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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/28/2026 has been entered.
Receipt of Applicant’s Remarks and Amendments filed on 04/28/2026 is acknowledged.
Claims 1, 2, 4,12, 21-23, 29, 33, 46, 51, 52, 60-62, 68, 72, 85-87 were pending.
Claims 3, 5-11, 13-20, 24-28, 30-45, 47-50, 53-59, 63-67, 69-84 and 88-96 are cancelled.
Claims 1, 12, 46, 52, 97 and 98 are amended.
Claims 99-100 are new.
Claims 1, 2, 4,12, 21-23, 29, 46, 51, 52, 60-62, 68, 85-87 and 97-100 are pending and under examination in this application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/28/2026, 12/30/2025, 09/03/2025, 12/12/2024, 01/29/2024 and 12/20/2023 are in compliance with the provisions of 37 CFR 1.98. Accordingly, the information disclosure statements has been considered by the examiner. Signed copies have been attached to this office action.
Claim Objections
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: Claim 4(ii) recites the shelf temperature during primary drying set forth in step (c) is from 15° C to 30° C. The specification at page 7, lines 25-26 expressly states “In a further embodiment of the second method, the shelf temperature during primary drying set forth in step (c) is from about -15°C to about -30°C. In a preferred embodiment, the shelf temperature is -25°C.” The instant claim 4(ii) recites “shelf temperature range of 15° C to 30° C“ which does not appear in the originally-filled specification. Therefore, it lacks antecedent basis. Suggested amendment: conform to the range recited in specification (e.g., -15°C to -30°C) or provide antecedent basis.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1, 12 and 99-100 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.
Claims 1 and 12 recites “wherein the mass ratio of the stabilizing agent and the pharmaceutical substance is 200-2000 of the stabilizing agent:1 of the pharmaceutical substance”.
First, the claim fails to specify the units for the mass ratio (e.g., mg : mg, µg : µg, or w/w). Without units, a person of ordinary skill in the art would not know with reasonable certainty whether the ratio refers to grams, milligrams, micrograms, or some other mass unit. See Nautilus, Inc. v. Biosig Instruments, Inc. , 572 U.S. 898, 901 (2014).
Second, the phrase “200 - 2000 of the stabilizing agent : 1 of the pharmaceutical substance” is grammatically incorrect and non-standard. A proper ratio recitation should clearly indicate the relationship between the two components, such as “from 200:1 to 2000:1 (w/w)” or “from 200 to 2000 parts by weight of stabilizing agent per 1 part by weight of pharmaceutical substance.”
Third, the recitation “200 - 2000” is ambiguous as to whether the endpoints are included and whether only integer values are intended.
Appropriate correction is required. Suggested amendment: “wherein the mass ratio of the stabilizing agent to the pharmaceutical substance is from 200:1 w/w to 2000:1 w/w.”
Claims 99-100 recites “the RNA” and “wherein the at least one encapsulating agent comprises lipid nanoparticles or lipoplexes, wherein the lipid nanoparticles or lipoplexes comprise the RNA”. The phrase “the RNA” lacks clear antecedent basis. Claim 100 depends from claim 12, which recites a pharmaceutical substance that “is an RNA.” However, claim 12 introduces RNA in the context of the pharmaceutical substance being mixed with a stabilizing agent to produce a stable liquid formulation; it does not recite RNA as a component that is separately encapsulated within the at least one encapsulating agent. Claim 100’s recitation that “the lipid nanoparticles or lipoplexes comprise the RNA” introduces a new structural relationship — encapsulation of the pharmaceutical substance within the nanoparticles — that is not established in claim 12. Accordingly, it is unclear whether “the RNA” refers to the pharmaceutical substance RNA of claim 12 as a free molecule in admixture with the encapsulating agent, as an encapsulated payload within the LNPs or lipoplexes, or both simultaneously. This ambiguity renders claim 100 indefinite. Appropriate correction is required, e.g., by clarifying that the pharmaceutical substance RNA is encapsulated within the lipid nanoparticles or lipoplexes, or by otherwise specifying the relationship between the RNA and the encapsulating agent. Suggested amendment: “wherein the lipid nanoparticles or lipoplexes comprise the pharmaceutical substance RNA.”
