DETAILED ACTION
Status of the Claims
Claims 1-9 and 12 are pending in the instant application. Claims 1-8 have been withdrawn based upon Restriction/Election. Claims 9 and 12 are being examined on the merits in the instant application.
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/27/2026 has been entered.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
Applicant claims priority to KR 10-2022-0021275 filed 02/18/2022. The U.S. effective filing date has been determined to be 02/17/2023, the filing date of the instant application. Applicant's claim for a priority date of, 02/18/2022, the filing date of document KR10-2022-0021275, is acknowledged, however no English translation of the foreign priority document has been provided for the examiner to verify 112(a) support therein.
Information Disclosure Statement
The information disclosure statement(s) submitted on 05/13/2026 was filed before the mailing date of the first office action on the merits subsequent to the above filed Request for Continued Examination. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
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 9 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over KIM (WO 2020/222399 A1; published 05/11/2020; US 2022/0202894 relied on as English language translation and cited herein) in view of Allison (“Analysis of initial burst in PLGA microparticles,”2008, Informa Healthcare, Expert Opinion Drug Delivery, Vol. 5, No. 6, pp. 615-628; of record as cited by Applicant on 07/07/2025 – Non-Patent Literature document Citation No. 2); and LEE (KR10-2022-00323011; Application No. KR10-2020-01139242 with a public availability date of 07-SEP-2020; US 2022/0249452 A1 relied on as English language translation herein).
Applicants Claims
Applicant claims a method for preparing a composition for sustained-release injection comprising deslorelin, the method comprising:
preparing a first mixture by mixing deslorelin and a biodegradable polymer; preparing a second mixture by dissolving a surfactant in a solvent;
injecting the first mixture and the second mixture into a first microchannel and a second microchannel, respectively, the first microchannel and the second microchannel having an intersection point therebetween, and allowing the first mixture and the second mixture to flow through the first microchannel and the second microchannel, respectively, to produce microparticles at the intersection point;
collecting the microparticles in a water tank containing the second mixture; removing an organic solvent present in the microparticles collected in the water tank;
washing the microparticles with purified water and drying the microparticles that are washed with the purified water; and
mixing the microparticles with a suspension solution,
wherein a value according to a following Equation 1 is 1-10: Cmax(1d-28d)/Cmax(0-1d), where the composition for sustained release injection comprising deslorelin is administered as an injection product to measure a blood concentration of deslorelin, Cmax(1d-28d) is a maximum blood concentration of deslorelin within 1 to 28 days after injection the injection product, and Cmax(0-1d) is a maximum blood concentration of deslorelin within 1 day after injecting the injection product,
wherein a value according to the following Equation 2 is 1 to 2: [Equation 2] D90-D50/D50-D10
where, D10 denotes a diameter of the microparticles corresponding to 10% of a maximum value in a cumulative distribution of the particles, D50 denotes a diameter of the microparticles corresponding to 50% of the maximum value in the cumulative distribution of particles, and D90 denotes a diameter of the microparticles corresponding to 90% of the maximum value in the cumulative distribution of particles,
wherein the injecting the first mixture into the first microchannel comprises: injecting the first mixture under a pressure of 700 to 1,500 mbar;
increasing the pressure at a first rate of 10 to 30 mbar/min until the pressure reaches 900 to 1,700 mbar; and subsequently increasing the pressure at a second rate of 2 to 8 mbar/min, thereby maintaining a constant flow rate of the first mixture in the first microchannel, wherein the first mixture has a weight ratio of deslorelin and the biodegradable polymer of 1:5 to 1:8, wherein the second mixture is injected into the second microchannel under a second pressure that is 2 to 4 times greater than the pressure under which the first mixture is injected into the first microchannel, and
wherein the removing of the organic solvent includes: performing a primary stirring at 15 to 20°C, performing secondary stirring [at] 30 to 40°C, and performing tertiary stirring at 40 to 45°C (instant claim 9). Applicant further claims the primary, secondary and tertiary stirring is performed at a speed of 100 to 300 rpm, for a time period of 20 to 40 minutes, 60 to 120 minutes, and 4 to 8 hours, respectively (instant claim 12).
Determination of the scope
and content of the prior art (MPEP 2141.01)
KIM teaches sustained-release microparticles containing deslorelin, and a preparation method therefor, as discussed above and incorporated herein by reference.
