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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/19/2026 has been entered.
Applicants' arguments, filed 02/19/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 1 and 3-20 are pending and under examination.
Claim Rejections - 35 USC § 112(b) or pre-AIA 2nd ¶
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 18 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 18 recites the limitation "removing organic solvent(s)" in line 5. There is insufficient antecedent basis for this limitation in the claim. Claim 18 depends from claim 1 where “an organic solvent” (i.e., singular) is recited. Accordingly, organic solvent(s), which includes plural solvents, lacks antecedent basis. For purposes of examination, the claim is interpreted as “removing the organic solvent.”
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, 3-14, and 16-20, are rejected under 35 U.S.C. 103 as being unpatentable over Bowman et al (US 20170196809 A1, hereinafter “Bowman”), in view of PharmTech (PharmTech, 2017, pp 1-9), MacSweeney et al (US 20200060321 A1, hereinafter “MacSweeney”, cited on IDS dated 08/19/2025), and Johnson et al (Ind. Eng. Chem. Res., 2009, 48, 17, pp 7945-7958, hereinafter “Johnson”).
Bowman discloses methods of formulating lipid nanoparticle formulations comprising intersecting an aqueous nucleic acid stream and a stream of lipids in organic solvent at high linear velocities (abs). The lipid nanoparticles may be liposomes (¶ 243). Bowman discloses embodiments comprising a single nucleic acid stream and a single lipid stream mixed from opposing directions using a T-shaped mixing chamber (fig. 3a) and subsequently diluted with water (¶ 349). The T-shaped mixing chamber has two entry passages for one nucleic acid stream and one lipid stream (¶ 287). The lipids stream was made up of 45% cationic lipid A1, 2% PEG lipid B1, 44% cholesterol (amphiphilic lipid, see pg 5 of the instant specification), and 9% DSPC (comprises phosphatidylcholine, a glycerophospholipid and amphiphilic lipid, see pg 5 of the instant specification) (¶¶ 346, 349). The total concentration of the lipids in the ethanol stream was 16.7 mg/mL (¶ 349). The lipid linear velocities were 1.7 and 3.4 m/s and the siRNA linear velocity was as low as 5.1 and as high as 13.6 m/s (table 7). The lipid flow rates were 20 and 40 mL/min and the siRNA flow rate was 60, 80, or 120 mL/min (table 7). The nanoparticles have a z-average diameter ranging from 58-67 nm (table 7). Table 7 discloses 3 embodiments as with a PDI of 0.110, 0.100, and 0.108 (table 7). The flow rates of the two streams can be the same (table 8). The flow rate ratio of the lipid stream and aqueous stream can be adjusted to achieve the targeted lipid to nucleic acid ratio (¶¶ 277, 298). In embodiments, the flow rates of lipid stream to aqueous stream ranged from 1:1 to about 1:9 (table 10). The resulting nanoparticles can be further processed by filtration (¶ 259), including sterile filtration (¶ 317). The process may be further optimized by various optimization techniques known to those of skill in the art, such as adjusting the lipid molar ratio, adjusting the desired particle size, processing parameters, etc. (¶ 263).
Bowman is discussed above but does not specifically teach the use of a jet impingement reactor comprising pinholes as instantly claimed, nor the distance between the pinholes as instantly claimed.
PharmTech teaches microjet reactor technology, comprising a mixing chamber where two liquid streams are delivered though nozzles with sizes between 50-1200 microns, forming impinging gets that meet in the middle of the reactor here a quick and efficient mixing takes place. Microjet impinging mixing was known to be used for the production of nano- and micro- particle formulations, including liposomes (pg 2). Microjet reactor technology enables the production of homogenous particles with a narrow particle size distribution because it is a continuous production technology, in which the particle size is not affected by the batch size, but is controlled throughout production (pg 4). Particle size and particle size distribution are controlled with variation of production parameters such as nozzle size, flow rate temperature, and pressure (pg 3). The combination of the nozzle size and flow rate determines the mixing velocity of the two phases, which affects the particle size (pg 3). The mixing time of solvent and non-solvent can be controlled by the flow rates of solvent and non-solvent (pg 3). If the flow rate is increased, the velocity of the impinging jets are also increased, in which case they meet with a higher pressure in the microjet reactor, resulting in shorter mixing times (pg 3). Shorter mixing times of the solvent and the non-solvent in the reactor create smaller particles (pg 3). An increase in the temperature results in an increase in the particle size (pg 3). Particle size can be optimized through production parameters, including flow rate, mixing ratio, temperature, and pressure, of the microjet impingement reactor setup (pg 4 last ¶).
