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 .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-12) in the reply filed on June 25, 2026 is acknowledged. The traversal is on the grounds that groups I and II are not distinct groups of invention and that there would be no serious search or examination burden for the examination of groups I and II. This is not found persuasive because the differing classifications of groups I and II as described in the Restriction Requirement establishes that examination of the two groups involves different fields of search. Furthermore, per the tests for determination of independent and distinct status of groups provided in MPEP § 806.05(e), the apparatus may be used to perform a different process and used for a different purpose. The recitation of “for producing a liquid with liposomes” in the preamble of claim 13 does not require the device to only be used for that purpose, as the claim is drawn to an apparatus, which is defined by its structural limitations (MPEP § 2111.02(II)).
Claims 13-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on June 25, 2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
The requirement is deemed proper.
Status of Claims
Claims 1-21 are pending.
Claims 13-21 have been withdrawn from consideration.
Claims 1-12 are under examination.
Information Disclosure Statement
The information disclosure statements filed May 19, 2023 and August 25, 2025 are acknowledged and have been considered by the examiner.
Claim Rejections - 35 USC § 112(b)
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.
Claim 8 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 8 recites the broad recitation "at least one organic active substance", and the claim also recites "including an active ingredient for treating a disease" which is the narrower statement of the limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8, 10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Walsh (WO 2015/057998 A1 – provided by applicant in IDS filed May 19, 2023) in view of Cullis 2011 (WO 2011/140627 A1 – provided by applicant in IDS filed May 19, 2023).
Walsh teaches methods and devices for preparing liposomes (pg. 6, lines 6-16). This process involves flowing one stream of one liquid down one channel and flowing a second stream of a second liquid down a second channel and introducing them to a mixer, which may be a microfluidic mixer, in a continuous flow (pg. 8-10). Walsh teaches that the flow rate of either or both of the fluids or the ratio of the two flow rates may be further altered and optimized (pg. 10, second paragraph). Walsh also teaches that gases such as nitrogen or argon may be used to provide pressure to flow the liquids through the system (pg. 10, third paragraph). Walsh teaches that this method is useful for the manufacture of high quality particles at small scales (pg. 2, second paragraph).
Walsh does not explicitly teach a method in which the total flow rate of the liquids is at least 10 mL/min at the outlet of the micromixer. Walsh also does not teach a method further comprising directing the liquid with liposomes along a third fluid line into a further mixer and directing a further liquid from a third containing along a fourth fluid line into a second inlet of the further mixer in a flow adjacent to the liquid with liposomes up to the outlet of the further mixer wherein the liquid with liposomes and further liquid mix inside the further mixture and a changed liquid with liposomes is discharged, wherein directing the liquid with liposomes and the further liquid into the further mixer is performed via gas pressure from at least one gas source and/or via at least one device for delivering liquid.
Cullis 2011 teaches a method of preparing lipid nanoparticles using a microfluidic mixing device (Abstract). One embodiment of Cullis 2011 uses the device of Figure 3 wherein solutions containing a therapeutic agent (in the “A” sections) are mixed with solutions containing lipid particle forming materials (in the “B” sections) in C-b to produce lipid nanoparticles and a further solution (in the “D” section) is added to the system and mixed with the liposomes in E-b to produce a product that has been further processed through either dilution, pH adjustment, or other events (pg. 28, second paragraph). Cullis 2011 teaches that such devices can be arrayed (such as is depicted in Figures 6-7) to increase flow rates (pg. 28, last paragraph to pg. 29, first paragraph). Cullis 2011 describes that any number of parallel reagent inlets, sequential mixing chambers, and branching architectures may be used to optimize lipid nanoparticle formulation (pg. 31, first paragraph). Cullis 2011 describes that Figure 10 depicts a device in which two or more mixers in sequence allow for the sequential addition of lipid nanoparticle reagents or formulation processing steps, allowing for the integration of dilution, pH adjustments, and other events (pg. 31, first paragraph). Figures 11 and 12 depict alternative arrangements of such devices. Cullis 2011 teaches that the flow rate of the described method can be increased by preparing arrays of the mixing microfluidics; teaching that a system with a single mixer may be used at 1 mL/min, while a 10 mixer array can be used at 40 mL/min and a 100-plex array used at 400 mL/min (pg. 25, second paragraph). Example 4 of Cullis 2011 describes a sequential mixing method wherein an aqueous solution with siRNA is mixed with a lipid solution in ethanol to form liposomes, acetate buffer is introduced to reduce the ethanol concentration, and another lipid solution is further added and mixed with the liquid with liposomes to produce a final product (pg. 50). The examiner notes that Figure 29 appears to depict a diagram for a microfluidic device that could perform the method of Example 4.