KIM teaches that: “At this time, when injected into the channel in a linear direction, the first mixture is injected under a constant pressure condition and allowed to flow at a constant flow rate, and at this time, the pressure condition is 200 to 2,000 mbar, preferably 1,100 mbar, but is not limited thereto.” ([0060]). And that: “Also, when injected into the microchannel in either side or one side, the second mixture is injected under a constant pressure condition and allowed to flow at a constant flow rate, and at this time, the pressure condition is 500 to 2,400 mbar, preferably 2,200 mbar, but is not limited thereto.” [emphasis added]([0061])(instant claims 9, “wherein the second mixture is injected […] under a second pressure that is 2 to 4 times greater than […] the first mixture is injected”). KIM teaches that: “That is, in order to make the flow of the second mixture forming a cross-point with the flow of the first mixture faster than that of the first mixture injected into the channel in the linear direction, the second mixture is allowed to flow under a higher pressure condition.” ([0062]). And that: “As described above, by varying the flow rates of the first mixture and the second mixture, and making the flow rate of the second mixture faster than that of the first mixture, the second mixture having a relatively faster flow rate compresses the first mixture at the point where the flow of the first mixture meets the flow of the second mixture and at this time, due to the repulsive force of the first mixture and the second mixture, the biodegradable polymer and the deslorelin in the first mixture generate spherical microparticles, and more specifically, the microparticles in which the deslorelin is evenly distributed in the spherical biodegradable polymer, are formed.” ([0063]).
Regarding instant claim 12, KIM teaches that: “The step is, after the step of collecting the microparticles, a step of stirring the microparticles collected in the water bath, the microparticles are stirred under a constant temperature condition and at a stirring speed to evaporate and remove the organic solvent present on the surface of the microparticles. At this time, the step of stirring microparticles is performed in the order of: a first stirring step under the stirring conditions of a speed of 200 to 600 rpm for 0.5 to 2 hours at 15 to 25° C.; after the first stirring step, a second stirring step under the stirring conditions of a speed of 200 to 800 rpm for 2 to 6 hours at 30 to 50° C.; and after the second stirring step, a third stirring step under the stirring conditions of a speed of 200 to 800 rpm for 0.5 to 1.5 hours at 15 to 25° C.” ([0070]). And that: “As the stirring process is performed by varying the stirring speed and temperature conditions for stirring the microparticles, the evaporation speed of the organic solvent present on the surface of the microparticles may be regulated. That is, by evaporating the organic solvent present on the surface of the microparticles through the stirring process, it is possible to remove the harmful solvent and prepare microparticles having a smooth surface.” ([0071])(instant claim 12).
KIM further teaches that: “Although the preferred embodiments of the present
disclosures have been described in detail above, the scope of the present disclosure is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concept of the present invention defined in the following claims also belong to the scope of rights of the present disclosure.” ([0119]).
KIM teaches that “The first mixture may be mixed with the API mixture and the biodegradable polymer mixture at a weight ratio of 1:4 to 1:20.” ([0020]) (instant claim 1, “wherein the first mixture has a weight ratio of deslorelin and the biodegradable polymer of 1:5 to 1:8”). MPEP §2144.05(I) - In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of KIM is that KIM does not expressly teach “wherein the injecting the first mixture into the first microchannel comprises: injecting the first mixture under a pressure of 700 to 1,500 mbar; increasing the pressure at a first rate of 10 to 30 mbar/min until the pressure reaches 900 to 1,700 mbar; and subsequently increasing the pressure at a second rate of 2 to 8 mbar/min, thereby maintaining a constant flow rate of the first mixture in the first microchannel, wherein the first mixture has a weight ratio of deslorelin and the biodegradable polymer of 1:5 to 1:8, wherein the second mixture is injected into the second microchannel under a second pressure that is 2 to 4 times greater than the pressure under which the first mixture is injected into the first microchannel,” (instant claim 9), or the timing of the primary, secondary and tertiary stirring times of 20 to 40 minutes, 60 to 120 minutes, and 4 to 8 hours, respectively(instant claim 12).