PharmTech does not teach the hydrodynamic pressures and flow rates of each stream in the microjet mixer, nor the distance between the pinholes as instantly claimed.
MacSweeney teaches a microjet reactor of colliding jet streams at a defined pressure and flow rate in order to produce nanoparticles (abs, ¶ 33). The microjet reactor has at least two nozzles oriented to impinge their respective flow streams at an angle ranging from 90-180 degrees relative to the other (¶ 40). The nozzles of the microjet reactor at preferably smaller than 1,000 microns and have a driving pressure of at least 0.2 bar (¶ 47). The pressure can be controlled by the pressure regulator associated with the feed stream to each of the first and second microjet nozzles (¶ 47). The streams each independently have a flow rate of greater than 0.1 ml/min and produce impinging jets (¶ 46). The method was known to produce nanoparticles with a polydispersity index of less than 0.5, preferably within the range of 0.001 to less than 0.25 (¶¶ 52, 57).
MacSweeney does not specifically teach the distance between the pinholes as instantly claimed.
Johnson teaches impinging jet reactors with a confined mixing chamber to produce nanoparticles, where it was known that the chamber diameter to jet diameter ratio can have an effect on the mixing process performance (pg 2265 2nd col 2nd ¶). Internozzle separation was known to be 4.76, 9.5, and 19.0 times the jet diameter, which was tested at 250 microns (pg 2276 1st col last ¶). From the multiples of 4.8 to 19.0, the chamber had no effect on process performance compared to free impinging jets, and the mixing was completed prior to reaching the mixing chamber outlet (pg 2278 2nd col 2nd ¶).
Regarding the jet impingement reactor of claim 1, it would have been obvious to modify the process of Bowman, by using other known techniques suitable for liposomal nanoparticle formulation by mixing two streams, such as a micro jet impingement reactor as taught by PharmTech, and where micro jet impingement reactors were known to produce liposomes with controllable particle size and particle size distribution. While PharmTech does not specifically teach the processing parameters of the micro jet impingement reactor (i.e., pressure, flow rate, etc.), it was known from MacSweeney that microjet reactors, were used to mix two streams at angle up to 180 degrees relative to the other, in order to formulate nanoparticles. As such, it would have been obvious for the skilled artisan to substitute a the microjet impingement reactor of PharmTech (i.e., a jet impingement reactor, see pg. 2 of the instant specification) for the device used by Bowman, where micro jet impingement reactors were known to be suitable for formulating liposomes, and where the device of Bowman and the microjet impingement reactor were known for impinging two streams at 180 degrees for nanoparticle formation. Further, it appears that the device used by Bowman performs the identical function in the claim in substantially the same way, such as by impinging two streams at 180 degrees for nanoparticle formation, and produces substantially the same results as the jet impingement reactor made obvious above. A person of ordinary skill in the art would have recognized the interchangeability of the element shown in the prior art for the corresponding element disclosed in the specification. See MPEP 2183(A) and (B).
Regarding the collision point of claim 1, where the two streams made obvious above collide at 180 degrees, the limitation of colliding at a collision point is met.
Regarding the distance between the pinholes of claim 1, it would have been obvious to use known distances between the two jet nozzles in the jet impingement reactor in the method made obvious above, such as from 4.8 to 19.0 times the nozzle diameter, where these distances were known to not have a negative impact on mixing performance in reaction chambers, as taught by Johnson. Accordingly, where nozzle diameters ranging from 50-1200 microns were suitable for microjet impinging reactors, as taught by PharmTech, it would have been obvious to set the distance from the two nozzles ranging from 240 microns to 22,800 microns (i.e., 0.024 to 2.28 cm), falling within the claimed range.