A person or ordinary skill in the art would recognize that both Walsh and Cullis 2011 teach methods of making liposomes using micromixers. It would be recognized that Cullis 2011 teaches that arraying microfluidic mixing systems for producing lipid nanoparticles allows the increase of flow rate by a factor roughly equivalent to that of the ratio of the number of micromixers (e.g., 10 mixer to 100 mixer resulting in a flow rate change from 40 mL/min to 400 mL/min, both are 10-fold increases). It would also be recognized that Cullis 2011 teaches appending additional sequential additions and mixing after a first mixing step and demonstrates compatibility of adding further mixing steps with the performance of a first mixing step.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Walsh with the arraying of the microfluidic system and integration of further liquids and mixers as taught by Cullis 2011 because these claim elements were known in the art and one of ordinary skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method of producing a liquid with liposomes using an arrayed microfluidic mixing system and comprising further liquids and further mixers.
A person of ordinary skill in the art would have had a reasonable expectation of success in applying the microfluidic arraying as taught by Cullis 2011 because in Figure 6 of Cullis 2011, the first and second inlet and the 610a region of the microfluidic system is analogous to that of Figure 3 of Walsh in that there are two inlets, a micromixer region, and an outlet. Cullis 2011 teaches a way to prepare such a device in an arrayed form in Figure 7. Furthermore, the skilled artisan would have had a reasonable expectation of success integrating the further liquids and mixers as taught by Cullis 2011 because Cullis 2011 teaches appending sequential mixing steps to a first mixing step. It would be recognized that Figure 2 of Cullis 2011 is analogous to Figure 2 of Walsh wherein the mixer of Walsh is similar to feature C-b of Cullis 2011. Figure 3 of Cullis 2011 depicts a way to modify a microfluidic device such as that of Figure 2 of Cullis 2011 to incorporate a further solution addition and mixing step in a way that would be compatible with the device of Walsh. Cullis 2011 teaches additional microfluidic device structures, further exemplifying ways to introduce further mixing steps in a microfluidic device for liposome production (Figures 4, 6, 10, 11, and 12).
The skilled artisan would have been motivated to make these modifications because arraying the microfluidic system enables use at higher flow rates, generating larger volumes of product and larger scales of production, which is desirable in manufacturing. Furthermore, the sequential addition and mixing steps enable the continuous addition of further components and formulation of liposome products, which is a faster and simpler process than stopping production after each step, isolating a product, and performing the next step.
Regarding claim 1, Walsh teaches a method of making particles, including liposomes (pg. 6, lines 6-16), in which mixing is performed with continuous flow (pg. 10, first paragraph). Therefore, the examiner interprets the method of Walsh to be a continuous method. The mixer chip used by Walsh (Figures 2, 3, 7, and 7) contain two wells for inputs, which in the context of liposome preparation can be one well for a lipid solution and one well for an aqueous solution (Figure 3). The brief description of Figure 3 describes that the lipid well is for an ethanol/lipid phase, thus the examiner interprets this to be a liquid comprising at least one lipid in a container. The aqueous phase in the other well is interpreted to be a second liquid comprising water in a second container. Figure 3 shows that from these input wells (containers), the first and second liquid are directed along first and second fluid lines to inlets into the micromixer section. Figure 10 depicts a syringe containing air attached to the mixing system. Walsh describes that the air-filled syringe plunger can be pushed down to provide pressure using the air to force fluids through the mixing device (pg. 5, last paragraph). Walsh teaches that the flow rates of one or both of the fluid streams can be altered by changing the fluid line impedances and pressure applies (pg. 10, second paragraph). Walsh further describes that the microfluidic process utilizes relatively rapid mixing and high flow rates (pg. 16, 5th paragraph). While Walsh does not explicitly teach a flow rate of at least 10 mL/min at the outlet of the micromixer, as the method is to be performed at “high flow rates,” and the pressure of the gas applied may be varied, it would amount to routine optimization to select the particular flow rate to perform the method (MPEP § 2144.05(II)). Furthermore, Cullis 2011 teaches preparing an array of microfluidic mixers for preparing liposomes and that doing so increases the total flow rate that can be put through the system (pg. 25, second paragraph). Cullis 2011 teaches that an array can multiply the possible total flow rate of the system, for example scaling from 10 mixers to 100 mixers enables a flow rate change from 40 mL/min to 400 mL/min (both are 10-fold increases). This suggests a wide range of flow rates, including those over 10 mL/min would be achieved by applying the multiplexing taught by Cullis 2011 to Walsh. Additionally, the nature of Walsh teaching that the flow rate can be altered suggests a reader should optimize such a parameter in the method for preparing liposomes. The skilled artisan would be motivated to do so to optimize product quality and speed up production time. The skilled artisan would have an expectation of success because Walsh teaches that flow rate can be altered and this would be done by simply applying different amounts of gas pressure. Therefore, the combined teachings of Walsh and Cullis 2011 render claim 1 obvious.
