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
Claims 1-14 and 18-23 are pending in this office action. Claims 15-17 and 24 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on April 4, 2024 is a 371 of PCT/EP2022/077859 filed October 6, 2022. The current application claims foreign priority to EP21201247.0 filed October 6, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed September 2, 2025 and November 5, 2024 are acknowledged. A signed copy of both documents are attached to this office action.
Claim Objections
Claim 4 is objected to because of the following informality: Claim 4 needs an “and” amended prior to the end of the PEGylated lipid clause. 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.
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 2-5 and 14 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 claims 2-5 and 14 the term "preferably" 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 Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 21 and 22 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 21 has no additional limitation than shown within claim 1. Claim 22 has no additional limitation than shown within claim 2. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1-14 and 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Polisky et al. (US2013/0039970A1) in view of Ting et al. (CN102151250A), and Panzner et al. (WO2007/107304A2).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Polisky et al.
Polisky et al. is the closest prior art to the present invention as it teaches processes and compositions for liposomal and efficient delivery of gene silencing therapeutics (see title). Furthermore, Polisky et al. disclose processes and compositions for liposomal delivery of therapeutics prepared by contacting an aqueous solution of an active agent with a solution of liposome-forming components containing one or more DILA2 amino acid compounds or lipids in organic solvent to form an impinging stream. A protocol including flow rates, pH, and an incubation period are used to control formation of liposomal components for therapeutic applications. The impinging stream may be collected and incubated to prepare a liposomal formulation which encapsulates the active agent. The composition can be quenched with buffer and filtered by tangential flow and diafiltration and other means for finishing as a pharmaceutical composition (see abstract).
2. Ting et al.
Ting et al. teach a novel preparation method of solid lipid nanoparticles (see title). Additionally, Ting et al. disclose that the present invention discloses a novel preparation method of solid lipid nanoparticles (SLN) (including nanostructured lipid carriers NLC), solving the unstable problem of easiness in aggregation, agglomeration, and the like of the solid lipid nanoparticles (including NLC). The preparation method comprises the steps of: a, dissolving lipid matters and lipotrophic matters (including medicines) in an organic solvent (such as tertiary butanol) capable of being mixed and dissolved with water to form an oil phase (O), or solubilizing hydrophilic matters (including medicines) in an organic solvent (O) capable of being mixed and dissolved with water by using a surfactant, wherein the lipid matters and the lipotrophic matters are used for forming the solid lipid nanoparticles (including NLC); b, dissolving water-soluble matters in water to form a water phase (W); c, injecting the oil phase (O) into the water phase (W) under stirring condition according to a proper volume proportion to obtain a solid nanoparticle dispersing solution; d, freezing and drying the obtained dispersing solution to remove the solvent to obtain a freeze-dried product; and e, hydrating the obtained freeze-dried product to obtain the solid lipid nanoparticles (including NLC). The preparation method is simple in procedures and easy to implement (see abstract).
3. Panzner et al.
Panzner et al. teach an efficient method for loading amphoteric liposomes with nucleic acid active substances (see title). In addition, Panzner et al. disclose a method for preparing amphoteric liposomes loaded with a polyanionic active agent as cargo, characterised by admixing an aqueous solution of said polyanionic active agent and an alcoholic solution of one or more amphiphiles and buffering said admixture to an acidic pH, said one or more amphiphiles being susceptible of forming amphoteric liposomes at said acidic pH, thereby to form such amphoteric liposomes in suspension encapsulating said active agent under conditions such that said liposomes form aggregates, and thereafter treating said suspension to dissociate said aggregates. Also disclosed are nucleic acid loaded amphoteric liposomes produced in accordance with the method, wherein said nucleic acids are oligonucleotides and said liposomes are multilamellar (see abstract).
Combination of Polisky et al. and Ting et al.
Regarding instant claim 1, Polisky and Ting et al. teach a method of preparing a composition comprising lipid nanoparticles and a biologically active agent selected from oligo- and polynucleotides. The necessary citations of Polisky et al. and Ting et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Polisky et al. and Ting et al. Citations
A method of preparing a composition comprising lipid nanoparticles and a biologically active agent selected from oligo- and polynucleotides, wherein the biologically active agent is associated with and/or encapsulated within the lipid nanoparticles, comprising the steps of:
Polisky et al. disclose processes, compositions and methods to deliver active nucleic acid agents or molecules to cells. The active agents may provide therapeutic or pharmacological effects, either through pharmaceutical action, or by producing the response of RNA interference, or antisense or ribozyme effects. Active agents of this disclosure may be useful in the regulation of genomic expression, or for gene therapy (see paragraphs [0011] and [0085-0088] within Polisky et al.).