Regarding the jet velocity of claim 1, it would have been obvious to use known velocities of the two streams taught to be suitable for liposomal formation, such as 1.7, 3.4, 5.1, and 16.3 m/s, as taught by Bowman, and where Bowman teaches the velocities of the two streams can be the same, all falling within the claimed range. Additionally, it would have been obvious for the skilled artisan to adjust the processing parameters, such as the flow rate, etc., in order to routinely optimize the resulting liposomal dispersion to achieve desired characteristics for desired uses, as taught by PharmTech. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144(II)(A).
Regarding the liposome dispersion of claim 1, while not explicitly stated as such, where the combination made obvious above teaches a method as instantly claimed, comprising a first stream comprising an organic solvent and an amphiphilic lipid, a second stream comprising nucleic acid active agent and aqueous, where the two streams are ejected and collided at opposing directions (i.e., 180 deg angle), it appears a liposome dispersion is produced where the same components instantly claimed and the same active steps are met. Additionally, where a lipid stream is mixed with an aqueous stream, it would be expected that the resulting liposomes would be dispersed in the aqueous solution.
Regarding ejecting through pinholes of claim 1, the instant claims and specification do not limit the term “pinholes,” and the instant specification recites that pinholes are also referred to as nozzles where the streams are directed to collide at an angle of 180 deg (see pg. 5 of the instant specification).
Regarding claim 3, the aqueous stream of Bowman comprises a nucleic acid, which reads on an active pharmaceutical ingredient where nucleic acids are listed as suitable active pharmaceutical ingredients in the instant specification (see pp. 5 and 6 of the instant specification).
Regarding claims 4-6, it would have been obvious to formulate the liposome dispersion made obvious above with a first or second stream hydrodynamic pressure of at least 0.2 bar (i.e., at least 20 kPa), which were known to be suitable for nanoparticle formulations by colliding a first and second stream prepared by a microjet reactor, as taught by MacSweeney. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Additionally, it would have been obvious for the skilled artisan to adjust the processing parameters, such as pressure, etc., in order to routinely optimize the resulting liposomal dispersion to achieve desired characteristics for desired uses, as taught by PharmTech. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144(II)(A).
Regarding claim 7, where pressures of at least 0.2 bar (i.e., at least 20 kPa) are made obvious above, where Bowman teaches flow rates and velocities of the streams vary, and where MacSweeney teaches that the flow rates and pressures of each stream can be controlled, it would have been obvious for the skilled artisan to start with equal pressures and adjust from there in order to achieve desired liposomal properties. Additionally, it would have been obvious for the skilled artisan to adjust the processing parameters, such as flow rate, pressure, etc., in order to routinely optimize the resulting liposomal dispersion to achieve desired characteristics for desired uses, as taught by PharmTech. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144(II)(A).
Regarding claim 8, the lipid stream of Bowman comprises amphiphilic lipids cholesterol and DSPC.
Regarding claim 9, the lipid stream of Bowman comprises a total lipid concentration of 16.7 mg/mL, which comprises 9% DPSP, thereby resulting in 1.503 mg/mL DSPC (comprises phosphatidylcholine).
Regarding claim 10, the lipid stream of Bowman comprises a total lipid concentration of 16.7 mg/mL, which comprises 44% cholesterol, thereby resulting in 7.35 mg/mL cholesterol.
Regarding claim 11, where flow rate is volume per unit time, it appears that the volume ratio given over the same time interval would be proportional to the flow rate. Further support is provided by the instant specification were it is recited that the volume ratio is proportional to the flow rate ratio, and that volume ratio may also be understood as the flow rate ratio (see end of pg. 10 of the instant specification). Therefore, where the embodiments of Bowman have flow rate ratios of the lipid stream to aqueous stream ranging from 1:1 to about 1:9, it would have been obvious to use these ratios, thereby resulting in a volume ratio of the lipid stream to aqueous stream that falls within the volume ratio instantly claimed. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). Additionally, it would have been obvious for the skilled artisan to adjust the processing parameters, such as flow rate, mixing ratio, etc., in order to routinely optimize the resulting liposomal dispersion to achieve desired characteristics for desired uses, as taught by PharmTech. See MPEP 2144(II)(A).
