DETAILED ACTION
Status of the Claims
Claims 1, 3 and 5-12 are pending in the instant application. Claims 9-12 have been withdrawn based upon Restriction/Election. Claims 1, 3 and 5-8 are being examined on the merits in the instant application.
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All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.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
Applicants claim priority to US 18/170,602 filed 02/17/2023 and KR10-2022-0021275 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.
Claim Rejections - 35 USC § 112(b)
Claims 1, 3 and 5-8 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 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: (1) the solvent, (2) the biodegradable polymer concentration in the solvent, and (3) the temperature for the determination of “a viscosity” of the “two or more biodegradable polymers”. Particularly, depending on the solvent used, the concentration of the biodegradable polymer and the temperature, the viscosity measurement will be variable. Therefore, the claim fails to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention, and the claim is properly rejected under 35 U.S.C. 112(b). Claims 3 and 5-8 depend from and inherit the above discussed issue with claim 1, and are therefore rejected for the same reasoning.
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 and 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over KIM (WO 2020/000399 A1; published 11/05/2020, US 2022/0202894 relied on as English language translation and cited herein) in view of SU (CN 110404054 A; published November, 2019; Machine-English-Translation relied on herein); ALLISON (“Analysis of initial burst in PLGA microparticles,” 2008, Informa Healthcare; Expert Opinion Drug Delivery, Vol. 5, No. 6, pp. 615-628); and LEE (KR10-2022-0032301; Application No. KR10-2020-0113924 with a public availability date of 07-SEP-2020; US 2022/0249452 Al relied on herein as English language Translation).
Applicants Claims
Applicant claims a composition for sustained-release injection comprising deslorelin, the composition comprising microparticles, wherein the microparticles comprise the deslorelin and two or more biodegradable polymers, and wherein the composition has a value of 1 to 10 according to Equation 1: 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, wherein the microparticles have a value of 1 to 2 according to a following Equation 2: D90-D50/D50 where D10 denotes a diameter of the microparticles corresponding to 10% of a maximum value in a cumulative distribution of microparticles, D50 denotes a diameter of the microparticles, and D90 denotes a diameter of the microparticles corresponding to 90% of the maximum value in the cumulative distribution of the microparticles, wherein an area-under-curve (AUC) value of the deslorelin within 1 week after injection is 500 to 1500 d*pg/ml, wherein the two or more biodegradable polymers have different viscosities, respectively, one of the two or more biodegradable polymers having a viscosity of 0.1 to 0.3 dl/g, another of the two or more biodegradable polymers having a viscosity of 0.3 to 0.7 dl/g (instant claim 1).
Elected Species: Applicants have elected the following species in the reply filed 09/23/2024: (a) a species of biodegradable polymer is PLA + PLGA (Preparation Example 1, Specification p. 25, [000162]).
Determination of the scope
and content of the prior art (MPEP 2141.01)
KIM teaches sustained-release microparticles containing deslorelin (title, see whole document), and particularly “sustained-release microparticles containing deslorelin, and a preparation method therefor, of the present invention, sustained-release microparticles containing deslorelin in a formulation for subcutaneous administration are provided so that pain can be relieved during administration to animals, and a chemical castration effect can last for 2 to 36 months.” [emphasis added](abstract)(instant claims 6-7). The examiner notes that the chemical castration level is defined in the instant Specification as a plasma testosterone of < 0.4 ng/mL (pp. 9-10, paragraph [0066], as filed; [0062], as published). The examiner notes that Deslorelin is an oligopeptide, and is a gonadotropin releasing hormone super-agonist also known as an LHRH agonist.
KIM teaches that: “the first mixture is mixed with the API mixture and the biodegradable polymer mixture at a weight ratio of 1:4 to 1:20.” ([0042] & [0078])(instant claim 5). KIM teaches the biodegradable polymer “is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, polyamino acid, and a combination thereof […].” [emphasis added]([0043])(instant claim 1, two or more biodegradable polymers, instant claim 3).
KIM teaches that: “The composition for subcutaneous injection comprising sustained-release microparticles containing deslorelin according to another embodiment of the present disclosure may contain sustained-release microparticles and a suspension solvent.” (instant claim 8).
