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 1-18, 20, and 23 are pending in this office action. Claims 19 and 21-22 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on June 14, 2024 is a 371 of PCT/US2022/081623 filed December 15, 2022, which in turn claims domestic priority to provisional patent application 63/290,112 filed December 16, 2021.
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.
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 1-18, 20, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Gindy et al. (WO2015/130584A2) in view of Burke et al. (WO2011/127255A1), Almarsson et al. (WO2020/061295A1, published in March 2020) and Steffen et al. (DE102006054192A1).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Gindy et al.
Gindy et al. is considered the closest prior art to the present invention as it teaches lipid nanoparticle vaccine adjuvants and antigen delivery systems (see title). In addition, Gindy et al. disclose that the instant invention provides for novel lipid nanoparticle (LNP) formulations, containing cationic lipids, for use as vaccine adjuvants and/or as antigen delivery systems. It is an object of the instant invention to provide LNP formulations that demonstrate enhancements in humoral and cellular immunogenicity of vaccine antigens, particularly subunit vaccine antigens, when utilized alone or in combination with immunostimulatory agents (e.g. small molecule or oligonucleotide TLR agonists). The instant invention further identifies physical and chemical properties of the LNP formulations that can be manipulated to enhance antigen efficiency and adjuvant tolerability in vivo (see abstract).
2. Burke et al.
Burke et al. teach preparation of lipid nanoparticles (see title). Also, Burke et al. disclose that the present invention provides a process for producing lipid nanoparticles encapsulating therapeutic products, said process comprising: a) providing one or more aqueous solutions in one or more reservoirs; b) providing one or more organic solutions in one or more reservoirs, wherein one or more of the organic solutions contains a lipid and wherein one or more of the aqueous solutions and/or one or more of the organic solutions includes therapeutic products; c) mixing said one or more aqueous solutions with said one or more organic solutions in a first mixing region, wherein said first mixing region is a Multi-Inlet Vortex Mixer (MIVM), wherein said one or more aqueous solutions and said one or more organic solutions are introduced tangentially into a mixing chamber within the MIVM so as to substantially instantaneously produce a lipid nanoparticle solution containing lipid nanoparticles encapsulating therapeutic products (see abstract).
3. Almarsson et al.
Almarsson et al. teach high-purity PEG lipids and uses thereof (see title). Additionally, Almarsson et al. disclose that the present disclosure is based, at least in part, on the discovery that high-purity PEG lipids exhibit superior physical and biological properties, particularly when used in lipid nanoparticle (LNP) formulations. Therefore, the present disclosure provides PEG lipids at a recommended purity, e.g., for use in formulations, such as LNP formulations. The present disclosure also provides LNPs comprising the high-purity PEG lipids, and methods for delivering therapeutic agents to a subject using the same (see abstract).
4. Steffen et al.
Steffen et al. teach method for loading nucleic acid active substances within amphoteric liposomes, comprises: mixing lipid mixture solution and aqueous solution of nucleic acid active substances; and sterile filtrating the liposomes containing the substances (see title). In addition, Steffen et al. disclose a method for loading of nucleic acid active substances within amphoteric liposomes, comprises: (a) providing a lipid mixture solution; (b) providing an aqueous solution of the nucleic acid active substance; (c) mixing the two solutions by injecting the alcoholic solution of the lipid mixture into the nucleic acid solutions or vice versa; (f) separating the non-included active substance, saturation of the liposome suspension, exchange of the aqueous medium and/or separation of the water-miscible solvent, and (g) optionally sterile filtrating the liposomes containing the active substance. The method for loading of nucleic acid active substances within amphoteric liposomes, comprises: (a) providing a solution of a lipid mixture in a water-miscible solvent, preferably an alcohol that can be optionally acidified; (b) providing an aqueous solution of the nucleic acid active substance to be included that can be optionally acidified, where at least one of the two solutions in (a) and (b) has to be set to a pH value with the help of acids and/or buffer substances; (c) mixing the two solutions by injecting the alcoholic solution of the lipid mixture into the aqueous solution of the nucleic acids or vice versa or by combination of two partial flows of the provided lipid solution and nucleic acid solutions, optionally in one or more mixers; (d) optionally diluting the mixed solutions; (e) breaking up of the interactive forces between the amphoteric liposomes and the nucleic acids through an increase of the pH value to more than 7 or by an increase of the ionic strength and subsequent increase of the pH value to more than 7; (f) separating the non-included active substance and/or saturation of the liposome suspension and/or exchange of the aqueous medium and/or separation of the water-miscible solvent, where each of these steps is independently optional; and (g) optionally sterile filtrating the liposomes containing the active substance, where between the steps (c) and (d) and/or between (d) and (e) and/or between (e) and (f) and/or between (f) and (g), an extruding step can take place and/or between the steps (e) and (f) and/or between (f) and (g), one or more freezing/thawing cycle(s) can take place and/or after step (e), (f) or (g), one or more freezing/thawing cycle(s) and/or a lyophilization of the liposomes containing the active substance can take place. An independent claim is included for the amphoteric liposomes comprising the nucleic acids obtained by the above method (see abstract).