Regarding claim 12, it would have been obvious to use known velocities of the two streams taught to be suitable for liposomal formation, such as 1.7, 3.4, 5.1, and 16.3 m/s, as taught by Bowman, and where Bowman teaches the velocities of the two streams can be the same, all falling within the claimed range.
Regarding claim 13, it would have been obvious to use known flow rates suitable for liposomal formulations, such as a lipid flow rates of 20 and 40 mL/min and the siRNA flow rate was 60, 80, or 120 mL/min, as taught by Bowman, all falling within the claimed ranges.
Regarding claim 14, it would have been obvious to adjust the flow rates of the lipid stream to aqueous stream within the ranges of 1:1 to 1:9, where flow rate can be adjusted to achieve a desired lipid to active agent ratio, as taught by Bowman, and were each stream of a microjet reactor can be independently controlled, as taught by MacSweeney. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding claim 16, the lipid streams of Bowman comprise ethanol, which is miscible with water as evidenced by the instant claim.
Regarding claims 17 and 18, where Bowman teaches a similar process of impinging two streams at a collision point to formulate liposomes as the process used in the microjet reactor made obvious above, and discloses embodiments with a polydispersity index of 0.110, 0.100, and 0.108, and an average diameter ranging from 58-67 nm, it would have been reasonably expected that liposomes with a polydispersity index falling within those ranges instantly claimed would similarly be achieved using the jet impingement reactor, where the flow rates, pressures, etc., overlap those in the method disclosed by Bowman. Further, microjet impingement reactors were known to produce monodisperse nanoparticles, as taught by PharmTech, and MacSweeney teaches microjet reactors are suitable for forming nanoparticles with a polydispersity index of less than 0.5, preferably ranging from 0.001 to less than 0.25. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
The skilled artisan would also recognize that adjusting processing parameters, such as flow rate, flow rate ratios, pressures, etc., would impact the average particle size and polydispersity index of the resulting liposomal dispersion, as suggested by Bowman and PharmTech. As such, it would have been obvious for the skilled artisan to routinely optimize the processing parameters in order to achieve desired average particle size, polydispersity index, etc., depending on desired uses. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144(II)(A).
Regarding claim 19, it would have been obvious to perform further processing methods including filtration, such as sterile filtration, as taught by Bowman, to the liposomal dispersion made obvious above.
Regarding claim 20, the method made obvious above teaches a liposome dispersion comprising an active pharmaceutical ingredient and at least one amphiphilic lipid, for the same reasons discussed above.
Response to Arguments
First, Applicants assert Bowman, Ramsay, and MacSweeney do not teach the newly amended limitations. Applicants assert the skilled artisan would not have had motivation or a reasonable expectation of success in combining the references. Applicants assert Bowman is silent regarding a jet impingement reactor with the newly amended limitations. Applicants assert the skilled artisan would be discourages starting from Bowman to replace its syringe pump to a jet impingement reactor to handle complex liposomes.
Second, Applicants assert the examiner used hindsight bias to pick out jet impingement from a generic listing recited in Ramsay. Applicants assert it is very unlikely that the skilled person would pick out jet mixing from Ramsey’s brief mention of jet mixing.
Third, Applicants assert MacSweeney relates to jet stream containing one target molecule colliding with a second stream of a non-solvent, and MacSweeney describes that the target molecules are omega-3 fatty acids. Applicants assert that since coated omega-3 fatty acid particles have completely different form and composition as liposome dispersions, the skilled person would not turn to MacSweeney in order to glean teachings to apply the synthesis of such dispersions.
Fourth, Applicants assert that even if a successful prima facie case of obviousness were made, this is rebutted by the surprising and unexpected results that controllable formation of liposome dispersions with positive characteristics such as low polydispersity and stability with encapsulation of active ingredients can be obtained with the claimed methods.