KIM teaches that “the prepared microparticles […] have an average diameter of 25 to 140 μm ([0016], [0031] & [0077]).
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: (i) the value of Equation 1 in instant claim 1; (ii) the microparticle size distribution (Equation 2, instant claim 2); or (iii) the viscosity of the biodegradable polymers (instant claim 4).
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 and a specific surface area of the microparticles of 0.75x10-1 to 2.0x10-1 m2/g, 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 a specific surface area per unit mass of 0.75x10-1 to 2.0x10-1 m2/g.” ([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 1, Equation 1, overlapping range of 2-10).
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).
Regarding Equation 1 as recited in instant claim 1, and the limitation “wherein the area-under-curve (AUC) value of the deslorelin within 1 week after injection is 500 to 1,500 day*pg/ml”, 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).
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).
SU teaches an exenatide microsphere preparation (see whole document), and particularly an exenatide microsphere injection of the invention small burst release, quick effect, long medicine releasing period (abstract). SU teaches that: “exenatide is a North American toxic external secretion peptide artificially synthesized, composed of 39 amino acid residues, of glucagon-1 (GLP-1) receptor agonist.” (p. 1,§Background, 1st paragraph, lines 1-2). And that: “to reduce the dosing frequency and improved patient compliance, Amylin and Biovitrum company developed a peripheral exenatide microsphere preparation […], but the microsphere preparation in presence of significant initial burst, early drug release lag time is long ([…]), easy to cause large fluctuation of blood concentration and cause obvious side effect. Therefore, it is necessary to develop a low burst release for exenatide microsphere preparation, early drug release lag time is short, the effect is fast, small fluctuation of blood concentration.[emphasis added]” (p. 2, 1st paragraph).
SU teaches that: “The purpose of the invention is to provide a rapid onset of long-acting exenatide microsphere preparation and preparation method and use thereof, to solve the problem that the existing product has fast release, long drug release lag time, steady state blood concentration fluctuation is large.” (p. 2, § summary of the invention, 1st paragraph). And that: “The invention claims an exenatide microsphere preparation, comprising the following components according to weight percentage: 3-10% of exenatide or exenatide peptide salt, and 90-97 % of polymer blend, said polymer blend comprises lactide and-glycolide and lactide, the lactide and-glycolide comprises a terminal carboxylic acid group of the first lactide and-glycolide and the tail end is the second lactide and-glycolide of the ester group.” (Id., 2nd paragraph). SU further teaches that: “In some embodiments, the first polylactide glycolide by the-intrinsic viscosity is 0.20-0.55 dL/g, preferably is 0.35-0.50dL/g, more preferably is 0.40-0.50 dL/g.” “In some embodiments, the intrinsic viscosity of the second lactide and-glycolide is 0.50-0.90 dL/g, preferably 0.60-0.80 dL/g.” “In some embodiments, the intrinsic viscosity range of polylactide is 0.05-0.25 dL/g, preferably 0.05-0.15 dL/g.” (p. 2, § summary of the invention, paragraphs 8-10).
SU teaches that: “to facilitate description, in the present invention, named PLGA is the mol ratio of lactide to glycolide + optical + G + polymer end type, and represents the intrinsic viscosity range and a weight average molecular weight in the parentheses. the expression way of optical activity is: D represents right, L represents left, DL stands for racemic. the expression way of the polymer end type: A is the carboxy terminus, E is ester end. e.g., "5050 DEM/DOM A (0.4-0.5, 61000)" indicates that the PLGA is a racemic substance, wherein the mol ratio of lactide to glycolide is 50:50, the terminal group is a carboxyl, an intrinsic viscosity of 0.4-0.5 dL/g, a weight average molecular weight of 61000 Daltons.” (p. 4, 3rd paragraph). And that: “to facilitate description, in the present invention, naming of the PLA is composed of: lactide content polymer end type + activity +, and represents the intrinsic viscosity range and a weight average molecular weight in the parentheses. e.g., "100 DL A (0.15-0.25, 16000)"indicates that the PLA is a racemic substance, wherein the mol ratio of lactide to glycolide is 100:0, the terminal group is a carboxyl, an intrinsic viscosity of 0.15-0.25 dL/g, a weight average molecular weight of 16000 Daltons.” (p. 4, 4th paragraph).
