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 .
Summary
Receipt of Applicant’s Remarks and Amendments filed on 12/30/2025 is acknowledged.
Claims 1, 2, 4,12,19, 21-23, 29, 33, 44, 46, 51, 52, 58, 60-62, 68, 72, 83, 85-87 are pending.
Claims 3, 5-11, 13-20, 24-28, 30-32, 34-45, 47-50, 53-59, 63-67, 69-71, 73-84, and 88-96 are cancelled.
Claims 1, 4, 12, 21, 29, 52, 60-62, 68, 87 are amended.
Claims 97-98 are new.
Claims 1, 2, 4,12, 21-23, 29, 33, 46, 51, 52, 60-62, 68, 72, 85-87, and 97-98 are pending and under examination in this application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 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 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.
Claim 97 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 97 recites the limitation "the method of claim 87, wherein the preservative containing diluent is bacteriostatic water for injection (BWFI)" in lines 1-2. However, neither claim 86 (independent claim) nor claim 87 (dependent claim) requires a preservative containing diluent, and thus there is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Modified Rejections
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, 33, 46, 51, 52, 60-62, 68, 72, 85-87, and 97-98 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.
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).
Regarding claims 1-2, and 4, Bourles teaches in examples 1-5 (¶ 0143 - ¶ 0229) a method of lyophilizing a liquid formulation comprising:
freezing at -52 °C (¶ 0145- ¶ 0147)
annealing step at -10 °C (¶ 0148 - ¶ 0150)
freezing at -50 °C (¶ 0151 - ¶ 0152))
primary drying at 80 µbar and -30 °C for 24 hrs (¶ 0153 - ¶ 0154)
secondary drying at -25 °C to + 10 °C at 40 µbar for 6 hrs (¶ 0155 - ¶ 0156)
and at the end of the freeze drying cycle, the chamber was filled with dry nitrogen until a chamber pressure of 825 mbar was reached (¶ 0157).
Furthermore, Bourles discloses physical stability of lyophilized pharmaceutical substance comprising sucrose, sorbitol and trehalose (examples 1-5, ¶ 0144 - ¶ 0225), amorphous sugar trehalose (¶ 0004, and the effect of the sorbitol content on the Tg of the freeze-dried composition impacted the appearance of the resulting cake and the stability of the adenoviral particle stored therein (¶ 0207), and Also the freeze-drying cycle was evaluated in order to improve the stability of the cake appearance after storage (especially at +25° C. (room temperature) in order to cover the time for reconstitution and administration to the patient after storage at cold temperature) (¶ 0210). Furthermore, Bourles discloses In Example 2, the impact of decreased Tg in the
presence of sorbitol was determined to be directly correlated with the moisture content (residual humidity) measured in the cake after the freeze-drying step. Although the data
showed that the moisture content had a protective effect on the infectivity of adenovirus upon stability, poor appearance of the cakes (melted aspect) is undesirable. For that purpose, the freeze-drying or lyophilisation cycle was further optimized (¶ 0212 - ¶ 0216). Bourles teaches adenoviral vectors may be used to deliver desired RNA or protein sequences (¶ 0063).
Regarding claims 12, 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 21 and 60, Bourles teaches adenoviral vectors may be used to deliver desired RNA or protein sequences (¶ 0063), and desirable RNA molecules include tRNA, dsRNA, ribosomal RNA …one example of a useful RNA sequence is a sequence which extinguished expression of a targeted nucleic acid sequence in the treated animal (¶ 0065), and expression control sequences include appropriate transcription, initiation, termination, promoter and enhancer sequences, sequences that stabilize cytoplasmic mRNA sequences that enhance translation efficiency (¶ 0075) corresponding to the pharmaceutical substance is an RNA, mRNA.
Regarding claim claims 22, 23, 61 and 62, Bourles teaches an immunologically effective amount of a nucleic acid may suitably be between 1µg and 100 mg, an appropriate amount of the particular nucleic acid (e.g., vector) can readily be determined by those of skill in the art, exemplary effective amounts of a nucleic acid component can between 100 µg and 500 µg (¶ 0091) and generally, a human dose will be contained in a volume of between 0.3 ml and 2 ml, for example the composition can be formulated such that upon reconstitution of the dried composition of a volume of, for example 0.3, 0.4, 0.5, 0.6, 1.0, 1.5 or 2.0 ml (¶ 0092), and one of skill in the art may adjust these doses (¶ 0093), corresponding to the limitation wherein the pharmaceutical substance has a concentration of less than and/or at least about 0.05 mg/ml.
Regarding claims 29, 33, 68 and 72, as noted above, Bourles teaches pharmaceutical substance at 1 µg and 100 mg, 100 µg and 500 µg, and sorbitol, trehalose, sucrose, mannitol (¶ 0032) as the stabilizing agent, and in a specific embodiment, the amorphous sugar is trehalose and is present in an amount between
12 % and 18% (120 mg/mL and 180 mg/mL) (¶ 0036) corresponding to the limitation of the stabilizing agent is at a concentration from 100 mg/mL to 200 mg/ML). The limitation of a ratio of stabilizing agent and pharmaceutical substance in no greater than 5000 is taught.
