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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 19 June 2026 has been entered.
CLAIMS UNDER EXAMINATION
Claims 1-3, 5-7, 9-11,13, 16-17, 22, 38-48 and 51-55 have been examined on their merits.
PRIORITY
Provisional Application 62/801225, filed on 05 February 2019, is acknowledged. Claim 1 has been amended to recite first flow rate, a second flow rate and a feed rate ratio of 1:26 to 1:132. The Provisional Application does not provide support for homogenization with the recited feed rate ratio.
WITHDRAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment.
REJECTIONS
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3, 5-7, 9-11,13, 16-17, 22, 38-48 and 51-54 are rejected under 35 U.S.C. 103 as being unpatentable over Bitterfield et al. (previously cited; Microglassification: Rapid protein dehydration enabling high concentration suspension formulations, Lindy Biosciences. 2015. See IDS) in view of Needham et al. (previously cited; Stabilized Products, Processes And Devices For Preparing The Same. Patent 8512754), Panagiotou et al. (Apparatus, systems, and methods for continuous manufacturing of nanomaterials and high purity chemicals US2022/0047510, with benefit to 16/624631 (filed 19 December 2019) and Provisional Applications 62/788,298 (filed 04 Jan 2019) and 62/688755 (filed 22 June 2018)) and Modena et al (Hyaluronidase-injectable microparticles intended for the treatment of extravasation (J. Microencapsulation, 1998, Vol 15, No. 1, 85-92).
Bitterfield uses microglassification, a protein dehydration technique, to produce solid spherical protein particles (first sentence of Abstract; see Summary at bottom right corner of the disclosure). A drop of protein solution comprising a protein (a biologic) is dehydrated in (contacted with) a decanol drying medium (an organic solvent) to form microbeads (section titled “Kinetics-Single Micordroplet Dehydration” and “Dehydration is Rapid, and decreases as Particle Size Decreases). As evidenced by Needham et al., decanol will dissolve in water “to some extent” (see column 12, lines 17-18). Therefore decanol has at least partial water solubility. An emulsion is a liquid dispersed in an immiscible liquid. Bitterfield teaches aqueous beads are formed in decanol. Therefore decanol is immiscible in water. Because Bitterfield combines two liquids that are immiscible to form the disclosed particles, the art is interpreted to form an emulsion. Following formation, particles are collected via filtration (hence, isolated; see Moisture Analysis).
Bitterfield teaches single-pass homogenization can be used to successfully produce microglassified protein (see bottom third of page). The art teaches “overall flow rates up to 180 mL/min” with no effect on size distribution (see section titled “Scale-up Feasibility). Bitterfield teaches high concentration protein “suspensions” are produced (see first bullet point of Summary section).
Bitterfield teaches microglassified particles are suitable for dry powder delivery (first sentence of Abstract; see Summary at bottom right corner of the disclosure). A powder is formed with less than 5% water content (see text to the right of the section titled “Moisture Analysis”). It is noted Bitterfield teaches 0.5 water activity for protein dehydrated with pentanol (see text to the right of “Moisture Analysis” section).
The deficiencies of Bitterfield are:
The art does not explicitly teach homogenized particles with less than 5% water and less than 0.25 water activity.
Bitterfield is silent regarding the flow rate of the aqueous and organic solvent when added to the disclosed homogenizer.
Bitterfield does not teach washing with a second organic solvent.
Needham makes glassified, stabilized particle preparation having a low water activity (between about 0.1 and 0.9) (Abstract; see Figure 4). The water activity level “greatly affects” susceptibility to growth of bacteria and molds (column 1, lines 20-25). The compositions can be processed to reduce water activity (column 4, lines 45-57).
Needham teaches the water activity (aw) of a material is dependent on the water content of the material (column 1, lines 40-41). Needham teaches decanol is a second phase solvent that reduces the water content of a protein solution (column 12, lines 17-21). Needham teaches the desired amount of water can be removed by using water-in oil emulsions in second phase solvents (column 12, lines 36-40). Needham teaches proteins may be more or less hydrated by choosing a solvent that has the capacity to dissolve more or less of the water of hydration (over and above the excess water), or by adjusting the relative volumes of the two phases. (see column 13, lines 35-40).