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, 2, 4,12, 21-23, 29, 46, 51, 52, 60-62, 68, 85-87 and 97-100 are rejected under 35 U.S.C. 103 as being unpatentable over Bourles et al. (US 2019/0365930 A1) hereinafter the reference is referred as “Bourles” in view of Barz et al. (WO 2020/070040 A1) hereinafter the reference is referred as “Barz” and further in view of Rast (EP 2970 465 B1) hereinafter the reference is referred as “Rast” and further in view of Tchessalov (WO 2008/042408 A2).
Bourles teaches a method of using freeze-dried composition whereby the composition is reconstituted with a low salt aqueous liquid, e.g., water for injection or an aqueous solution of a non-ionic isotonifying agent (¶ 0005). Furthermore, Bourles discloses that adenoviral vectors can be subaerially impacted by the presence of salt, for example sodium chloride, either when in dry or when in liquid form, the invention thus further relates to formulations, i.e., aqueous mixtures for lyophilization and dried compositions (¶ 0037). Bourles fails to specifically teach at least one encapsulating agent lipid.
Barz teaches a method for delivering RNA to a target cell in a subject comprising the administration of the RNA particles (page 38, lines 18-20). In some embodiments, a lyophilized form or a spray-dried form, in liquid or a solid, may comprise salts, for example organic or inorganic salts, and salts of ethylenediaminetetraacetic acid (EDTA and amino acids (page 44 lines 33-33 to page 45 line 5). Barz fails to specifically teach mTorr.
Rast teaches a method for providing a lyophilized formulation of anti-CD 20 antibody Veltuzumab, comprising the steps of: I) providing a solution comprising the anti-CD 20 antibody Veltuzumab, II) freezing the antibody solution, III) subjecting the antibody solution to at least one drying step at a shelf temperature of -10 °C to 30 °C, in order to obtain the lyophilized formulation (page 3 to page 4, Summary ¶ 0014).
Tchessalov teaches a method and apparatus for optimizing the primary drying step of a lyophilization cycle of a biological or pharmaceutical materials comprising the steps of calculating a designed primary drying cycle for the material based on a product temperature profile for the material and modifying both a chamber pressure and a shelf temperature according to a designed primary drying cycle during a primary drying step (abstract).
Prima Facie Obviousness & Motivation to Combine
A person having ordinary skill in the art (PHOSITA) would have been motivated to combine Bourles, Barz, Rast, and Tchessalov for the following reasons:
1. Same technical field – All references relate to lyophilization or stabilization of pharmaceutical formulations, including viral vectors, RNA, lipid nanoparticles (LNPs) and lipoplexes.
2. Predictable results – Lyophilization cycles (freezing, annealing, primary drying, secondary drying) are standard pharmaceutical engineering steps. Adapting a known cycle from one biological system (adenovirus) to another (RNA-LNP) is a predictable adaptation.
3. Express motivation to combine – Bourles teaches a complete lyophilization cycle for adenoviral vectors, including freezing at -52°C, annealing at -10°C, primary drying at -30°C and 80 μbar, and secondary drying at +10°C to +25°C (Bourles ¶¶ 0144–0157; Figs. 1, 4, 13, 14). Bourles also teaches trehalose concentrations of 14%, 18.5%, and 23% w/v as cryoprotectants (Bourles Example 1 ¶ 0144; Example 2 ¶ 0164; Fig. 11). Bourles teaches low salt conditions (e.g., ≤50 mM NaCl) for stability (Bourles ¶¶ 0039–0040, 0164). Bourles teaches reconstitution with water for injection or low-salt diluent (Bourles ¶¶ 0041–0044). Bourles teaches storage stability at 4°C, 25°C, and 37°C for up to 6 months (Bourles ¶ 0055). Barz teaches RNA-LNPs and lipoplexes for mRNA delivery and explicitly contemplates lyophilized forms (Barz page 19 lines 16–20; Barz page 35 lines 25–30 teaching RNA concentrations from 0.002 mg/mL to 5 mg/mL; Barz page 44–45 teaching that the composition may be in a lyophilized form; Barz page 54 lines 5–6 teaching RNA concentration of 0.2–0.5 mg/mL after concentration). Barz teaches that LNPs and lipoplexes serve as encapsulating agents that associate with RNA, specifically stating that they form “vesicles in which the RNA is enclosed or encapsulated” (Barz page 19 lines 16–20). Rast teaches specific lyophilization parameters including primary drying at 0.1 mbar (75 mTorr) and annealing at -15°C (Rast Table 1, ¶ 0180). Tchessalov teaches dynamic control of primary drying (shelf temperature and chamber pressure) to optimize product quality (Tchessalov Abstract, Fig. 11).