Regarding claim 46, Bourles teaches the increased stability during freeze-drying process and the formulation (liquid or dried) may also increase stability upon storage at 4 °C., 25 °C., or 37 °C., for up to 1 month, 3 months, 6 months (¶ 0055) 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, Bourles teaches citrate (¶ 0049) in the formulation. It is well known to skilled in the art that citrate has antioxidant and chelating activity where it binds to metal ions. Therefore, the limitation of any antioxidants or metal scavengers is taught.
Regarding claims 85, 86, 87 and 97, Bourles teaches a method for improving stability throughout lyophilization of a mixture and a freeze-dried composition comprising sorbitol, adenoviral vectors, amorphous sugar trehalose (¶ 0004-0005) and sterile water for injection (¶ 0042) as the diluent for reconstitution. Furthermore, Bourles discloses the increased stability during freeze-drying process and the formulation (liquid or dried) may also increase stability upon storage at 4 °C., 25 °C., or 37 °C., for up to 1 month, 3 months, 6 months (¶ 0055). Regarding the amended requirement to use bacteriostatic water for injection (BWFI) as a diluent, it would have been obvious for a PHOSITA to use BWFI in a stable lyophilizing mixture because aqueous mixtures are vulnerable to microbial ingress, and BWFI provides bacteriostatic protection during mixing/reconstituting, especially relevant in multi-use vial, batch, repeated puncture of the vial, or non-terminally sterilized preparations, thus BWFI is an expected precaution to improve robustness, and a design choice, not an inventive step.
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).
Regarding claims 12 and 52, Barz teaches in one embodiment the RNA particles comprise at least one lipid or lipid-like material, e.g., by forming complexes with the RNA or forming vesicles in which the RNA is enclosed or encapsulated (page 19 lines 16-20), and lipoplex formation using liposomes (page 10, lines 27-32; page 61 example 6), lipids used for LNP formation and in-vitro protein expression of luciferase-encoding mRNA LNPs in different cell lines, LNPs formulated with mRNA (page 9 lines 12-15).
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).
Regarding claim 4, as noted above, Rast teaches a lyophilization process of an antibody, wherein the process is exemplified in Table 1 (¶ 0180) comprises the steps of:
Freezing 1 hr at -50 °C, 1000 mbar
Annealing at -15 °C and 1000 mbar
Freezing at 2 hr at -50°C and 1000 mbar
Primary drying at -20°C and 0.1 mbar (= 75 mTorr)
Secondary drying at +20 °C and 0.1 mbar
And the lyophilized product is stable at 5 °C for 18 months (table 5).
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 use the method for lyophilizing a liquid formulation with the steps as taught by Bourles and incorporate the encapsulation agent of LNP as taught by Barz in view of Rast. One would have been motivated to do so because the combined teaching of Bourles, Barz in view of Rast discloses methods for using a stable lyophilization method directed to delivering RNA to a target cell in a subject comprising the administration of the RNA particles. One of ordinary skill in the art would have been motivated to do this because all the references are drawn to methods for lyophilizing a liquid formulation with the steps in claimed features of stabilizing agent, encapsulating agent, primary and secondary drying process, annealing process. Thus, the claimed subject matter and method are taught in prior art of record in addition to the claimed components.
One of ordinary skill in the art would have found it obvious to apply the different methods of producing a stable lyophilization liquid formation to improve process and use as taught by Bourles in view of Barz and further in view of Rast.
From the combine 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
The rejection of claim 87 under 35 U.S.C. 112(b) is withdrawn in view of the amendment.
Applicant's arguments filed 12/30/2025 have been fully considered but they are not persuasive.
Lack of Criticality and Unexpected results
The prior art of record teaches the method of a stable lyophilizing a mixture, comprising the claimed components/steps and encompassing the same pharmaceutical substance RNA, mRNA, LNP in a formulation, therefore, one of ordinary skill in the art would find the lyophilizing a liquid formulation with the steps in the claimed features comprising of a stabilizing agent, encapsulating agent, primary and secondary drying process, annealing process, is predictable and obvious effect after such a method in carrying out lyophilization of the composition. Moreover, it would have be obvious for a PHOSITA to use BWFI in a stable lyophilizing mixture because aqueous mixtures are vulnerable to microbial ingress, and BWFI provides bacteriostatic protection during mixing/reconstituting, especially relevant in multi-use vial, batch, repeated puncture of the vial, or non-terminally sterilized preparations, thus BWFI is an expected precaution to improve robustness, and choosing BWFI would therefore be a design choice, not a technical departure or inventive step.
There is no evidence showing criticality or unexpected results comparing the claimed invention with that of the prior art.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached at 571-272-0323. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615