KIM clearly teaches “varying the flow rates of the first mixture and the second mixture” to generate “microparticles in which the deslorelin is evenly distributed in the spherical biodegradable polymer” ([0063]), and teaches pressures that overlap with the claimed pressures (the pressure condition is 200 to 2,000 mbar, preferably 1,100 mbar – the first mixture)([0060])( the pressure condition is 500 to 2,400 mbar, preferably 2,200 mbar – the second mixture)([0061]). And specifically teaches that: “At this time, when injected into the channel in a linear direction, the first mixture is injected under a constant pressure condition and allowed to flow at a constant flow rate, and at this time, the pressure condition is 200 to 2,000 mbar, preferably 1,100 mbar, but is not limited thereto.” [emphasis added]([0060]). And that: “Also, when injected into the microchannel in either side or one side, the second mixture is injected under a constant pressure condition and allowed to flow at a constant flow rate, and at this time, the pressure condition is 500 to 2,400 mbar, preferably 2,200 mbar, but is not limited thereto.” [emphasis added]([0061]). Therefore it would have been prima facie obvious to optimize the “pressure condition” and “flow rates of the first mixture and the second mixture” to generate “microparticles in which the deslorelin is evenly distributed in the spherical biodegradable polymer” (instant claim 10). The examiner argues that one of ordinary skill would have recognized that the pressure necessarily has an initial zero pressure, and must be increased to the desired working pressure. It would have been prima facie obvious to initially increase the pressure at a faster rate and subsequently at slower rate as the desired working pressure is approached so as to achieve the desired constant flow rate. Therefore, the prior art implicitly discloses at least a gradually increasing pressure by describing “a constant flow rate” (MPEP §2144.01).
The instant Specification discloses that: “Specifically, in a preparation method using the microchannel, when the flow rates of the first mixture and the second mixture flowing through the microchannel are set to constant values using a flowmeter and the pressure is measured through feedback control, it is confirmed that the pressure required to flow the first mixture through the microchannel at a constant flow rate is gradually increased with time.” [emphasis added](, p. 21, [00140]; [0130], as published). And that: “Therefore, a method of constantly increasing the pressure applied to the first mixture may be used to minimize the flow rate variability, prevent the problem of microparticle distribution nonuniformity or channel closure due to slow curing of the first mixture inside the microchannel, and increase the target preparation yield of the microparticles.” (p. 22, [00141]; [0131]). KIM clearly teaches “constant flow rate” as a feature of their invention ([0060] & [0061]), and the further teaches “Another object of the present invention is to provide sustained-release microparticles having a uniform diameter” ([0015], as published). It would have been within the ordinary level of skill to increase the pressure of the first mixture injected into the first microchannel to achieve a “constant flow rate” and to prevent channel closure while producing sustained-release microparticles having a uniform diameter, as per the teachings of KIM, and consistent with the instant Disclosure.
KIM clearly teaches “varying the stirring speed and temperature conditions for stirring the microparticles” thereby “evaporating the organic solvent present on the surface of the microparticles through the stirring process, it is possible to remove the harmful solvent and prepare microparticles having a smooth surface.” ([0071]). And that: “The step is, after the step of collecting the microparticles, a step of stirring the microparticles collected in the water bath, the microparticles are stirred under a constant temperature condition and at a stirring speed to evaporate and remove the organic solvent present on the surface of the microparticles. At this time, the step of stirring microparticles is performed in the order of: a first stirring step under the stirring conditions of a speed of 200 to 600 rpm for 0.5 to 2 hours at 15 to 25° C.; after the first stirring step, a second stirring step under the stirring conditions of a speed of 200 to 800 rpm for 2 to 6 hours at 30 to 50° C.; and after the second stirring step, a third stirring step under the stirring conditions of a speed of 200 to 800 rpm for 0.5 to 1.5 hours at 15 to 25° C.” ([0070]). The first two steps (5-1 and 5-2) overlap with Applicants claimed stirring speed, time and temperature, the difference is the third step (5-3) the stirring speed, time and temperature are within the scope of the second step of KIM (5-2). And given that raising the temperature implicitly includes temperatures below the final temperature (e.g. to raise the temperature to 45 °C from 15-20 °C, necessarily includes raising the temperature through 30-40 °C), and given that KIM teaches “varying the stirring speed and temperature conditions for stirring the microparticles” thereby “evaporating the organic solvent present on the surface of the microparticles through the stirring process, it is possible to remove the harmful solvent and prepare microparticles having a smooth surface.”, it would have been prima facie obvious to optimize the stirring speed, time and temperature in order to produce microparticles having a smooth surface.
