronavirus spike antigen. The antigen-encoding mRNA is formulated into the disclosed LNPs, which may be spray-freeze dried as explained above. It therefore satisfies the antigen alternative of the therapeutic-agent limitation [p. 187, Table 4 and section 1.4; p. 188, first full paragraph; p. 106, lines 13–30].
Regarding claim 20, Rauch discloses freeze-dried LNPs comprising ionizable cationic lipid, neutral lipid, cholesterol, PEG-lipid, and antigen-encoding mRNA, and teaches the use of trehalose lyoprotectant with drying of its LNP compositions [p. 101, lines 1–28; p. 106, lines 13–30; p. 187, section 1.4; p. 188, first full paragraph].
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, 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.
Claims 1–5, 7, 8, 10, 12, 13, 15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Suzhou (CN 112843019 A) in view of Wang (Wang et al., International Journal of Pharmaceutics 424 (2012), 98–106).
Regarding claim 1, Suzhou discloses preparing mRNA-containing LNPs using DLin-MC3-DMA, DSPC, cholesterol, and PEG-DSPE. DLin-MC3-DMA provides the claimed cationic ionizable lipid, DSPC provides the neutral lipid, cholesterol provides the steroid alcohol, and mRNA provides the nucleic acid. The lipids are dissolved in ethanol, mixed with mRNA in an aqueous citrate buffer using microfluidics, and subjected to tangential-flow removal of ethanol to obtain an mRNA-containing LNP solution. This solution is combined with an aqueous excipient solution, sprayed through a three-fluid spray device into a freezing spray tower operated at −60°C, and freeze-dried to form nucleic-acid LNP dry powder. [Example 9; p. 7].
Regarding claim 2, Suzhou discloses using a three-fluid spray device with compressed air at 0.3 MPa for that same formulation and process. This is pneumatic atomization and satisfies the pneumatic-nozzle alternative of claim 2 [Example 9, p. 7].
Regarding claim 3, the liquid composition is sprayed into a freezing spray tower operated at −60°C, thereby freezing the droplets in the cold gaseous environment of the tower and satisfying the cryogenic-atmosphere alternative. [Example 9; p. 7].
Regarding claim 4, Suzhou additionally freeze-dries the sprayed formulation to obtain nucleic-acid LNP dry powder. The method therefore includes the freezing method of claim 1 and the subsequent drying of the frozen droplets to obtain freeze-dried LNPs [Example 9; p. 7].
Regarding claim 7, the disclosed DLin-MC3-DMA, DSPC, and cholesterol correspond to expressly listed alternatives for the ionizable cationic lipid, neutral lipid, and sterol, respectively [Example 9; p. 7].
Regarding claim 8, the same LNP formulation contains PEG-DSPE, which is a PEG-lipid [Example 9; p. 7].
Regarding claim 10, PEG-DSPE is a PEGylated phosphatidylethanolamine and therefore falls within the expressly recited PEG-PE alternative [Example 9; p. 7].
Regarding claims 12 and 13, the nucleic acid in Example 9 is mRNA [Example 9; p. 7].
Regarding claim 15, Example 8 discloses DLin-MC3-DMA/DSPC/cholesterol/PEG-c-DMA LNPs containing RNA, with lactose and mannitol added to the aqueous LNP composition before spraying through a two-fluid device into a −85°C freezing spray tower and freeze-drying. Lactose and mannitol provide the cryoprotectant limitation [Example 8; p. 6].
Regarding claim 18, the freeze-dried mRNA-containing LNP product obtained in Example 9 is produced by the method mapped above to claim 4 and contains the required ionizable lipid, neutral lipid, sterol, and nucleic acid [Example 9; p. 7].
Regarding claim 5, Suzhou discloses the method of claim 4 as set forth above, including atomizing a nucleic-acid-containing LNP liquid composition in a freezing spray tower and freeze-drying the formulation to produce LNP dry powder.
Suzhou does not expressly identify the drying apparatus in Example 9 as one carried out by rotary drum vacuum lyophilization, atmospheric drying with a flow of cold air, vacuum chamber lyophilization, or vacuum tunnel lyophilization.
Wang discloses spray-freeze drying nanoparticle formulations by atomizing a feed into liquid nitrogen and subsequently lyophilizing the frozen droplets at −52°C and 0.05 mbar for 24 hours in an Alpha 1-2 LD Plus freeze dryer. This supplies vacuum-chamber lyophilization of previously frozen droplets [p. 100, section 2.2.3, left column, final paragraph, continuing at the top of the right column].
It would have been obvious before the effective filing date to perform Suzhou’s drying step using the vacuum-chamber lyophilization taught by Wang, because both references concern recovering lipid-containing nanoparticles as dry powders after spray freezing, and Wang supplies a known implementation for removing solvent from the frozen droplets. The modification uses the chamber dryer for its established sublimation function to complete the drying operation already required by Suzhou. A skilled artisan would reasonably have expected to obtain freeze-dried LNP-containing powder by adjusting drying conditions for the formulation.