Combination of Gindy et al. and Burke et al.
Regarding instant claim 1, Gindy et al. and Burke et al. teach a process for preparing lipid nanoparticles (LNPs). The necessary citations of Gindy et al. and Burke et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Gindy et al. and Burke et al. Citations
A process for preparing lipid nanoparticles (LNPs), comprising
Gindy et al. disclose the preparation of LNPs (see title, abstract, claims, and Example 1 within Gindy et al.).
mixing a lipid solution with an aqueous buffer solution in a T-Mixer, thereby forming a lipid nanoparticle solution (LNP solution) comprising LNPs,
Gindy et al. disclose mixing a lipid solution with an aqueous buffer solution in a T-Mixer, thereby forming a lipid nanoparticle solution (LNP solution) comprising LNPs, (see Example 1 within Gindy et al.).
wherein: the lipid solution is fed to a lipid inlet of the T-Mixer at a lipid inlet back pressure of about 60 psi or less;
Gindy et al. disclose the instant claim 1 preparation process of LNPs (see Example 1 within Gindy et al.). The process is driven by syringe pumps. The viscosity of the inputs, flow rate, and process chemistry design disclosed by Gindy et al. all suggest limited back pressure. This is further supported by the teachings of Gindy et al. which does not disclose any comment citing back pressure. Therefore, all inputs for the preparation process of LNPs would yield low back pressure using the Gindy et al. disclosure as a template. Furthermore, Gindy et al. disclose a process flow rate of 10-600 mL/min (see page 29, Preparation of LNPs within Gindy et al.).
In order to further support the “back pressure” argument above the Examiner brought in an additional reference (Burke et al.). Burke et al. disclose the preparation of lipid nanoparticles (see title and abstract within Burke et al.) using syringe pumps (see page 19, lines 14-23 within Burke et al.) and that the lipid nanoparticle formulations are prepared rapidly, at low pressure (e.g., <10 psi) and the apparatus and processes of the present invention are fully scaleable (e. g., 0.5 mL-5000 L). At a 1-L scale, lipid nanoparticles are formed at about 0.4-1.7 L/min (see page 18, lines 1-4 within Burke et al.). Moreover, Burke et al. disclose the term "mixing region" optionally is any "mixer" known in the Art (see page 6, lines 33-34 within Burke et al.).
the aqueous buffer solution is fed to a buffer inlet of the T-Mixer at a buffer inlet back pressure of about 60 psi or less; the LNP solution exits an LNP outlet of the T-Mixer at a flow rate of about 500 mL/min or greater;
and the LNPs have an average diameter of about 100 nm or less.
Gindy et al. also disclose the mean geometric diameter of a population of LNPs is about 60 nm, 75 nm, 100 nm, … (see page 30, paragraph 3 within Gindy et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Gindy et al. with the teachings of Burke et al. to support the low back pressure of the LNP preparation process. The motivation for doing so would be to create a low back pressure LNP preparation process for lab implementation.
Combination of Gindy et al., Burke et al., Almarsson et al., and Steffen et al.