Thus, a PHOSITA seeking a stable lyophilized RNA-LNP formulation would have selected the LNP composition from Barz, applied the lyophilization cycle from Bourles, optimized the primary drying parameters using Tchessalov, and confirmed suitable pressures from Rast.
4. Reasonable Expectation of Success - Lyophilization of liposomes and LNPs was well-established by the filing date as evidenced by Barz (page 44–45). The cycle parameters in Bourles were successfully applied to a complex biological (adenovirus). Extending them to RNA-LNPs would have been a routine design choice with a reasonable expectation of success.
Regarding Mass Ratio Limitation (200:1 to 2000:1) – as amended
The Examiner acknowledges that the specific mass ratio limitation in claims 1 and 12 is not explicitly taught in any single reference. However, a PHOSITA would have found it obvious to arrive at such a ratio through routine optimization of known parameters. See In re Aller, 220 F.2d 454, 456 (CCPA 1955) (selecting an appropriate ratio of ingredients within a range suggested by the prior art is a matter of ordinary skill, not patentable invention).
Bourles teaches trehalose concentrations of 14%, 18.5%, and 23% w/v (Bourles Example 1 ¶ 0144; Example 2 ¶ 0164; Fig. 11), which correspond to 140 mg/mL, 185 mg/mL, and 230 mg/mL respectively. A PHOSITA would have understood that trehalose is a cryoprotectant and that its concentration can be adjusted based on the amount of active ingredient to be stabilized.
The claimed ratio of 200:1 to 2000:1 parts stabilizing agent to 1 part pharmaceutical substance (RNA) is well within the range of ratios achievable by combining the trehalose concentrations taught in Bourles with RNA concentrations that were known in the art for LNP formulations (see Barz page 35 lines 25–30 teaching RNA concentrations from 0.002 mg/mL to 5 mg/mL; Barz page 54 lines 5–6 teaching RNA concentration of 0.2–0.5 mg/mL after concentration). Selecting a specific ratio from within an obvious range, without evidence of unexpected results, does not confer patentability. Therefore, this is prima facie case of obviousness.
Claim mapping of Rejections
Regarding claim 1, the claim recites a lyophilization method comprising freezing, primary drying, and secondary drying. Bourles at (¶¶ 0144–0157 and Figs. 1, 4, 13, and 14) teach a complete lyophilization cycle for a biological material, including freezing at -52°C, annealing at -10°C, primary drying at -30°C and 80 μbar (60 mTorr), and secondary drying at +10°C to +25°C. Tchessalov (Abstract, Fig. 11) teaches dynamic control of primary drying by adjusting shelf temperature and chamber pressure during the run. Claim 1 further recites an encapsulating agent selected from a lipid, LNP, or lipoplex. Barz (page 19 lines 16–20) teaches RNA-LNPs and lipoplexes wherein the RNA is enclosed or encapsulated. Barz (page 44–45) explicitly teaches that the composition may be in a lyophilized form. Claim 1 further recites a mass ratio of stabilizing agent to pharmaceutical substance of 200:1 to 2000:1. Bourles at (¶ 0144) teaches 23% trehalose (230 mg/mL). Bourles at (¶ 0164) teaches 14% and 18.5% trehalose (140–185 mg/mL). Barz at (page 35 lines 20–30) teaches RNA concentrations from 0.002 mg/mL to 5 mg/mL. Barz at (page 54 lines 5–6) teaches RNA concentration of 0.2–0.5 mg/mL after concentration. A PHOSITA would have found it obvious to select an appropriate ratio of trehalose to RNA within this range as a matter of routine optimization. In re Aller, 220 F.2d 454, 456 (CCPA 1955).