KIM does not disclose: “a value according to the following Equation 1 is 1 to 10: Cmax 1d-28d/Cmax 0-1d wherein, when the composition is administered as an injection product to measure a blood concentration of the deslorelin, Cmax 1d-28d denotes a maximum blood concentration of the deslorelin within 1 to 28 days after injecting the injection product, and Cmax 0-1d denotes a maximum blood concentration of the deslorelin within 1 day after injecting the injection product.” (instant claim 9). However, the method of making recited in claim 1 is identical to that of KIM therefore the results would have been the same (MPEP §2112).
Further Regarding Equation 1 as recited in instant claim 9, the prior art does not teach this equation, however, it would have been prima facie obvious to optimize a composition of deslorelin PLA/PLAG microparticles to minimize burst release. Particularly, ALLISON teaches that: "A major problem encountered in microparticle product development has been the inability to reproducibly control the initial burst release of drug." And further that: "In any case, excessive burst is wasteful, in that drug lost in the burst phase is not available for later release. A candidate product with burst release levels that are not reproducible from batch to batch will not be approvable. Accordingly, the goal of most efforts to control burst release is to minimize or eliminate burst entirely." [emphasis added](p. 615, §Introduction, 1st paragraph).
Regarding the limitation that: “wherein a value according to the following Equation 2 is 1 to 2: [Equation 2] D90-D50/D50-D10” (instant claim 9, Equation 2), KIM does not expressly teach the particle size or particle size distribution, however LEE does. LEE teaches: “sustained-release microparticles comprising a biodegradable polymer and a drug, wherein the biodegradable polymer and the drug are uniformly distributed throughout the particles, and the microparticles do not show an initial excessive release of the drug, and are composed of uniform-sized particles having a particle size distribution width of 35 microns or less analyzed by a particle size analyzer […] thereby exhibiting a sustained release pattern of the drug. The injection composition comprising the drug contained in such microparticles can control the release of the drug for a selected period during injection administration to release an effective drug concentration constantly, and when formulated as an injection product, can reduce foreign body sensation and pain to the subject to enable an injection formulation with high compliance to be provided." (abstract, see whole document). LEE teaches that “Many microparticulate drugs developed so far still have a problem of initial excessive release (burst) and a problem such as incomplete control of the drug release rate during the treatment period, and one of the fundamental reasons for these problems will be non-uniformity of the particle size.” [0011] “Therefore, the present applicant has studied intensively by focusing on completing sustained-release particles with guaranteed stability and reliability that can provide a drug in a controlled release pattern for a required period of time through the preparation of uniform particles.” ([0012]). LEE teaches that: “In order to achieve the above object, the present disclosure provides sustained-release microparticles comprising a biodegradable polymer and a drug, wherein the microparticles are perfectly spherical, the biodegradable polymer and the drug are evenly distributed throughout the particles, and the sustained- release microparticles are composed of particles having a particle size distribution width of 35 microns or less analyzed by the particle size analyzer and […].” ([0014]). LEE teaches that the drugs include deslorelin, among others ([0018]). LEE teaches the advantageous effects: “According to the microparticles of the present disclosure, the microparticles are composed of particles having a uniform particle size-showing narrow particle size distribution width and a specific surface area range, and are contained in a composition for injection to achieve control of the release rate of a drug upon injection into a patient, thereby providing the effect of enabling the drug to be continuously released for a desired period without causing the initial excessive release of the drug. Since it is possible to provide a drug with a stable release pattern for a desired selection period of time from such sustained-release microparticles, there are effects that the inconvenience that the drug should be taken every day is solved, and the problem of drug side effects or lack of efficacy due to initial excessive release or instability of release can be minimized.” ([0023]). LEE teaches that: The sustained-release microparticles of the present disclosure show that the release pattern of the drug from the particles has a ratio of initial blood concentration (Cint) to maximum blood concentration (Cₘₐₓ) of 1:2 to 30 without initial excessive release.” ([0055]). Where Cint refers to an initial blood concentration value, and its maximum blood concentration value measured within 24 hours ([0056])(instant claim 9, Equation 1, MPEP §2144.05(I)). Particularly regarding Equation 2, LEE teaches Example 6 including preparation of microparticles containing a six-month dose of deslorelin ([0165]-[0172]), and particularly that: “The diameter of the microparticles containing Deslorelin obtained as described above was analyzed by a wet analysis method using a particle size analyzer of Microtac's 53500 model, in which a small amount of surfactant was dissolved in water as a dispersion, and the microparticles had an average diameter of 73.05 µm, a diameter range of D10% Tile 65.02 µm to D90% Tile 83.63 µm, and a particle size distribution width of 15.27 µm.” ([0172], p. 11, Table 1 - Preparation Example 6 Deslorelin)(instant Equation 2, (83.63-73.05)/(73.05-65.02) = 1.32 - Numbers From Table 1¹, MPEP §2144.05(I)). The examiner notes that LEE teaches a method of making substantially identical to that of KIM, see for example, paragraphs [0062], [0083] through [0097], as well as the Examples.