Needham teaches suspending a water solution containing a protein in excess decanol at 100:1 to form a water-in-oil emulsion. Needham teaches this is sufficient to absorb all the free water in the protein solution (column 13, lines 56-67).
Panagiotou et al. teach a system for mixing streams of liquids ([0002]). The art teaches a system comprising an in-line mixer (element 112 of Figure 8) upstream of a microreactor which is a homogenizer ([0070] element 120 of Figure 8).The art teaches flowing a first and second liquid feed stream to the in-line mixer, and mixing to produce a homogenous mixture ([0017]). The first and second feed streams are immiscible ([0023]). The components interact in the microreactor to form an emulsion ([0023]).
The system can adjust the flow rates and the flow rate ratio of the two streams in real time, which results in a microparticles having the desired formulation ([0048] [0072] [0177]). Flow rate is identified as feed rate in the PG Pub of the specification ([0076]).
The flow rate of each stream is calculated as follows:
The total flow rate of the system is measured ([0155]). Each pump is set to provide the appropriate flow rate based on the desired volume fraction of the particular stream in the final formulation. The flow rate of each of the streams is calculated by multiplying the total flow rate with the percentage of that stream in the formulation ([0155]).
Modena prepares microparticles using water-in-oil emulsification (Abstract; page 87 third section of “Materials and Methods”). Residual oil phase is removed by washing with diethyl ether (page 88, first paragraph). Diethyl ether is an organic solvent which is not miscible with water. The art teaches washing three times (same section).
It would have been obvious to prepare a solid particle with less than 5% water content. Bitterfield teaches following formation, particles can be isolated and placed under a vacuum to reduce water content over time. The skilled artisan would reduce the water content of particles following homogenization to obtain solid, dried particles. One would be motivated to dry particles to less than 5% water content to produce a powder. One would have had a reasonable expectation of success since Bitterfield teaches water content can be reduced by drying.
It would have been obvious to combine the teachings of Bitterfield and Needham to produce a glassified particle with a water activity less than 0.25. Bitterfield prepares particles with less than 5% water content. Needham teaches water activity is dependent on water content. The skilled artisan would optimize the water content to lower water activity. One would have been motivated to do so to prevent microbial growth and increase stability of the glassified particles as taught by Needham. One would have had a reasonable expectation of success since Needham the desired amount of water can be removed. One would have expected similar results since Bitterfield and Needham are both directed to methods of making dehydrated, glassified solid particles.
It would have been obvious to feed an aqueous composition and an organic solvent to a homogenizer at a feed rate ratio of 1:100 (aqueous:solvent). Bitterfield teaches using a total flow rate of 180 ml/min to scale up glassification in a homogenizer. Needham teaches an aqueous:solvent ratio of 1:100 to produce stabilized particles with low water activity. One would use the calculation taught by Panagiotou to determine the flow rate for each stream: the flow rates of the 1:100 aqueous:solvent ratio taught by Needham would be 1.782 ml/min (multiply 0.99% by 180 ml/min) and 178.218 ml/min (multiply 99.01% decanol by 180 ml/min). This is approximately a 1:100 ratio which falls within the claimed range. One of ordinary skill would use a flow rate ratio of 1:100 since Needham teaches this ratio produces particles with the desired properties. One would have had a reasonable expectation of success using a homogenizer since Panagiotou taches the flow rate of each stream can be optimized to obtain a composition with the desired characteristics.
It would have been obvious to wash the particles prepared by Bitterfield. Modena teaches washing to remove residual oil phase. One would have been motivated to do so for particles that are administered. One would have had a reasonable expectation of success since Modena teaches microparticles prepared from a water-in-oil emulsion can be washed. One would have expected similar results since Bitterfield, Needham and Modena are both directed to water-in-oil emulsions. Therefore claim 1 is rendered obvious.