Regarding claim 2, the claim depends from claim 1 and adds an annealing step. Bourles at (¶¶ 0148–0150 and Figs. 1, 4, 13, and 14) explicitly teach an annealing step at -10°C.
Regarding claim 4, the claim recites additional process parameters. Regarding claim 4(i) (partially crystalline or amorphous components), Bourles at (¶¶ 0030–0032) teach amorphous trehalose and sorbitol. Regarding claim 4(ii) (primary drying shelf temperature 15°C to 30°C), this limitation is objected to for lack of antecedent basis as set forth above. Regarding claim 4(iii) (chamber pressure 25–100 mTorr), Rast at (Table 1) teaches primary drying at 0.1 mbar (75 mTorr), and Bourles at (¶ 0154) teaches primary drying at 80 μbar (60 mTorr). Regarding claim 4(iv) (initial freezing -30°C to -60°C), Bourles at (¶ 0145) teaches freezing at -52°C. Regarding claim 4(v) (annealing temperature -5°C to -25°C), Bourles at (¶¶ 0148–0150) teaches annealing at -10°C, and Rast at (Table 1) teaches annealing at -15°C. Regarding claim 4(vi) (cake height up to 3 cm), this is a routine design choice based on fill volume and container geometry, and no unexpected results have been shown.
Regarding claim 12, the claim recites a stable liquid formulation comprising RNA and an encapsulating agent. Barz (page 19 lines 16–20; page 35 lines 25–30; page 54 lines 5–6) teaches such formulations. The mass ratio limitation of claim 12 is addressed by the same analysis as claim 1 above.
Regarding claims 21 and 60, the claims recite that the RNA is mRNA. Barz (page 33 lines 25–30) explicitly teaches mRNA.
Regarding claims 22–23 and 61–62, the claims recite pharmaceutical substance concentrations of less than or at least 0.05 mg/mL. Barz (page 54 lines 5–6) teaches RNA concentration of 0.2–0.5 mg/mL after concentration, which is greater than 0.05 mg/mL. Additionally, Bourles at (¶¶ 0091–0093) teaches dose volumes of 0.3–2 mL and doses of 1 µg–100 mg, from which a PHOSITA could routinely calculate a concentration of approximately 0.05 mg/mL
Regarding claims 29 and 68, the claims recite stabilizing agent concentration of 100–200 mg/mL. Bourles at (¶ 0144) teaches 23% trehalose (230 mg/mL, slightly above the range) and (¶ 0164) teaches 14–18.5% trehalose (140–185 mg/mL, within the range). Fig. 11 further supports trehalose concentrations within this range.
Regarding claim 46, the claim recites storage stability at ambient or sub-ambient temperature. Bourles at (¶ 0055) teaches storage at 4°C, 25°C, and 37°C for up to 6 months, corresponding to component (i). Furthermore, Bourles teaches the term "annealing step" as a method step in freeze-drying cycles of a composition, wherein during the freezing phase, the product is maintained at a specified subfreezing temperature for a predetermined period of time, and as is known to the skilled person, annealing will lead to Oswald ripening of the ice crystals and cryo-concentration of the amorphous matrix, which typically, the annealing temperature is (slightly) above Tg', and in one embodiment, annealing is executed at a temperature between (Tg'+0.5° C.) and (Tg'+20° C.), e.g. at a temperature of -15° C.+/-9° C. or -15° C.+/-6° C., or between (Tg'+0.5° C.) and (Tg'+l0° C.), in any case, the annealing temperature should be between Tg' and the melting temperature (Tm) during annealing, and in specific embodiments, annealing is done at a temperature between -4° C. and -24° C., alternatively between -4° C. and -20° C., alternatively between -4° C. and-15° C., or alternatively between -8° C. and -15° C., e.g. at -10° C.+/-0.5° C and thus annealing can be done during the freezing of the product, i.e. whilst the frozen sample is being formed, provided the product is frozen (solid state) and in a glassy state (below Tg'), and alternatively, annealing is done post freezing of the product (¶ 0103) corresponding to instant component (ii); and in a further embodiment, the shelf temperature is increased to a temperature above Tg' to initiate the annealing step, such as to a temperature above Tg' plus 0.5° C., above Tg' plus 1 ° C., above Tg' plus 3° C., above Tg' plus 5° C., above Tg' plus 10° C. or above Tg' plus 20° C. (¶ 0107) corresponding to instant component (iii).