Regarding claim 2, Walsh teaches that the microfluidic device used to present containers for the first and second liquid and provide inlets, a micromixer, and an outlet is made by lithography of an elastomer or CNC milling or injection molding a hard thermoplastic (pg. 14). The use of such devices would result in the first and second fluid only contacting surfaces that do not comprise glass, reading on option iv). As the options i) through iv) in claim 2 are understood to be provided in the alternative, the teachings of Walsh rendering option iv) obvious renders the claim as a whole obvious. Therefore, the combined teachings of Walsh and Cullis 2011 render claim 2 obvious.
Regarding claim 3, Figure 10 of Walsh shows that a syringe filled with air may be attached to the two input wells in the device of Walsh using a connector. This connector is interpreted to make first and second fluidic connections to the first and second input wells (containers). Additionally, Walsh teaches that alternatively to air, nitrogen or argon gases may be used to force fluids through the mixer (pg. 10, third paragraph). Therefore, the combined teachings of Walsh and Cullis 2011 render claim 3 obvious.
Regarding claim 4, the description of Figure 3 (pg. 4, last paragraph) depicts and embodiment of Walsh for use to achieve a flow ratio of 3:1 or 2.5:1 aqueous (water-containing phase) to ethanol (lipid containing phase). Both of these are within the claimed range of less than 8:1, rendering this limitation obvious (MPEP § 2144.05(I)). As the options i) through vii) in claim 4 are understood to be provided in the alternative, the teachings of Walsh rendering option v) (flow rate ratio) obvious renders the claim as a whole obvious. Therefore, the combined teachings of Walsh and Cullis 2011 render claim 4 obvious.
Regarding claim 5, Walsh teaches that the micromixer used in the liposome preparation method may be a herringbone mixer, zig-zag mixer, micro-jet mixer, micro-vortex mixer, tesla mixer, or a tear drop mixer. These are understood by the examiner to include mixing structures extending obliquely or transversely to the flow direction, reading on option i). As the options i) through v) are provided in the alternative, the teachings of Walsh rendering option i) obvious renders the claim as a whole obvious. Therefore, the combined teachings of Walsh and Cullis 2011 render claim 5 obvious.
Regarding claim 6, Figure 3 of Walsh depicts an input well containing a lipid phase. The description of this figure (pg. 4) describes the input as an ethanol/lipid phase. This implies the presence of at least one lipid in this input well. Furthermore, Walsh teaches that the lipid particles may include PEG-lipid, which the examiner interprets to be a PEGylated lipid (pg. 18, last paragraph). Walsh also teaches that the lipid particles may include sterols, including cholesterol (pg. 24, second paragraph). Additionally, the example of Walsh teaches a first liquid containing CL, DSPC, cholesterol, and PEG-lipid in ethanol at a total lipid concentration of 30.5 mg/mL (pg. 36, last paragraph). Therefore, Walsh is understood to teach options i), ii), iii), iv), vi), and viii) of claim 6. As these options are listed in the alternative, the teachings of Walsh rendering any of these options obvious renders the claim as a whole obvious. Therefore, the combined teachings of Walsh and Cullis 2011 render claim 6 obvious.
Regarding claim 7, Walsh teaches that the aqueous phase may include citrate or acetate buffers (pg. 17, last paragraph). Additionally, the example of Walsh uses an aqueous phase including 25 mM acetate, pH 4.0 buffer (pg. 36, last paragraph). Therefore, Walsh is understood to teach a second liquid comprising a buffer substance. Therefore, the combined teachings of Walsh and Cullis 2011 render claim 7 obvious.