SU teaches examples including a blend of various PLA/PLGA polymers wherein the two or more biodegradable polymers have different viscosities, respectively, one of the two or more biodegradable polymers having a viscosity of 0.1 to 0.3 dl/g, another of the two or more biodegradable polymers having a viscosity of 0.3 to 0.7 dl/g.
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 produce a deslorelin microparticle comprising a biodegradable polymer such as PLGA and PLA, as suggested by KIM, and to select the appropriate viscosity for the PLGA and PLA polymers to reduce the burst release and associated side-effects and wasted drug product, as suggested by ALLISON and SU, and appropriate process parameters in order to achieve narrow particle size distribution and low burst release as suggested by ALLISON, SU and LEE, for producing a slow (sustained) release microparticle comprising deslorelin in a PLGA/PLA matrix.
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 KIM and LEE teaches methods of making the deslorelin PLGA/PLA microparticles and discloses that: “the present disclosure will be described in detail so that those skilled in the art to which the present disclosure pertains can easily carry out the present disclosure.” ([0089]), including various modifications to improve the same ([0119]). 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.
Response to Arguments:
Applicant's arguments filed 09/26/2025 have been fully considered and are persuasive to overcome the previous grounds of rejection. Applicant’s arguments with respect to the reference DUCREY have been considered but are moot because the new ground of rejection does not rely on DUCREY reference applied in the prior rejection of record.
Applicants argument regarding inherency of properties such as release profile in the prior art (MPEP 2112) (pp. 8-9) is acknowledged. Based on the amendment to require two or more biodegradable polymers (PLA + PLGA) the examiner withdraws this argument. However, maintains that based on the teachings of ALLISON and SU (newly cited), one of ordinary skill would have clearly been motivated to minimize the burst release of the deslorelin extended release formulation taught by KIM/LEE.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “in the instant application, the average diameter is 65 to 100 μm” – arguments p. 9, last 3 lines) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Double Patenting - Nonstatutory
Response to Arguments:
Applicant's Terminal Disclaimer over U.S. Application Nos. 18/170,602 and 17/762,701 has been received and approved. Therefore, the obviousness-type double patenting rejection over each of these cases have been withdrawn.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. SUN (US 2014/0050799) is cited as teaching “The microsphere formulation comprise risperidone […], and a polymer blend having a first uncapped lactide-glycolide copolymer and a second uncapped lactide-glycolide copolymer, in which the first uncapped lactide-glycolide copolymer is a copolymer with a high intrinsic viscosity and the second uncapped lactide- glycolide copolymer is a copolymer with a low intrinsic viscosity.” (abstract, see whole document). JAIN (US 2019/0117573) is cited as teaching “Compositions containing a plurality of biodegradable polymer microparticles having an active ingredient such as risperidone therein are disclosed. The plurality of biodegradable polymer microparticles include a first portion of biodegradable polymer microparticles having a 90% release in about 10 days to about 20 days for the active ingredient therefrom in vitro; a second portion of biodegradable polymer microparticles having 90% release in about 15 days to about 25 days for the active ingredient therefrom in vitro; […].” (abstract, see whole document). Makadia et al. (“Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier”, 2011, Polymers, Vol. 3, No. 3, pp. 1377–1397. doi:10.3390/polym3031377) is cited as teaching that: “Commercially available PLGA polymers are usually characterized in terms of intrinsic viscosity, which is directly related to their molecular weights.” (p. 3, 1st paragraph, last 3 lines).
Conclusion
Claims 1, 3 and 5-8 are pending and have been examined on the merits. Claims 1, 3 and 5-8 are rejected under 35 U.S.C. 112(b)(new rejection); and claims 1, 3 and 5-8 are rejected under 35 U.S.C. 103 (new grounds of rejection). No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on (571) 272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IVAN A GREENE/Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
1 The examiner notes that paragraph [0172] indicates “D90% Tile 85.87” however, based on Table 1 this is the D95%, where the D90% is indicated as 83.63.