ALLISON teaches factors affecting burst release from PLGA microparticles (see whole document, particularly pp. 615-617), and particularly that: "Higher molecular weight polymers have increased free volume, which may contribute to
higher burst release. Drug that is dissolved in the polymer matrix occupies this space and increases the free volume of the matrix. Higher loading of drugs that are miscible with PLGA therefore increases the initial diffusion coefficient of encapsulated drug, resulting in increased burst." (p. 617, §2.2, 1st paragraph), and further that: "A high initial solvent volume is necessary to control polymer phase viscosity to allow particle formation in the desired small size range, using accessible dispersing technologies. As solvent is removed from the polymer solution, droplet volume decreases. In addition to volume loss as solvent is removed, the polymer also solidifies in a composition-dependent manner. The rate at which solvent is removed from the oil droplet determines the degree to which the droplet shrinks as the polymer hardens. The relative rates of oil droplet shrinkage and polymer hardening can lead to differences in the polymer matrix density in finished microparticles. For example, if the polymer remains in a mobile, rubbery state until the solvent is fully removed (i.e., by slow solvent removal at temperatures above the composition- dependent polymer Tg), the polymer can anneal more completely during processing. The resulting microparticles will have maximum density, with minimum process- induced free volume. Conversely, more rapid solvent extraction can lead to lower density polymer matrices and higher burst release because microparticles harden in a more solvent-swollen state. This is supported by the observation that burst release has been shown to correlate inversely with formulation bulk density." (p. 615, 1st paragraph last two lines). ALLISON teaches that: "Burst release depends on a number of factors related to the physical properties of the microsphere system components and also on the conditions encountered during processing. Recent developments in understanding the mechanisms that underlie burst release have allowed the development of strategies to control burst. In general, the methods fall into several general categories: improving the miscibility of drug in the polymer phase, increasing the resistance to diffusion (coatings) and manipulation of processing methods to control or reduce microparticle porosity." (p. 619, §Strategies to control burst release).
ALLISON teaches that: "While the initial burst release of drug is not always detrimental, excessive drug release in the burst phase may be toxic, and irregularity in the amount of drug released (e.g., from batch to batch) is not acceptable." (abstract, lines 4-6).
ALLISON teaches that: "The link between microparticle processing conditions, particle structure and burst is becoming more predictable with the increased application of statistical approaches to formulation development." (p. 623, §Conclusion, lines 3-6). ALLISON teaches that: "Processing conditions can be adjusted to alter microparticle structure and burst release, and in situ annealing of microparticles is an effective strategy to limit burst release." (p. 623, §Expert Opinion, 1st paragraph, last four lines).
ALLISON teaches that: "Viscosity during processing is increased, reducing the tendency of drug to diffuse out of nascent microparticles. [...] Encapsulation efficiency increased and burst was reduced because of the higher initial viscosity, more rapid particle hardening and increased density/reduced porosity of the polymer matrix." (p. 622, col. 1, 2ⁿᵈ paragraph, lines 9-11 & 20-23). And that: "For example, an increase in temperature will increase mass transport rates but will also reduce viscosity and may reduce the capacity of an extraction liquid for the organic solvent." (p. 622, col. 1, 3ʳᵈ paragraph, lines 9-11).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to vary the parameters for flow rates and pressure for the injecting and to vary the stirring speed and temperature conditions for stirring the microparticles in the step of removing the organic solvent, as suggested by KIM, in order to generate “microparticles in which the deslorelin is evenly distributed in the spherical biodegradable polymer” and to “prepare microparticles having a smooth surface”, respectively as taught by KIM, the method of making recited in claim 1 is identical to that of KIM therefore the resulting initial burst release would have been the same (MPEP §2112), alternatively, one of ordinary skill would have optimized the process conditions to achieve a low initial burst release as suggested by Allison, the examiner notes that Equation 1 of instant claim 9 clearly implies a low initial burst release.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because it would have required no more than an ordinary level of skill to vary the parameters taught by KIM within the scope taught for those parameters in order to produce the microparticles described therein. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 11/05/2025 have been fully considered but they are not persuasive.