First, respectfully, this argument is not persuasive. The examiner agrees with Applicants that it does not appear that Bowman teaches a jet impingement reactor with the newly amended claim limitations. The examiner disagrees that the skilled artisan would be discouraged from replacing the syringe pump of Bowman to a jet impingement reactor. When viewed as a whole, Bowman teaches impinging a first and second stream having a velocity and flow rate at opposing directions through an opening into a mixing chamber, in order to mix the streams. When formulating the liposomes of Bowman, the skilled artisan would reasonably look to PharmTech for alternative formulation methods for impinging a first and second stream that were known to be suitable for liposomal formulations, such as by using a microjet impingement reactor, and would be motivated where microjet impingement reactors were known to have controlled particle size and particle size distributions, thereby resulting in homogenous particles and narrow particle size distributions. Following this, the skilled artisan could then turn to MacSweeney, for known processing parameters (i.e., pressures) suitable for microjet mixing of impinging streams. Regarding the newly amended pinhole distance limitation, it would have been obvious to use a pinhole distance as instantly claimed, for the same reasons discussed above by Johnson.
Applicants assert that liposomes are “complex” and the skilled artisan would have been discouraged from replacing the device of Bowman with a jet impingement reactor to handle “complex liposomes,” however, where the process of Bowman appears to be substantially the same as the process used in the microjet reactor made obvious above, both impacting streams at an angle of 180 degrees under overlapping flow rates and pressures, the skilled artisan would have reasonably expected that the formulations of Bowman could be made via a microjet reactor. Additionally, microjet impingement reactors were taught by PharmTech to be suitable for liposomal formation. The only difference between the two processes appear to be the size of the opening upon which the streams flow prior to colliding; where the flow rates and pressures in the microjet reactor made obvious above overlap those used in the process of Bowman. No matter the size of the opening, the resulting liposome dispersion would be expected to be substantially the same where the same streams are colliding at the substantially the same rates and pressures. It appears that the skilled artisan would recognize the interchangeability of the processes for the reasons discussed above. Nevertheless, it would have been obvious for the skilled artisan to adjust the processing parameters, such as flow rate, flow rate ratios, pressure of the streams, etc., in order to routinely optimize the resulting liposomal dispersion to achieve desired characteristics for desired uses, as taught by PharmTech. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144(II)(A).
Second, respectfully, this argument is not persuasive. While not agreeing, the examiner notes that Ramsay is longer cited, and accordingly, Applicants’ arguments with respect to Ramsay are moot. PharmTech is newly cited above for teaching that microjet impingement reactors were known to be used to formulate liposomes.
Third, respectfully, this argument is not persuasive. MacSweeney was only cited for teaching known pressures suitable for impinging a first and second stream in the microjet mixing of nanoparticles, and to confirm that the velocities and flow rates of Bowman were suitable parameters for microjet mixing. While MacSweeney may teach nanoparticles comprising omega-3 fatty acids, MacSweeney discloses general pressures and flow rates known to be used by microjet impingement reactors for nanoformulations.
Fourth, respectfully, this argument is not persuasive. Evidence of unexpected properties must be compared to the closest prior art to be effective to rebut a prima facie case of obviousness. See MPEP 716.02(e). Applicants point to examples 4 and 5 to show unexpected properties, however, this data appears to only be compared with other jet impingement processes of varying flow rates, pin hole diameters, and pressures, and does not compare the data to those of the closest prior art. Applicant has the burden of explaining the data they proffer as evidence of non-obviousness. See MPEP 716.02(b)(II). Nevertheless, Applicants assert the controllable formulation of liposome dispersions with low polydispersity and stability with encapsulation of active ingredients is unexpected, however, PharmTech is newly cited above and explicitly teaches that formulating micro- and nano- particles, including liposomes, by impinging two streams via a microjet impingement reactor, achieves homogenous particles with a narrow particle size distribution, and is taught to be controllable. As such, it appears to be expected that the liposomes produced via microjet impingement reactor would have controlled particle size, low polydispersity, and good stability due to tightly controlled particle size and the narrow particle size distribution.