Regarding instant claim 2, Gindy et al., Burke et al., Almarsson et al., and Steffen et al. teach wherein: the lipid inlet back pressure of the lipid solution in the T-Mixer is lower as compared to the lipid inlet back pressure of a comparable process using a V-Mixer; the buffer inlet back pressure of the lipid solution in the T-Mixer is lower as compared to the buffer inlet back pressure of a comparable process using a V-Mixer; the diameter of the T-Mixer is greater than the diameter of a V-Mixer used in a comparable process; the LNP flow rate of the LNP solution as the LNP solution exits the T-Mixer is greater than the LNP flow rate of a comparable process using a V-Mixer; and/or the average diameter of the LNPs is less than the average diameter of the LNPs being prepared by a comparable process using a V-Mixer.
A comparison of both V- and T-Mixers illustrate what each unit has as its advantages and disadvantages (see PTO-892 NPL V; 1st NF). Steffen et al. disclose that the overall scale is limited with a V-Mixer (see paragraph [0210] within Steffen et al.). Therefore, it would be obvious that upon scaling the LNP process a V-Mixer would experience more back pressure for the inputs than a T-Mixer. Another parameter to interpret would be the overall scale as a function of the mixing diameter. The Applicant addresses this by setting the limitation, “the diameter of the T-Mixer is greater than the diameter of a V-Mixer used in a comparable process.” However, the full impact of the back pressure would include several parameters (flow rate, diameter, solvent, temperature, etc.) that are captured by the phrase, “comparable process.” Due to the advantages with process scale it would also be obvious that a T-Mixer would experience a greater flow rate than a V-Mixer.
Combination of Gindy et al. and Burke et al.
Regarding instant claims 3-6, Gindy et al. and Burke et al. teach wherein the appropriate back pressure is minimal.
Gindy et al. disclose that the process is driven by syringe pumps. The viscosity of the inputs, flow rate, and process chemistry design disclosed by Gindy et al. all suggest limited back pressure. This is further supported by the teachings of Gindy et al. which does not disclose any comment citing back pressure. Therefore, all inputs for the preparation process of LNPs would yield low back pressure using the Gindy et al. disclosure as a template.
In order to further support the back pressure argument above the Examiner brought in an additional reference (Burke et al.). Burke et al. disclose the preparation of lipid nanoparticles (see title and abstract within Burke et al.) using syringe pumps (see page 19, lines 14-23 within Burke et al.) and that the lipid nanoparticle formulations are prepared rapidly, at low pressure (e.g., <10 psi) and the apparatus and processes of the present invention are fully scaleable (e. g., 0.5 mL-5000 L). At a 1-L scale, lipid nanoparticles are formed at about 0.4-1.7 L/min (see page 18, lines 1-4 within Burke et al.). Moreover, Burke et al. disclose the term "mixing region" optionally is any "mixer" known in the Art (see page 6, lines 33-34 within Burke et al.).
Regarding instant claims 7-9, Gindy et al. and Burke et al. teach wherein the LNP solution exits the LNP outlet of the T-Mixer at a flow rate of about 500 mL/min or greater.
Gindy et al. disclose a process flow rate range of 10-600 mL/min (see page 29, Preparation of LNPs within Gindy et al.).
Regarding instant claims 10 and 11, Gindy et al. and Burke et al. teach wherein the LNPs have an average diameter of about 95 nm or less.
Gindy et al. disclose the mean geometric diameter of a population of LNPs is about 60 nm, 75 nm, 100 nm, … (see page 30, paragraph 3 within Gindy et al.).
Combination of Gindy et al., Burke et al., Almarsson et al., and Steffen et al.
Regarding instant claim 12, Gindy et al., Burke et al., Almarsson et al., and Steffen et al. teach wherein the lipid nanoparticles have an average diameter of about 30 ± 5 nm, about 35 ± 5 nm, or about 40 ± 5 nm.
Almarsson et al. disclose the lipid nanoparticles may have a diameter from about 10 to about 100 nm such as, but not limited to, about 10 to about 20 nm, about 10 to about 30 nm, about 10 to about 40 nm … (see paragraph [00239] within Almarsson et al.).
Regarding instant claims 13-16, Gindy et al., Burke et al., Almarsson et al., and Steffen et al. teach wherein upon mixing, the lipid solution and the aqueous buffer solution form a transient mixture, wherein the concentration of the organic solvent in the transient mixture reduces over an organic solvent drop time, thereby forming the LNP solution.