Regarding claim 8, the example of Walsh produces a liposome encapsulating siRNA (pg. 36-38), which the examiner interprets to be an organic active substance. Walsh also teaches that the lipid nanoparticles are suitable for carrying therapeutic materials (pg. 6, lines 8-16). Walsh defines that such therapeutic materials may be used to treat disease (pg. 34, third paragraph). Therefore, the combined teachings of Walsh and Cullis 2011 render claim 8 obvious.
Regarding claim 10, the example of Walsh teaches preparation of liposomes with a diameter of 94.1 nm, as measured by dynamic light scattering (pg. 38, LNP Characterization; and Table 1). Additionally, Walsh teaches that the lipid particles made by the taught method may have diameters of about 30 to about 200 nm. This range overlaps with the claimed range of 20-200 nm, rendering it obvious (MPEP § 2144.05(I)), thus reading on option ii). As the limitations of claim 10 are listed in the alternative, the teachings of Walsh rendering any of these options obvious renders the claim as a whole obvious. Therefore, the combined teachings of Walsh and Cullis 2011 render claim 10 obvious.
Regarding claim 12, as described above, the teachings of Walsh and Cullis 2011 render the method of claim 1 obvious. Additionally, Cullis 2011 teaches a method of preparing liposomes including sequential addition of further solutions (such as a buffered aqueous solution or a lipid solution) and performing further mixing steps (Figure 3 and pg. 50). Based on the depiction of Cullis 2011 Figure 3, the examiner interprets the method of Cullis 2011 to direct the liquid with liposomes at the outlet of a first micromixer (C-b) along a third fluid line into an inlet of a further micromixer (E-b) and up to an outlet of the further micromixer and directing a further liquid from a third container along a fourth fluid line (D-a, D-b, D-c) into an inlet of the further micromixer (E-b) in a flow adjacent of the liquid with liposomes and up to the outlet of the further mixer. Cullis 2011 teaches that such sequential additions and mixing can be used to dilute the liquid with liposomes (reduce the ethanol concentration), adjust pH, or introduce additional components (such as additional lipids) (pg. 28, second paragraph). Thus, the examiner interprets this to mean that the mixing (such as that done in E-b of Cullis 2011 Figure 3) would produce a changed liquid with liposomes. As described above, the teachings of Walsh render the limitation of a flow rate of more than 10 mL/min obvious. Furthermore, Cullis 2011 teaches that arraying a microfluidic device for preparing liposomes, such as the one used for sequential addition of other liquids, can enable high flow rates such as 400 mL/min (pg. 25, second paragraph). Additionally, as described above, Walsh teaches using a gas source (such as an air-filled syringe) to provide pressure to force fluids through the mixing device (pg. 5, last paragraph; and Figure 10). As depicted in Walsh Figure 10, the gas source can be fitted with an adaptor such that the gas pressure from one source is applied to multiple inlets. As Cullis 2011 depicts example microfluidic devices in which a third inlet is provided with close proximity to a first and second inlet (Figures 6 and 10), it would be possible to modify an adaptor like that of Walsh to also apply gas pressure to the third inlet. Thus, the flow of the combined method would be induced by gas pressure from at least one gas source. Therefore, the combined teachings of Walsh and Cullis 2011 render claim 12 obvious.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Walsh and Cullis 2011 as applied to claims 1-8, 10 and 12 above, and further in view of Cullis 2013 (WO 2013/059922 A1).
As described above, the combination of Walsh and Cullis 2011 teaches methods and devices for preparing liposomes. The method of Walsh involves flowing one stream of one liquid down one channel and flowing a second stream of a second liquid down a second channel and introducing them to a mixer, which may be a microfluidic mixer, in a continuous flow (pg. 8-10). Walsh teaches that the flow rate of either or both of the fluids or the ratio of the two flow rates may be further altered and optimized (pg. 10, second paragraph). Walsh also teaches that gases such as nitrogen or argon may be used to provide pressure to flow the liquids through the system (pg. 10, third paragraph). Walsh teaches that this method is useful for the manufacture of high quality particles at small scales (pg. 2, second paragraph). Additionally, Cullis 2011 teaches a method of preparing lipid nanoparticles using a microfluidic mixing device (Abstract). Cullis 2011 teaches that such devices can be arrayed (such as is depicted in Figures 6-7) to increase flow rates (pg. 28, last paragraph to pg. 29, first paragraph). Furthermore, Cullis 2011 describes that any number of parallel reagent inlets, sequential mixing chambers, and branching architectures may be used to optimize lipid nanoparticle formulation (pg. 31, first paragraph). Cullis 2011 describes that Figure 10 depicts a device in which two or more mixers in sequence allow for the sequential addition of lipid nanoparticle reagents or formulation processing steps, allowing for the integration of dilution, pH adjustments, and other events (pg. 31, first paragraph). Figures 11 and 12 depict alternative arrangements of such devices.