(a) providing a first stream of a first liquid composition, wherein the first liquid composition comprises an organic solution of one or more lipids;
Polisky et al. describes the streams disclosed by the Applicant in reverse order. Therefore, stream 1 of Polisky et al. is stream 2 of the present invention, and stream 2 of Polisky et al. is stream 1 of the instant application.
Polisky et al. disclose providing a second stream comprising a non-aqueous solution of one or more liposome-forming compounds in organic solvent (see paragraphs [0012] and [0085-0088] within Polisky et al.).
(b) providing a second stream of a second liquid composition, wherein the second liquid composition comprises an aqueous solution of the biologically active agent;
Polisky et al. disclose a range of processes for making a composition, including liposomal compositions, containing one or more active agents by providing a first stream comprising an aqueous buffer solution of an active agent (see paragraphs [0012] and [0085-0088] within Polisky et al.).
(c) mixing the first stream and the second stream such as to form a third stream of a third liquid composition, wherein the third liquid composition comprises nascent lipid nanoparticles comprising the one or more lipids;
Polisky et al. disclose thereby forming an impinging stream having a concentration of the organic solvent of from about 20% to about 50% v/v. The impinging stream may have a pH of from about 6 to about 7.4. The impinging stream can be incubated in a collection reservoir for a period of from about 0.5 hours to about 8 hours at a temperature of from about 20° C. to about
35° C., thereby forming an incubate comprising liposomes (see paragraphs [0012] and [0085-0088] within Polisky et al.).
(d) directly filling the third liquid composition into a primary packaging container; and
Ting et al. disclose the direct filing of the third liquid into primary packaging containers (see claim 8 and paragraph [0035] within Ting et al.).
(e) subjecting the primary packaging container to freeze drying to obtain a lyophilized composition
Polisky et al. disclose that the concentration of the active agent may be adjusted by the addition of buffer to the retentate of the diafiltration step to achieve a desired final concentration. The
concentration-adjusted retentate may thereafter be provided to a sterilization unit in which direct flow filtration is used to sterilize the retentate product solution. The sterilized product may be used in a sterile vial-filling process, and the product
vials stored at low temperature. Flash freezing, lyophilizing, and low temperature lyophilizing, and other means can be used to prepare and store the product (see paragraph [0123] within Polisky et al.).
wherein between step (c) and step (d) no step of removal or addition of a constituent from or to the third liquid composition is conducted; and wherein steps (a) to (e) are conducted under aseptic conditions.
Ting et al. disclose wherein between step (c) and step (d) no step of removal or addition of a constituent from or to the third liquid composition is conducted; and wherein steps (a) to (e) are conducted under aseptic conditions (see claim 8 and paragraph [0035] within Ting et al.).
Therefore, a skilled artisan (POSITA) would consult the disclosures of Polisky et al. and Ting et al. to teach all the elements of instant claim 1.
The remainder of the instant claims which are either directly or indirectly dependent on claim 1 are taught in full by the combination of Polisky et al. and Ting et al.
Regarding instant claim 2, Polisky et al. and Ting et al. teach further comprising a step of (f) reconstituting the lyophilised composition obtained in step (e) by combining it with a liquid reconstitution solvent to obtain a reconstituted liquid composition comprising the lipid nanoparticles and the biologically active agent associated with and/or encapsulated within the lipid nanoparticles, wherein the liquid reconstitution solvent is preferably a buffered aqueous liquid. Polisky et al. disclose that a dosage form of the composition of this invention can be solid, which can be reconstituted in a liquid prior to administration. The solid can be administered as a powder. The solid can be in the form of a capsule, tablet or gel (see paragraph [0616] within Polisky et al.).
Regarding instant claim 3, Polisky et al. and Ting et al. teach wherein the biologically active agent is an RNA molecule, wherein the RNA molecule is preferably selected from siRNA and mRNA, and wherein the mRNA is optionally a modified RNA. Polisky et al. disclose making liposomal compositions suitable for delivery of therapeutic agents. In certain embodiments, an active agent of this disclosure is a UsiRNA. The methods of this disclosure may provide liposomal compositions of nucleic acid agents such as two- or three-stranded RNA structures, RNA peptide conjugates, condensed RNA nanoparticles, dicer substrate RNAs, dsRNAs, siRNAs, microRNAs, hairpin RNAs, and other active RNA forms (see paragraph [0063] within Polisky et al.).