The concept of a transient mixture and organic solvent drop time is well understood within the process chemistry arts. These both would be observed and modified by a skilled artisan (see PTO-892 NPL W; 1st NF). By adjusting the flow rate, temperature, and viscosity parameters of the organic solvent, a skilled artisan (POSITA; person of ordinary skill in the art) would be able to obtain the instant claim 14-16 limitations (modifications of organic solvent drop time), thereby forming the LNP solution.
Combination of Gindy et al. and Burke et al.
Regarding instant claims 17 and 18, Gindy et al. and Burke et al. teach wherein the lipid solution further comprises a structural lipid, a phospholipid, and an organic solvent.
Gindy et al. disclose the use of the organic solvent ethanol (see Example 1 within Gindy et al.). Furthermore, Gindy et al. disclose the use of a structural lipid (cholesterol) and a phospholipid (DSPC) (see Example 1 within Gindy et al.).
Regarding instant claim 20, Gindy et al. and Kumar et al. teach wherein: the lipid solution further comprises a PEG lipid; and/or the aqueous buffer solution comprises a buffering agent.
Gindy et al. disclose the PEG lipid, PEG-DMG, and an aqueous buffer solution of sodium citrate buffered salt (buffering agent) (see Example 1 within Gindy et al.).
Regarding instant claim 23, Gindy et al. and Burke et al. teach a lipid nanoparticle being prepared by the process of instant claim 1.
Please see the discussion and citations within instant claim 1.
Analogous Art
The Gindy et al., Burke et al., Almarsson et al., and Steffen et al. references are directed to the same field of endeavor as the instant claims, that is, a process for preparing lipid nanoparticles (LNPs) 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 process for preparing lipid nanoparticles (LNPs) disclosed by Gindy et al., using the teachings of Burke et al., Almarsson et al., and Steffen et al. in order to arrive at the subject matter of the instant claims.
The Gindy et al., Burke et al., Almarsson et al., and Steffen et al. references all have considerable overlap with the preparation of LNPs. In this instance, Gindy et al. and Burke et al. supply the template for the process of preparing LNPs, while both Almarsson et al. and Steffen et al. support this process and supplies claim specific examples. All references are directed to the preparation of LNPs and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the four references when seeking to develop a preparation process of LNPs.
Starting with Gindy et al., the skilled person only had to substitute the necessary claim limitations disclosed by Burke et al., Almarsson et al., and Steffen et al. The combination of Gindy et al., Burke et al., Almarsson et al., and Steffen et al. would allow one to arrive at the present application without employing inventive skill. This combination of the process for preparing LNPs taught by Gindy et al. along with the use of the necessary claim limitations taught by Burke et al., Almarsson et al. and Steffen 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 preparation process of LNPs disclosed by Gindy et al. with the use of the necessary claim limitations taught by Burke et al., Almarsson et al., and Steffen et al. Incorporating the disclosure of Gindy et al. into the LNPs prepared by Burke et al., Almarsson et al., and Steffen 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 Burke et al., Almarsson et al., and Steffen et al. would have been viewed by a POSITA as routine design optimizations or known modifications for the preparation of LNPs. The motivation to combine these disclosures would be to expand the research and development work by Gindy et al. within the LNP arena and provide a low back pressure alternative for skilled artisans. Implementing these features in Gindy et al.’s process of preparing LNPs would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Gindy et al., supplemented by Burke et al., Almarsson et al., and Steffen et al. provides all the elements of the claimed invention. The resulting preparation process for LNPs 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.
Response to Arguments
Applicant's arguments filed July 21, 2026 have been fully considered but they are not persuasive.
Applicant Argument: The Applicant argues that the 35 U.S.C. §102 is improper because it does not address the back pressure.
Examiner’s Rebuttal: The 35 U.S.C §102 rejection has been withdrawn from the record due to a full cited explanation not being offered. An additional reference has been added (Kumar et al.), and the rejection has been moved to provide an improved 35 U.S.C. §103 rejection.
[Furthermore, Applicant may also argue impermissible hindsight reasoning. However, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight [or piece-meal reasoning.] But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).]
Thus, the 35 U.S.C. §103 rejection for instant claims 1-18, 20, and 23 is maintained.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
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