The combination of Walsh and Cullis 2011 does not teach specifically tempering any step of the method to a temperature between 10°C and 70°C.
Cullis 2013 teaches methods and apparatuses for preparing lipid nanoparticles with a diameter of 10-100 nm (Abstract). Such lipid nanoparticles may be used for the delivery of therapeutic and/or diagnostic agents (pg. 2, third paragraph). The method of Cullis 2013 includes providing a first solution in a first inlet and second solution in a second inlet, flowing the solutions at different flow rates along adjacent streams, mixing the solutions, and producing a third stream out the outlet (pg. 3-4). Cullis 2013 teaches that the mixer used to prepare the lipid nanoparticles is may be a micromixer (pg. 12, fourth paragraph). Cullis 2013 specifically teaches using a staggered herringbone micromixer (Figure 1; and pg. 29, last paragraph). Cullis 2013 teaches that the method can be performed using parallel fluidic structures in which an array of mixing structures enables production of lipid nanoparticles at flow rates of about 2 to about 1600 mL/min (pg. 22-23, Parallel Fluidic Structures; and Figures 7A-C). Cullis 2013 teaches embodiments in which the solutions are passed through heating elements (Figures 12-14). Cullis 2013 teaches that the heating element is effective to increase the temperature of the first and second streams in the first and second microchannels at a desired temperature (pg. 24, second paragraph). Cullis 2013 describes preparing doxorubicin-loaded POPC/PEG with heating the solutions to 60°C prior to mixing while doxorubicin-loaded POPC/Chol/PEG liposomes were prepared at 37°C (pg. 20-21), suggesting the heating element temperature can be varied depending on the composition of the liposomes being made.
A person of ordinary skill in the art would recognize that both Walsh, Cullis 2011, and Cullis 2013 teach methods of making liposomes using micromixers. It would also be recognized that Cullis 2013 discloses embodiments with and without heating chambers, suggesting that heating chambers can be applied to systems not already possessing them.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Walsh and Cullis 2011 with the heating chambers of Cullis 2013 because these claim elements were known in the art and one of ordinary skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method of preparing a liquid with liposomes wherein the input liquids are tempered.
A person of ordinary skill in the art would have had a reasonable expectation of success in incorporating the heating chambers of Cullis 2013 into the combined method of Walsh and Cullis 2011 because Cullis 2013 teaches incorporating heating elements into a similar microfluidic device to that of Walsh. Cullis 2013 Figure 1 is similar to Walsh Figure 3 in that there are two fluid inlets, two stream paths, a mixing section, and an outlet path. Cullis 2013 Figures 12-14 depict how heating chambers may be introduced between inlets and/or the outlet and the micromixer section. Thus, the skilled artisan would be able to understand from Cullis 2013 how to incorporate heating chambers into the apparatus used in the method of Walsh.
The skilled artisan would have been motivated to make this modification because Cullis 2013 teaches that using specific temperatures in liposome preparation can increase stability (pg. 21, second paragraph) and that heating solutions can enable increased flow rate (pg. 28, second paragraph). Increased flow rate and increased liposomes stability are desired in the production of liposomes.
Regarding claim 9, as described above, the combined teachings of Walsh and Cullis 2011 render the method of claim 1 obvious. Additionally, Cullis 2013 teaches a method of preparing liposomes using a micromixer incorporating heating chambers between inlets and the micromixer (Figures 12-14; and pg. 24, second paragraph). Cullis 2013 includes specific examples in which the heating element is used to prepare POPC/PEG lipid nanoparticles at 60°C and POPC/Chol/PEG lipid nanoparticles at 37°C by applying heat between the inlet and the micromixer, while the fluid is directed along a fluid line. As both 60°C and 37°C fall within the claimed range of > 10°C to < 70°C, this teaching renders the claimed range obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Walsh, Cullis 2011, and Cullis 2013 render claim 9 obvious.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Walsh and Cullis 2011 as applied to claims 1-8, 10, and 12 above, and further in view of Dimov (Dimov, N.; et all, Sci. Rep., 2017).