Claims 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over Bowman et al (US 20170196809 A1, hereinafter “Bowman”), PharmTech (PharmTech, 2017, pp 1-9), MacSweeney et al (US 20200060321 A1, hereinafter “MacSweeney”, cited on IDS dated 08/19/2025), and Johnson et al (Ind. Eng. Chem. Res., 2009, 48, 17, pp 7945-7958, hereinafter “Johnson”), as applied to claims 1, 3, 8-14, and 16-20 above, and further in view of MacLachlan et al (US 20040142025 A1, hereinafter “MacLachlan”).
Bowman, PharmTech, MacSweeney, and Johnson, are discussed above, and for the sake of argument, if the pressures made obvious by MacSweeney are somehow not suitable for liposomal formation, the following applies.
MacLachlan discloses a method of preparing a liposome encapsulating a therapeutic product by providing an aqueous solution and an organic lipid solution comprising an organic solvent, wherein one of the solutions includes a therapeutic product, and mixing the aqueous solution with organic lipid solution (claim 1, ¶ 34). As evidenced by the instant specification, liposomes are formed from amphiphilic lipids (see pg. 7 of instant specification). The mixing includes introducing the aqueous and organic lipid solution at substantially equal flow rates (claim 25). The mixing environment includes a T-connector, wherein the aqueous and organic lipid solution are introduced as opposing flows at substantially 180 deg angle relative to each other (claim 26, fig. 3). The fluid from the first reservoir and the second reservoir flows into mixing chamber simultaneously at separate apertures (¶ 90). In certain aspects, the liposomes are prepared at low pressure (e.g., <10 psi) (¶ 85), resulting in less than 68.95 kPa.
Regarding claims 4-6, it would have been obvious to formulate the liposome dispersion made obvious above with a first or second stream hydrodynamic pressure of <10 psi (i.e., less than 68.95 kPa), as taught by MacLachlan, where these pressures are taught to be suitable for liposomal dispersions by colliding a first and second stream. Further, the hydrodynamic pressures taught by MacLachlan fall within the pressure ranges suitable for nanoparticle formulation via a microjet reactor.
Regarding claim 7, where pressures of <10 psi are made obvious above, suggesting the pressures can vary within that range, and where Bowman teaches flow rates and velocities of the streams vary and MacSweeney teaches that the flow rates and pressures of each stream can be controlled, it would have been obvious for the skilled artisan to start with equal pressures and adjust from there in order to achieve desired liposomal properties. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144(II)(A).
Response to Arguments
Applicants assert that while it is understood that the Examiner cites MacLachlan only for teaching known pressures suitable for formulating liposomes by impacting two streams, using only a portion of a reference’s teaching is improper, where a reference must be considered in its entirety. Applicants assert that MacLachlan teaches embodiments where lipid vesicles are prepared at low pressure and where non-turbulent flow may be advantageous, teaching away from the jet impingement conditions that operate under highly turbulent mixing conditions.
Respectfully, this argument is not persuasive. While the examiner again notes that MacLachlan does appear to teach embodiments under non-turbulent flow and says this can be advantageous, a preference for non-turbulent flow does not constitute a teaching away from systems that were already known to be suitable for liposomal formulations, considering the reference does not appear to teach or suggest that turbulent flow would be unsuitable for liposomal formation. As previously discussed and acknowledged by Applicants, MacLachlan was merely cited for teaching that the pressures made obvious above were known to be suitable for use with liposomal formulations comprising impinging a first and second stream at an angle of 180 degrees.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Bowman et al (US 20170196809 A1, hereinafter “Bowman”), PharmTech (PharmTech, 2017, pp 1-9), MacSweeney et al (US 20200060321 A1, hereinafter “MacSweeney”, cited on IDS dated 08/19/2025), and Johnson et al (Ind. Eng. Chem. Res., 2009, 48, 17, pp 7945-7958, hereinafter “Johnson”), as applied to claims 1, 3-14, and 16-20 above, and further in view of Polisky et al (US 20150209283 A1, hereinafter “Polisky”).
Bowman, PharmTech, MacSweeney, and Johnson, are discussed above but do not teach surfactants in each stream as instantly claimed.
Polisky teaches a method of formulating a liposomal composition encapsulating therapeutics comprising contacting an aqueous solution of an active agent with a solution of liposome-forming components with an impinging stream (abs). It was known to include surfactants to the liposomal formulations, which can be used to enhance or maintain stability (¶¶ 70, 612).