Regarding instant claim 4, Polisky et al. and Ting et al. teach the specific lipids identified within the instant claim 4 limitation. Polisky et al. disclose all the relevant lipids (see paragraphs [0399-0405] for cationic lipids, see paragraphs [0409-0410] for PEGylated lipids, and see paragraphs [0408] and [0413] non-PEGylated zwitterionic lipid)
Regarding instant claim 5, Polisky et al. and Ting et al. teach wherein the first liquid composition comprises a water-miscible solvent, wherein the water-miscible solvent is preferably selected from ethanol, methanol, acetone, acetonitrile, acetic acid, formic acid, trifluoroacetic acid, acetaldehyde, n-butanol, ethylamine, and any combinations thereof. Polisky et al. disclose a process of this invention may include adding organic solvent to the first stream at a concentration of from about 1 % to about 40% v/v. The organic solvent may be a (C1-6)alkanol at a concentration of about 40 to about 99% v/v in sterile water for injection, or about 70 to about 95% (see paragraphs [0022-0023] within Polisky et al.).
Regarding instant claim 6, Polisky et al. and Ting et al. teach wherein the total concentration of lipids in the first liquid composition is from about 20 to about 100 mg/mL, and optionally from about 50 to about 100 mg/mL. Polisky et al. disclose lipid mol % concentrations within the following range (see paragraphs [0458-0460] within Polisky et al.):
DILA2 (PONA) 683.30 g/mol 1812.5 µmol 1.238 g 70%
CHEMS 486.74 g/mol 129.5 µmol 0.063 g 5%
DMPE-PEG2K ~2000 g/mol 517.9 µmol 1.034 g 20% CHOL 386.60 g/mol 129.5 µmol 0.050 g 5%
This hypothetical range is for a 100 mL stock solution as described within Example 1 (see paragraph [0657] within Polisky et al.). The total µmol amount of lipids was 2589.3 µmol. This corresponds to ~24 mg/mL. [C18:1-norArg-C16 (PONA) = DILA2 amino acid compound, cholesteryl-hemisuccinate (CHEMS) powder, DMPE-PEG2K powder, and (CHOL) cholesterol].
Regarding instant claim 7, Polisky et al. and Ting et al. teach wherein the first liquid composition essentially consists of a solution of the one or more lipids and optionally one or more further lipophilic excipients in the water-miscible solvent. Polisky et al. disclose providing a second stream comprising a non-aqueous solution of one or more liposome-forming compounds in organic solvent (see paragraphs [0012] and [0085-0088] within Polisky et al.). Additionally, please see the discussion and citations within instant claim 5 regarding the organic/water-miscible solvent.
Regarding instant claim 8, Polisky et al. and Ting et al. teach wherein the first liquid composition essentially consists of a solution of a cationic or cationisable lipid, a PEGylated lipid, a non-PEGylated zwitterionic lipid, cholesterol, and optionally one or more further lipophilic excipients in ethanol. Please see the discussion and citations within instant claims 4-5 for the necessary rejection text. Furthermore, Polisky et al. disclose the lipid mixture can include cholesterol (see paragraph [0414] within Poliaky et al.).
Regarding instant claim 9, Polisky et al. and Ting et al. teach wherein the second liquid composition comprises an osmotic agent, and wherein the osmotic agent is optionally selected from sodium chloride, potassium chloride, sorbitol, mannitol, and sucrose and/or wherein the second liquid composition comprises a lyophilisation aid, and wherein the lyophilisation aid is optionally selected from sucrose, trehalose, mannitol,sorbitol, glucose, fructose, proline, glycine betaine, polyethylene glycol, starch and dextran. Polisky et al. disclose usage of the osmotic agent sodium chloride (see paragraphs [0067-0068] within Polisky et al.).
Regarding instant claim 10, Polisky et al. and Ting et al. teach wherein the first stream is provided in step (a) and/or the second stream is provided in step (b) at a pressure in the range of 10 kPa (0.1 bar) to 12,000 kPa (120 bar) and/or wherein the first stream is provided in step (a) and/or the second stream is provided in step (b) at a flow rate in the range of 1 to 1,000 ml/min, and wherein the flow rate of the second stream is preferably higher than the flow rate of the first stream. Polisky et al. disclose a flow rate of 40±0.5 mL/min within Example 1 (see paragraph [0659] within Polisky et al.).
Regarding instant claim 12, Polisky et al. and Ting et al. teach wherein the primary packaging container is empty when provided for filling according to step (d). Ting et al. disclose the direct filing of the third liquid into primary packaging containers (see claim 8 and paragraph [0035] within Ting et al.). The product would be transferred into an empty, clean, and sterile container.
Regarding instant claim 18, Polisky et al. and Ting et al. teach wherein the mixing of the first stream and the second stream in step (c) is performed using a T-piece, a Y-piece, a static mixer, or a microfluidic mixer. Polisky et al. disclose the use of a static mixer within the disclosed process (see paragraph [0100] within Polisky et al.).