Regarding claim 51, the claim recites antioxidants or metal scavengers. Bourles at (¶ 0049) teaches citrate as a chelator, which functions as a metal scavenger.
Regarding claims 52 and 98, Bourles teaches the stable formulation comprises a salt (¶ 0038 - ¶ 0042, claims 55-56), a buffer (¶ 0048 - ¶ 0051), a surfactant (¶ 0045 - ¶ 0048), a preservative (¶ 0049), and excipients (¶ 0054, ¶ 0164) or combinations thereof (¶ 0049).
Regarding claims 85–87 and 97, the claims recite reconstitution with a diluent, including bacteriostatic water for injection (BWFI). Bourles at (¶¶ 0041–0044) teach reconstitution with water for injection. The use of BWFI for multi-dose or non-terminally sterilized preparations is a known art recognized variant.
Regarding claims 99–100, the claims recite that the LNP or lipoplex comprises the RNA. Barz (page 19 lines 16–20) teaches that LNPs and lipoplexes are “vesicles in which RNA is enclosed or encapsulated.”
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to combine the lyophilization method of Bourles with the RNA-LNP encapsulation and lyophilization cycle system of Barz and Tchessalov, using the cycle parameters further confirmed by Rast. The motivation to combine is supported by the following: (1) All four references address the common technical problem of preparing stable lyophilized pharmaceutical formulations; Bourles contributes the freeze-drying cycle, Barz contribute the RNA-LNP/lipoplex delivery vehicle, and Rast confirms suitable primary drying pressures (75 mTorr, Table 1) compatible with the cycle. (2) Lyophilization of lipid-based nucleic acid delivery systems was a recognized and established approach in the field as evidenced by Tchessalov and Barz (page 44–45), such that a PHOSITA would have had a reasonable expectation of success in adapting a lyophilization cycle designed for one type of pharmaceutical formulation to an RNA-LNP system.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Response to Arguments
Applicant's arguments filed 4/28/2026 have been fully considered but they are not persuasive.
Applicant argues:
Argument 1: Bourles does not teach RNA or LNPs.
Bourles is relied upon for the lyophilization cycle and cryoprotectant concentrations — not for RNA or LNPs. Barz supplies those limitations. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
Argument 2: Bourles states adenovirus formulations are serotype-specific (¶ 0028).
Bourles at (¶ 0028) discusses stabilization strategies across different adenoviral serotypes, an entirely distinct question from whether a lyophilization cycle optimized for a protein-capsid viral vector would serve as a suitable starting point for a PHOSITA adapting those parameters to a lipid-based RNA formulation. The motivation to extend Bourles’ cycle parameters derives independently from Barz, which explicitly teaches lyophilized RNA-LNP and lipoplex compositions (Barz page 44–45).
Argument 3: No teaching of 200:1 to 2000:1 mass ratio.
Bourles at (¶ 0144) teaches 23% trehalose (230 mg/mL). Bourles at (¶ 0164) teaches 14% and 18.5% trehalose (140–185 mg/mL). Barz (page 35 lines 25–30) teaches RNA concentrations from 0.002 mg/mL to 5 mg/mL. Barz (page 54 lines 5–6) teaches RNA concentration of 0.2–0.5 mg/mL after concentration. Selecting a ratio of stabilizing agent to RNA within the claimed range would have been a matter of routine optimization for a PHOSITA. In re Aller, 220 F.2d 454, 456 (CCPA 1955); In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003).
Argument 4: Rast does not teach RNA.
Rast is relied upon only for lyophilization parameters (pressure, temperature), not RNA — proper for a combination rejection.
Applicant has not submitted objective evidence of unexpected results, commercial success, or long-felt need. Therefore, the prima facie case stands.
Conclusion
No claims are allowed
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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