Regarding claim 15, it would have been obvious to further include a surfactant to the solutions made obvious above, where surfactants were known to be used in liposomal formulations for enhancing or maintaining stability of the formulations, as taught by Polisky.
Regarding the amounts, a skilled artisan would reasonably be expected to determine the optimal working range of surfactant in the streams in order to achieve optimal stability for desired formulations. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See MPEP 2144.05(II)(A).
Response to Arguments
Applicants assert Polisky does not cure the above mentioned deficiencies.
Respectfully, this argument is not persuasive. The claims stand rejected for the same reasons above and of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1 and 3-20 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/558,368 (reference application), hereinafter referred to as ‘368, in view of Bowman et al (US 20170196809 A1, hereinafter “Bowman”) and Johnson et al (Ind. Eng. Chem. Res., 2009, 48, 17, pp 7945-7958, hereinafter “Johnson”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘368 disclose a method for producing a dispersion of nanoparticles comprising at least one amphiphilic lipid, wherein the method comprises the steps of: a) providing a first stream comprising an organic solvent and the amphiphilic lipid; b) providing a second stream comprising an aqueous solvent; c) pumping the first stream under a raised pressure through a first nozzle and pumping the second streams under a raised pressure through a second nozzle into a reaction chamber; wherein the first nozzle is located at an angle of about 180 deg from the second nozzle; d) colliding the first stream and the second streams frontally in a reaction chamber; and wherein the flow rate ratio between the first stream and the second stream is in a range from 1:1.5 to 1:4.5 (claim 1). The flow rate ranges from 1-1000 ml/min (claim 4, 34). The nanoparticles are selected from liposomes (claim 8). The amphiphilic lipid is selected from glycerophospholipids, phosphatidylcholine, etc. (claim 9). The first stream comprises cholesterol (claim 12) and an active pharmaceutical ingredient (claim 15). The nanoparticles have an average particle size of 20-100 nm (claim 19). The jet impingement reactor has a nozzle (claim 20). Each stream has a pressure from 0.1 to 120 bar (claim 22).
The claims of ‘368 do not disclose the concentration of glycerophospholipids, the velocity of the streams, nor the newly added limitation of the pinhole distance.
Bowman is discussed above.
It would have been obvious to include known amounts of lipids suitable for liposome formulations, such as those taught by Bowman above and for the same reasons.
It would have been obvious to use a known velocity of the streams suitable for formulating liposomal dispersions, such as those of Bowman discussed above and for the same reasons.
It would have been obvious to use known distances between pinholes suitable for jet impingement reactors, such as those discussed above by Johnson for the same reasons discussed above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants assert the skilled person would have no motivation or reasonable expectation of success in applying the lipid amounts or velocities of impinging streams of Bowman’s syringe pump setup to the jet impingement reactor of the claims of ‘368. Applicants assert the skilled person would not assume that Bowman’s results would be applicable to a different reactor system that relies on much harsher conditions such as highly turbulent mixing, high pressures, and jet velocities. Applicants assert Bowman notes that its flow-based syringe system already provides efficient encapsulation, so it is unclear why the skilled person would be motivated to take an already satisfactory process and modify with a harsh jet impingement reactor conditions with a reasonable expectation of success.
Respectfully, this argument is not persuasive. As discussed above, the process of Bowman and the process used in jet impingement reactors appears to be substantially the same as the process used in the microjet reactor made obvious above, both impacting streams at an angle of 180 degrees under overlapping flow rates and pressures, the skilled artisan would have reasonably expected that the lipid amounts and velocities of Bowman would be capable of being used in a microjet reactor. The only difference between the two processes appear to be the size of the opening upon which the streams flow prior to colliding; where the flow rates and pressures in the microjet reactor of ‘368 overlap those used in the process of Bowman. It appears that the skilled artisan would recognize the interchangeability of the processes for the reasons discussed above and would have a reasonable expectation of success in using the lipid amounts and velocities of Bowman in another process that impinges a first and second stream to formulate liposomes.
Conclusion
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/JOSHUA A ATKINSON/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612