Regarding instant claim 19, Polisky et al. and Ting et al. teach wherein the static mixer comprises a mixing chamber into which each of the first and the second stream are injected through a nozzle such that said streams collide with one another frontally in the mixing chamber. The Examiner established the use of a static mixer by Polisky et al. (see instant claim 18). It would be within the scope of a skilled artisan (POSITA; person of ordinary skill in the art) to have a static mixer design within the claim limitations of instant claim 19.
Regarding instant claim 20, Polisky et al. and Ting et al. teach wherein the mixing chamber is part of a jet impingement reactor. The specific design of the reactor is not novel. A skilled artisan (POSITA) would use the knowledge within the literature (see PTO-892 NPL V) in developing a similar design as taught within instant claim 19.
Regarding instant claim 21, Polisky et al. and Ting et al. teach a primary packaging container comprising the lyophilised composition as obtained in step (e) of the method according to instant claim 1. Please see the discussion and citations within instant claims 1-2 for the necessary rejection text.
Regarding instant claim 22, Polisky et al. and Ting et al. teach a reconstituted lyophilised composition as obtained in step (f) of the method according to instant claim 2. Please see the discussion and citations within instant claims 1-2 for the necessary rejection text.
Regarding instant claim 23, Polisky et al. and Ting et al. teach a kit comprising at least a first kit component and a second kit component, wherein the first kit component comprises a primary packaging container according to claim 21, and wherein the second kit component comprises an amount of a liquid reconstitution solvent according to instant claim 2. A kit-of-parts is not novel. A skilled artisan (POSITA) with the present invention disclosed could construct a kit encompassing the lipid nanoparticle composition and a reconstituting solvent.
Combination of Polisky et al., Ting et al., and Panzner et al.
Regarding instant claim 11, Polisky et al., Ting et al., and Panzner et al. teach wherein the flow rate of the second stream in step (b) is from about 2 times to about 4 times higher than the flow rate of first stream in step (a). Panzner et al. disclose a flow rate for the antisense solution of 56 mL/min, and a flow rate for the lipids of 24 mL/min (see Example 4 within Panzner et al.).
Regarding instant claims 13 and 14, Polisky et al., Ting et al., and Panzner et al. teach wherein the primary packaging container contains an amount of a fourth liquid composition when provided for filling according to step (d), and wherein step (d) results in the mixing of the third and the fourth liquid composition such as to form a fifth liquid composition. Panzner et al. disclose the use of a cryoprotectant such as sucrose at 1-25 wt% (see claims 18-20 and 35 within Panzner et al.). It would be within the scope of a skilled artisan (POSITA) to have a solution of sucrose within the discharge/collection container to act as a cryoprotectant.
Analogous Art
The Polisky et al., Ting et al., and Panzner et al. references are directed to the same field of endeavor as the instant claims, that is, a method of preparing a composition comprising lipid nanoparticles and a biologically active agent selected from oligo- and polynucleotide as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method for preparing a lipid nanoparticle composition as disclosed by Polisky et al., using the teachings of Ting et al., and further in light of the claim-specific feature described in Panzner et al., in order to arrive at the subject matter of the instant claims.
The Polisky et al., Ting et al., and Panzner et al. references all have considerable overlap for the preparation of lipid nanoparticles. In this instance, Polisky et al. supplies the method for preparing the lipid nanoparticle, Ting et al. teach the direct filling of the third liquid composition into a primary packaging container, while Panzner et al. supplies a claim-specific example employing the correct flow rate, and the use of a fourth liquid composition with an additional solution. All references are directed to the preparation of lipid nanoparticle compositions and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the three references when seeking to improve or adapt a method for preparing a lipid nanoparticle composition.
Starting with Polisky et al., the skilled person only had to try the necessary claim limitations disclosed by Ting et al. and Panzner et al. The combination of Polisky et al., Ting et al., and Panzner et al. would allow one to arrive at the present application without employing inventive skill. This combination of the method for preparing lipid nanoparticle compositions taught by Polisky et al. along with the use of the necessary claim limitations taught by Ting et al. and Panzner 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 method for preparing lipid nanoparticle compositions disclosed by Polisky et al. with the use of the necessary claim limitations taught by Ting et al. and Panzner et al. Incorporating the disclosure of Polisky et al. into the specific process nuances presented by Ting et al. and Panzner et al. represents a predictable use of prior art elements according to their established functions, consistent with MPEP §2143 and KSR.
Furthermore, the additional claim limitations taught by Ting et al. and Panzner et al. would have been viewed by a POSITA as routine design optimizations or known modifications to prepare lipid nanoparticle compositions. Implementing these features in Polisky et al.’s method for preparation of lipid nanoparticle compositions would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Polisky et al., supplemented by Ting et al. and Panzner et al. provides all the elements of the claimed invention. The resulting method for preparing lipid nanoparticles constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
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