Bitterfield teaches protein concentrations of 33.4, 35.2 and 54.4 mg/ml (see “Kinetics-Single Microdroplet Dehydration” section). These concentrations read on claim 2.
Needham teaches dehydration removes water, thereby preserving a material (see column 13, lines 1-5).Therefore claim 3 is included in this rejection.
Bitterfield (supra) and Needham teach a material of interest is added to an aqueous phase (column 8, line 34). Needham teaches cells (column 8, line 67, column 9, lines 2-4; column 12, line 64; column 19, lines 15-16). Therefore contact with the disclosed first organic solvent would be expected to at least partially lyse cells. Claim 5 is included in this rejection.
Needham teaches a material of interest is added to an aqueous phase (column 8, line 34). The art teaches cells (column 8, line 67, column 9, lines 2-4; column 12, line 64; column 19, lines 15-16). Needham teaches the emulsion is stabilized against coalescence by the inclusion of small amounts glycerol mono-oleate (a lipid; column 13, lines 30-21).Therefore claim 6 is rendered obvious.
Bitterfield adds a one drop of aqueous solution (100 picoliters) to 100 ml organic solvent (see Kinetics-Single Microdroplet Dehydration). This is interpreted to be a water-in-oil emulsion. Therefore claim 7 is included in this rejection.
The interfacial tension of decanol is well known to be 8.97 mN/m. This reads on claim 9.
Bitterfield is silent regarding the water activity of the emulsion.
Needham teaches decanol is used in the second phase of an emulsion to dissolve bulk water (column 12, lines 17-21). Needham teaches the desired amount of water can be removed by using water-in oil emulsions in second phase solvents (column 12, lines 36-40). It would have been obvious to prepare an emulsion with a water activity of less than 1. One would remove excess water in the emulsion to prepare glassified particles with reduced water activity. Therefore claim 10 is rendered obvious.
Bitterfield teaches a fractional saturation of 0.3 (see right side of “Kinetics-Single Microdroplet Dehydration”). This reads on claim 11.
Bitterfield and Needham teach decanol (an alcohol). Claim 13 is included in this rejection.
Bitterfield teaches an overall flow rate of up to 180 ml/min (10.8 L/hour). Therefore claim 16 is included in this rejection.
Regarding claim 17: Bitterfield teaches contact with the organic solvent dehydrates proteins (supra). Therefore homogenization of the feeds using the system taught in Panagiotou would be expected to dehydrate the biologic in the emulsion substantially simultaneously. Claim 17 is included in this rejection.
Panagiotou teaches an aqueous phase can be contacted with an immiscible organic solvent in the in-line mixer upstream of a homogenizer to form an emulsion (supra). This reads on contacting an aqueous composition with an emulsion solvent prior to feeding to the homogenizer. Claim 22 is included in this rejection.
Bitterfield adds a one drop of aqueous solution (100 picoliters) to 100 ml organic solvent (see Kinetics-Single Microdroplet Dehydration). This is interpreted to be a water-in-oil emulsion comprising a droplet. Needham teaches a micro droplet forms in a water-in-oil emulsion (see column 11, lines 59-60; column 13, lines 29-30). The droplet size in the emulsion reduces until the beads form (column 13, lines 65-67). The particle size can be about 2-30 microns (claim 13, line 26). Therefore a droplet less than about 1000 um is rendered obvious. Claim 38 is rejected.
Needham teaches a 1:100 ratio of aqueous:first organic solvent (supra). Therefore claim 39 is included in this rejection.
Bitterfield prepares particles using a vacuum (see text to the right of “Moisture Analysis” section). Needham teaches either heat or vacuum can be used to remove water and dry particles (column 23, lines 49-50).
It would have been obvious to heat as an alternative to vacuum drying. One would have been motivated to do so since Needham teaches heat can be used to remove water. See KSR E. One would have had a reasonable expectation of success since Needham teaches heat is an alternate method of dehydrating particles. One would have expected similar results since Bitterfield and Needham are both directed to methods of making glassified protein particles. Claim 40 is rendered obvious.