As described above, the combination of Walsh and Cullis 2011 teaches methods and devices for preparing liposomes. The method of Walsh involves flowing one stream of one liquid down one channel and flowing a second stream of a second liquid down a second channel and introducing them to a mixer, which may be a microfluidic mixer, in a continuous flow (pg. 8-10). Walsh teaches that the flow rate of either or both of the fluids or the ratio of the two flow rates may be further altered and optimized (pg. 10, second paragraph). Walsh also teaches that gases such as nitrogen or argon may be used to provide pressure to flow the liquids through the system (pg. 10, third paragraph). Walsh teaches that this method is useful for the manufacture of high quality particles at small scales (pg. 2, second paragraph). Additionally, Cullis 2011 teaches a method of preparing lipid nanoparticles using a microfluidic mixing device (Abstract). Cullis 2011 teaches that such devices can be arrayed (such as is depicted in Figures 6-7) to increase flow rates (pg. 28, last paragraph to pg. 29, first paragraph). Furthermore, Cullis 2011 describes that any number of parallel reagent inlets, sequential mixing chambers, and branching architectures may be used to optimize lipid nanoparticle formulation (pg. 31, first paragraph). Cullis 2011 describes that Figure 10 depicts a device in which two or more mixers in sequence allow for the sequential addition of lipid nanoparticle reagents or formulation processing steps, allowing for the integration of dilution, pH adjustments, and other events (pg. 31, first paragraph). Figures 11 and 12 depict alternative arrangements of such devices.
The combination of Walsh and Cullis 2011 does not teach a method of preparing a liquid with liposomes comprising a further purification step.
Dimov teaches a continuous method of preparing drug loaded liposomes including a purification step (pg. 1, Abstract). More specifically, Dimov teaches using a micromixer to generate liposomes and continuously feeding a tangential flow filtration unit (pg. 6, last paragraph and Figure 4). Dimov teaches using the tangential flow filtration to perform cycles of diafiltration (pg. 7, first paragraph). Dimov teaches performing the same method with drug-loaded liposomes (pg. 7, second paragraph). Dimov teaches that the filtration purification successfully removed free (non-encapsulated) drug from the liquid with liposomes (pg. 7, third paragraph). Dimov teaches that the continuous method incorporating a filtration step improves ease and speed of production of drug-loaded liposomes compared to alternative methods such as dialysis (pg. 3, second and third paragraphs).
A person of ordinary skill in the art would recognize that Walsh, Cullis 2011, and Dimov teach methods of preparing therapeutic-loaded liposomes using micromixers. It would also be recognized that Dimov teaches appending a filtration purification step to receive the contents of the outlet of a micromixer.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Walsh and Cullis 2011 with the addition of a further purification step as taught by Dimov because these claim elements were known in the art and one of ordinary skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method of preparing a liquid with liposomes further comprising a filtration purification step.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding the purification step of Dimov to the method of Walsh because Dimov depicts the apparatus including the purification step in which the micromixing formation unit (Figure 4) is similar to that which is taught by Walsh (Figure 3) in that there are two inlet streams, a micromixer, and an outlet fluid line. Dimov teaches appending additional components after the micromixer and demonstrates feasibility in doing so. Likewise, it would be predictable that the purification component of Dimov could be applied after any series of sequential mixers (such as those taught in Cullis 2011).
The skilled artisan would have been motivated to make this modification because Dimov teaches that the continuous purification method enables faster purification of drug-loaded liposomes products. Faster production times is desirable in liposome manufacturing.
Regarding claim 11, as described above, the teachings of Walsh and Cullis 2011 render the method of claim 1 obvious. Additionally, Dimov teaches a method of preparing liposomes wherein the liquid with liposomes that exits the micromixer is then purified by tangential flow filtration (pg. 6, last paragraph and Figure 4). Dimov teaches performing this purification in the preparation of drug-loaded liposomes results in the removal of free drug from the liquid with liposomes (pg. 7, third paragraph). The examiner understands this to mean that a substance (the free drug) present in addition within the liquid with liposomes upon exit from the micromixer was removed, thus reading on option ii) in the claim. Therefore, the combined teachings of Walsh, Cullis 2011, and Dimov render claim 11 obvious.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached at (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
Prosecution Insights