Applicant argues that: “First, Applicant respectfully submits that none of the cited references discloses the claimed feature, "wherein a value according to a following Equation 2 is 1 to 2 ... where, D10 denotes a diameter of the microparticles corresponding to 10% of a maximum value in a cumulative distribution of particles, D50 denotes a diameter of the microparticles corresponding to 50% of the maximum value in the cumulative distribution of particles, and D90 denotes a diameter of the microparticles corresponding to 90% of the maximum value in the cumulative distribution of particles," as recited in amended claim 9.” And that: “Amended claim 1 clearly defines the uniformity of the particles by specifying the particle size distribution of the microparticles with the quantitative indicator of (D90-D50)/(D50-D10) = 1 to 2.” (p. 7, last paragraph through, p. 8, 2nd paragraph). Applicant further argues that: “Kim completely fails to disclose any indicator that quantitatively specifies or evaluates the uniformity of the particles.” (p. 8, 3rd paragraph).
In response the examiner cites LEE (KR10-2022-0032301; Application No. KR10-2020-0113924 with a public availability date of 07-SEP-2020; US 2022/0249452 A1 relied on as English language translation herein), teaching a method of making substantially identical to that of KIM, see for example, paragraphs [0062], [0083] through [0097], as well as the Examples. And particularly that: “The diameter of the microparticles containing Deslorelin obtained as described above was analyzed by a wet analysis method using a particle size analyzer of Microtac's 53500 model, in which a small amount of surfactant was dissolved in water as a dispersion, and the microparticles had an average diameter of 73.05 µm, a diameter range of D10% Tile 65.02 µm to D90% Tile 83.63 µm, and a particle size distribution width of 15.27 µm.” ([0172], p. 11, Table 1 - Preparation Example 6 Deslorelin)(instant Equation 2, (83.63-73.05)/(73.05-65.02) = 1.32 - Numbers From Table 1¹, MPEP §2144.05(I)).
Applicant argues that: “Furthermore, amended claim 1 does not merely aim for uniform particles, but through the combination of specific process conditions such as second to fourth features below, it simultaneously achieves the aforementioned specific range of particle size distribution of Equation 2 and the characteristic of [Equation l]: Cmax ld-28d / Cmax 0-ld = 1 to 10. Since the process conditions of amended claim 1 are different, particle characteristics and initial burst suppression characteristics identical or similar to those of amended claim 1 cannot be naturally derived from Kim.” (p. 8, 4th paragraph).
In response the examiner argues that LEE teaches that: The sustained-release microparticles of the present disclosure show that the release pattern of the drug from the particles has a ratio of initial blood concentration (Cint) to maximum blood concentration (Cₘₐₓ) of 1:2 to 30 without initial excessive release.” ([0055]). Where Cint refers to an initial blood concentration value, and its maximum blood concentration value measured within 24 hours ([0056])(instant claim 9, Equation 1, MPEP §2144.05(I)).
Applicant argues that: “Second, Applicant respectfully submits that none of the cited references discloses the claimed feature, "wherein the first mixture has a weight ratio of deslorelin and the biodegradable polymer of 1:5 to 1:8," as recited in amended claim 9.” And that: “Amended claim 1 specifies the mixing ratio of deslorelin and the biodegradable polymer as 1:5 to 1:8. This composition ratio is a key variable that directly affects the viscosity, phase separation behavior, and drug distribution during the microparticle formation process, and is not a mere design choice.” (p. 8, last two paragraphs). And that: “Additionally, through this ratio, amended claim 1 can achieve the particle size distribution of the aforementioned "Equation 2" and the initial burst suppression characteristics of "Equation 1."” (p. 9, 1st paragraph). And that: “In this regard, Kim broadly discloses a range of 1 :4 to 1 :20 as an allegedly corresponding ratio, and discloses only 1 :4 in specific examples. Furthermore, Kim does not disclose any feature corresponding to the aforementioned values from "Equation 2" and "Equation 1."” And that: “Therefore, Kim would provide absolutely no technical suggestion to select the narrow numerical range (1:5 to 1:8) of amended claim 1, which falls outside the example (1:4) of Kim, from within the broad range of 1 :4 to 1 :20.” (p. 9, paragraphs, 2-3).