Claims 1, 4, 6-9, 11-12, 14-15, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Rauch et al., WO 2021/156267 A1, in view of Kauffman (Kauffman et al., Nano Letters 15 (2015), 7300–7306).
Regarding claim 1, 4, 7-8 12, and 15, Rauch discloses RNA-containing LNPs comprising the ionizable cationic lipid ALC-0315, the neutral lipid DSPC, cholesterol, and the PEG-lipid ALC-0159, including a formulation with a lipid molar ratio of approximately 50:10:38.5:1.5 [p. 101, lines 1–28]. Rauch provides an aqueous preparation procedure in which an ethanolic lipid solution is mixed with an aqueous mRNA solution, followed by removal of ethanol and buffer exchange [p. 187, section 1.4; p. 188, first full paragraph]. Rauch expressly teaches spray-freeze drying compositions comprising these LNPs to obtain temperature-stable dried compositions and identifies trehalose as a preferred lyoprotectant (i.e., cryoprotectant as it protects biomolecular structures) [p. 106, lines 13–30]. Spray-freeze drying entails atomizing the liquid feed into droplets, freezing the droplets, and drying the frozen material. Thus, the spray-freeze-drying embodiment directly supplies the liquid LNP composition, spraying, and freezing required by claim 1; the additional drying is permitted by the open-ended claim.
Regarding claim 6, the disclosed molar composition also falls within the claimed broad weight-percentage alternatives when converted on the proper basis. Weight percentage is calculated as 100(nᵢMᵢ)/Σ(nⱼMⱼ), where n is relative molar amount and M is molecular weight. For ALC-0315/DSPC/cholesterol/ALC-0159 at 50:10:38.5:1.5, using approximately 766.3, 790.15, and 386.65 g/mol for the first three components and Rauch’s disclosed approximately 2,000–3,000 g/mol PEG-lipid molecular-weight range, the respective weight percentages are approximately 58.4–59.8%, 12.0–12.3%, 22.7–23.2%, and 4.7–6.9%. Consequently, the first three components satisfy, respectively, the 20–60%, 5–50%, and 20–55% alternatives of claim 6 [p. 99, lines 1–4; p. 101, lines 18–28; p. 188, Table A, structures and mass information].
Regarding claim 9, the same calculation establishes approximately 4.7–6.9% PEG-lipid by weight of total lipid, within the expressly recited 0.5–15% alternative [p. 99, lines 1–4; p. 101, lines 18–28].
Regarding claim 14, Rauch’s mRNA encodes coronavirus spike antigen. The antigen-encoding mRNA is formulated into the disclosed LNPs, which may be spray-freeze dried as explained above. It therefore satisfies the antigen alternative of the therapeutic-agent limitation [p. 187, Table 4 and section 1.4; p. 188, first full paragraph; p. 106, lines 13–30].
Regarding claim 20, Rauch discloses freeze-dried LNPs comprising ionizable cationic lipid, neutral lipid, cholesterol, PEG-lipid, and antigen-encoding mRNA, and teaches the use of trehalose lyoprotectant with drying of its LNP compositions [p. 101, lines 1–28; p. 106, lines 13–30; p. 187, section 1.4; p. 188, first full paragraph].
Regarding claim 11, Rauch teaches aqueous, nucleic-acid-containing LNPs comprising ALC-0315, DSPC, cholesterol, and ALC-0159, thereby providing the ionizable cationic lipid, neutral lipid, steroid alcohol, nucleic acid, and PEG-lipid required by claims 1 and 8 [p. 100, lines 31–34; p. 101, lines 1–28; pp. 187–188, section 1.4]. Rauch expressly teaches spray-freeze-drying such LNP compositions, which entails spraying the liquid composition into droplets, freezing those droplets, and subsequently drying them [p. 106, lines 13–30].
Rauch does not expressly exemplify the first alternative of claim 11 as a weight composition. However, Rauch teaches variation of the relative lipid amounts, including 30–70 mol% cationic lipid, a cationic-lipid:DSPC molar ratio of 2:1–8:1, 10–60 mol% sterol, and 0.1–20 mol% PEG-lipid, expressly including approximately 0.3 mol% PEG-lipid [p. 96, lines 9–24; p. 99, lines 11–15; p. 100, lines 4–9 and 14–18]. As shown by the accompanying conversion, the claimed 50/10/38.5/1.5 weight composition corresponds to approximately 36.64/7.11/55.92/0.337 mol% for the disclosed lipid species and a PEG-lipid molecular weight of approximately 2500 g/mol, and falls within these teachings.
Kauffman teaches that the relative proportions of the same four functional classes of LNP components affect formulation potency and describes systematic experimental optimization of lipid ratios and structures for mRNA delivery [Abstract]. Accordingly, the relative lipid proportions were recognized result-effective variables.