Panagiotou et al. teach a concentrated emulsion can be homogenized ([0152]). Therefore claim 41 is rendered obvious.
Bitterfield teaches a dry powder comprising solid particles is formed (see Abstract). This reads on claim 42.
Panagiotou teaches the shear rate of at least about 1.2x106 s-1 ([0021]). Therefore claim 43 is included in this rejection.
Bitterfield teaches protein concentrations of 33.4, 35.2 and 54.4 mg/ml (see “Kinetics-Single Microdroplet Dehydration” section). These concentrations read on claim 44.
Bitterfield does not require a stabilizer in decanol. Therefore claim 45 is included in this rejection.
Modena teaches washing three times. The third wash with diethyl ether is interpreted to read on a third organic solvent. Therefore claim 46 is included in this rejection.
Bitterfield teaches resuspending in DMSO (a solvent) (see text to the right of “Moisture Analysis” section). Therefore claim 47 is included in this rejection.
Bitterfield teaches a dry powder comprising solid particles is formed (see Abstract). This reads on claim 48.
Panagiotou teaches the first and second stream interact in the microreactor (the homogenizer) to form an emulsion ([0023]). This reads on claim 51.
Panagiotou et al. teaches mixing the first and second stream in an in-line mixer and introducing the mixture to a homogenizer (supra). Therefore claim 52 is included in this rejection.
Panagiotou teaches an embodiment where the oil and water passes are fed separately to a high pressure homogenizer (Example 3; [0210]). Therefore claim 53 is included in this rejection.
Modena teaches a diethyl ether wash solvent (second organic solvent). This is different than the first solvent taught by Needham (decanol). Therefore claim 54 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Bitterfield in view of Needham, Panagiotou and Modena as applied to claim 46 above, and further in view of Zala et al. (Laboratory Techniques of Purification and Isolation. International Journal of Drug Development & Research Int. J. Drug Dev. & Res., April-June 2012, 4 (2): 41-55).
Claim 46 is rejected on the grounds set forth above. The teachings of the prior art are reiterated. Bitterfield obtains particles form a water-in-oil emulsion. Modena uses a water-immiscible, non-polar organic solvent to wash particles formed in a water-in-oil emulsion. The washing is performed three times.
The art does not teach using the same solvent for the first two washes and a different solvent for the third wash.
Zala teaches polar compounds are soluble in polar solvents and insoluble in non-polar solvents. Such characteristics are summarized by the adage of “like-dissolves-like” (page 43, last line of right column bridging first 5 lines of right column). The art teaches
non-polar solvents like n-hexane, n pentane, diethyl ether are used to remove non-polar impurities (see page 49, left column, third paragraph).
It would have been obvious to use the same nonpolar organic solvent for the first two washes and a different nonpolar organic solvent for a third wash. Modena uses a nonpolar organic solvent to remove the oil phase of a water-in-oil emulsion. It would have been obvious to use a different solvent for a third wash since Zala teaches non-polar solvents like n-hexane, n pentane and diethyl ether can be used to remove non-polar impurities. One would use wash solvents with similar polarity to the non-aqueous phase to remove organic solvent. See KSRB. One would have had a reasonable expectation of success since Zala teaches polar compounds are soluble in polar solvents. Therefore claim 55 is rendered obvious.
Therefore Applicant’s invention is rendered obvious as claimed.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 28 August 2025 are acknowledged.
Argument 1: The arguments state Bitterfield does not teach the claimed feed rate ratio, the claimed water activity, isolating the biologic particles and washing the solidified particles. The arguments states Bitterfield does not teach water activity or water content for the particles produced by homogenization. The arguments state Aniket does not teach a water immiscible was solvent.
Response: Examiner notes Bitterfield teaches glassified particles can be isolated. New grounds of rejection have been set forth above to address amended claim 1.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
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