In response the examiner argues that KIM teaches that “The first mixture may be mixed with the API mixture and the biodegradable polymer mixture at a weight ratio of 1:4 to 1:20.” ([0020]) (instant claim 1, “wherein the first mixture has a weight ratio of deslorelin and the biodegradable polymer of 1:5 to 1:8”). MPEP §2144.05(I) - In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Applicant further argues that: “Third, Applicant respectfully submits that none of the cited references discloses the claimed feature, "wherein the removing of the organic solvent includes: performing primary stirring at 15 to 20°C, performing secondary stirring 30 to 40°C, and performing tertiary stirring at 40 to 45°C," as recited in amended claim 9.” And that: “In amended claim 1, the temperature increases stepwise in the three-step stirring process, whereas, in Kim, the temperature increases stepwise up to the second step and then rather decreases in the third step.” And that: “Such a difference in the temperature profile is not a mere change in process conditions, but an important technical factor that directly affects the shape, surface smoothness, uniformity, and particle size distribution of the microparticles. See paragraph [0141] of the published specification […].” (p. 9, paragraphs 4-6). And further that: “In other words, the case where the temperature gradually increases as in amended claim 1 and the case where the temperature increases and then decreases as in Kim inevitably result in fundamentally different solvent removal rates, polymer hardening rates, and internal structure formation mechanisms.” Therefore, there is no motivation to adopt a temperature-increasing structure like that of amended claim 1 from the stirring process of Kim, and the resulting particle characteristics would also be inevitably different.” (p. 10, paragraphs 2-3).
In response, KIM clearly teaches that: “Another object of the present invention is to provide sustained-release microparticles having a uniform diameter.” ([0015]). And that: “More specifically, the microparticles have a spherical shape, and are in uniformly mixed state of the biodegradable polymer and the deslorelin.” ([0036]). “As the stirring process is performed by varying the stirring speed and temperature conditions for stirring the microparticles, the evaporation speed of the organic solvent present on the surface of the microparticles may be regulated. That is, by evaporating the organic solvent present on the surface of the microparticles through the stirring process, it is possible to remove the harmful solvent and prepare microparticles having a smooth surface.” [emphasis added]([0071]). The particle size distribution (Equation 2) is taught by LEE as discussed above. The examiner notes that, while the microparticle shape, smooth surface, and uniformity are not expressly claimed, the disclosure of KIM is consistent with the instant Specification (see, Published Application @ [0015]; [0134], last 3-lines; [0141], lines 7-11), thus suggesting the claimed method as obvious over the prior art, as the resulting particles have the same the shape, surface smoothness, uniformity, and particle size distribution of the microparticles.
Applicant further argues that: “Fourth, Applicant respectfully submits that none of the cited references discloses the claimed feature, "wherein the second mixture is injected into the second microchannel under a second pressure that is 2 to 4 times greater than the pressure under which the first mixture is injected into the first microchannel," as recited in amended claim 9.” And that: “In contrast, Kim only qualitatively mentions that the injection pressure of the second mixture can be greater than that of the first mixture, and there is no description that quantitatively specifies or limits the pressure difference between the two.” And that: “Furthermore, the pressure ratio derivable from the example of Kim is only about 1.75 times, which clearly falls short of the numerical range (2 to 4 times) of amended claim 1. Therefore, a person skilled has no motivation or reasonable basis to expand the pressure to 2 times or more based on the example of Kim.” (p. 10, paragraphs 4-7).
In response the examiner argues that KIM clearly teaches injecting the first mixture at a preferred 1,100 mbar ([0060]) and the second mixture is injected at a preferred 2,200 mbar ([0061]) 2,200 is 2.00 times (i.e. 1:2), and is within the scope of the claims. And this is just the preferred pressures, the full scope is within the teachings of KIM, for example, 500 mbar for the first mixture ([0060]), and 2000 for the second mixture ([0061]), where 2000/500 is 4.00 (i.e. 1:4).
Double Patenting
Applicants Terminal Disclaimer over USPN 12,251,419 has been filed and approved overcoming the obvious-type double patenting rejection over the same.
Conclusion
Claims 9 and 12 are pending and have been examined on the merits.
Claims 9 and 12 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
1 Of record as cited by Applicant on 01/12/2026, Foreign Patent Citation No. 1 on IDS.
2 Of record as cited by Applicant on 01/12/2026, Foreign Patent Citation No. 2 on IDS
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