A person of ordinary skill would have been motivated before the effective date of the claimed invention to vary the proportions in Rauch’s disclosed formulation ranges to obtain a workable LNP formulation with suitable mRNA-delivery potency, using the systematic screening taught by Kauffman, with a reasonable expectation of obtaining functional LNPs from these known components. Selection of the claimed first weight-percentage alternative represents optimization within those disclosed formulation parameters rather than introduction of a different constituent or process.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Rauch (WO 2021/156267 A1) as applied to claims 1 and 15, in view of Haas (US 2020/0246267 A1, published August 6, 2020).
Rauch teaches the inherited method and a trehalose-containing LNP formulation, as explained above. It identifies dextran among suitable lyoprotectants and expressly contemplates trehalose with an additional lyoprotectant [p. 106, lines 13–23].
Rauch does not teach a mixture of trehalose and dextran.
Haas demonstrates trehalose/dextran cryoprotectant mixtures for frozen RNA lipoplexes, including 10% dextran with 2.6% or 3.1% trehalose, and 8% dextran with 4.7% trehalose, all expressed as weight/volume percentages [Example 26, Table 10, formulations 2, 4, and 6; Results; Fig. 40].
It would have been obvious to employ that demonstrated combination in Rauch’s cryoprotectant-containing feed to stabilize the RNA-containing lipid particles during freezing. Rauch’s express invitation to add a further lyoprotectant, together with Haas’s demonstrated mixtures, supplies a reason and reasonable expectation for using both materials.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Rauch (WO 2021/156267 A1), in view of Haas (US 2020/0246267 A1, published August 6, 2020) as applied to claims 1, 15 and 16, and further in view of Murugappan (Murugappan et al., European Journal of Pharmaceutics and Biopharmaceutics 85 (2013), 716–725).
The teachings of Rauch and Haas are discussed above as applied to claims 1 and 15-16. Rauch and Haas do not teach wherein the trehalose and the dextran are present in an equal amount of weight by volume percent, relative to the total volume of the composition.
Murugappan teaches a 1:1 weight mixture of dextran and trehalose at 5% w/v total stabilizer in an aqueous vaccine feed sprayed into liquid nitrogen and subsequently freeze-dried [section 2.3; p. 33]. This corresponds to 2.5% w/v of each stabilizer. The reference explains that dextran raises the glass-transition temperature and addresses stickiness associated with spray-freeze-dried trehalose [Introduction; p. 32].
It would have been obvious to employ this known equal-weight mixture in the Rauch/Haas composition to obtain those processing benefits in the shared spray-freeze-drying process. Rauch’s express suitability teaching, Haas’s RNA-lipoplex results, and Murugappan’s working spray-freeze-drying formulation collectively support a reasonable expectation of success. Equal masses in the same feed volume satisfy claim 17’s equal weight-by-volume percentages.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Rauch (WO 2021/156267 A1) as applied to claim 18, in view of Eber (WO 2016/184576 A2, published November 24, 2016).
The teachings of Rauch are discussed above as applied to claims 1, 4, and 18 and similarly apply to claim 19. Rauch discloses nucleic-acid-containing LNPs comprising an ionizable cationic lipid, a neutral lipid, and cholesterol, and expressly teaches spray-freeze drying these LNP compositions. Rauch further identifies WO 2016/184576 as a suitable source of the spray-freeze-drying process [p. 101, lines 1–28; p. 106, lines 19–30].
Rauch does not expressly characterize the resulting LNP-containing dry particles as the generally spherical micropellets.
Eber discloses a spray-freeze-drying operation in which an RNA formulation is dispensed into droplets using a PipeJet dispenser, the frozen pellets are collected and transferred to vials, and the pellets are lyophilized to produce a free-flowing powder [pp. 71–72, Example 4, Tables 1–3]. Scanning electron microscopy demonstrates that the resulting dry particles are spherical and approximately 100–200 micrometers in size [p. 72, Example 5, continuing on p. 73, first paragraph; Fig. 6]. These particles have the generally spherical, micrometer-scale morphology described for micropellets in paragraph [0108] of the present specification.
It would have been obvious to use Eber’s droplet-dispensing, pellet-freezing, and lyophilization technique to carry out Rauch’s expressly contemplated spray-freeze drying of its LNP composition, thereby recovering the LNPs in discrete freeze-dried micropellets. Rauch itself directs the skilled artisan to Eber for that processing technique, and Eber identifies a particulate, free-flowing product resulting from freezing and drying individual droplets. The proposed modification retains Rauch’s nucleic-acid-containing LNP chemistry and applies Eber’s physical droplet-processing technique to that composition. The reasonable expectation is production of discrete dry pellets containing the LNPs, not guaranteed reproduction of Eber’s biological performance or applicant’s storage results.
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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