aNotice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Receipt of response and amendment dated on 6/24/25 is acknowledged.
Claims 5-8 have been previously withdrawn from consideration. It is noted that Applicants have not mentioned the status of claims 5-8 in their response.
Claims 1-4 have been examined in the previous action.
Priority
A certified copy of the foreign priority application to has been noted in the present Application.
The following rejection has been maintained:
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.
Claim(s) 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Kirsch et al (Supplemental attached) in view of US 20240269340 to Benny et al and Lee et al (cited on IDS dated 4/10/25).
Kirsch teaches human relaxin-2 (RLX) as a promising anti-fibrotic and antifibrogenic activity and is a promising biotherapeutic candidate for musculoskeletal fibrosis. Kirsch teaches a tailored drug delivery system for the sustained release of RLX (abstract). A single articular RLX-loaded PLGA microsphere was prepared to provide sustained release of bioactive protein for several weeks.
Preparation of microparticles of human relaxin-2 using a water-in-oil-in-water double emulsion method is disclosed in Supplementary Materials, a solution of 5% PLGA (0-120 kDa, 30: 50, ester terminated) (lactic acid absorbable polymer) in dichloromethane, a mixture of 10% BSA solution and human relaxin-2 in 1:7 weight ratio in PBS was prepared to make up the aqueous phase. 100 microliters of the aqueous phase was mixed with 2 mL of the oil phase, and the resulting mixture was pulse emulsified to give an emulsion which was diluted into 5 mL of 8% PVA (MW: 45 kDa) and rapidly stirred for 5 minutes. 20 mL of 2% isopropanol were added, and the residual organic solvent was evaporated. The microspheres were washed by centrifugation (1000 x 9} for 5 minutes and then resuspended in dH20 (sec Supplementary Materials pp. 3-4).
As can be seen, Kirsch discloses the preparation of RLX-loaded slow-release microspheres by centrifugation, washing after evaporation of the organic solvent by mixing emulsion followed by addition of PVA solution in PBS as internal water phase, dissolution of PLGA in dichloromethane as oil phase.
Kirsch does not teach the claimed porous microspheres, and lacks the instant claimed step 2. .
Instant claims are directed to a method of preparation and the preamble term “for inhalable” does not carry patentable weight. Any terminology in the preamble that limits the structure of the claimed invention must be treated as a claim limitation. See, e.g., Corning Glass Works v. Sumitomo Elec. U.S.A., Inc., 868 F.2d 1251, 1257, 9 USPQ2d 1962, 1966 (Fed. Cir. 1989). In the instant case, the claimed process steps do not limit the resulting composition only to inhalable composition.
In any event, Lee discloses washing and lyophilize the solidified microspheres to obtain the porous microspheres, for pulmonary delivery.
Kirsch also discloses that RLX can be used to treat lung fibrosis, while one skilled in the art would readily envision adapting the protein drug of the pulmonary delivered porous microspheres in Lee (described herein) to RLX and screening for suitable PLGA types for the need of disease treatment.
Lee describes polymer microspheres with uniform porous structures were prepared using an osmotic agent, which can control the particle size and pore size independently (abstract and fir. 1). BSA is used in inducing osmosis between internal and external phases in a water-in-oil-in-water (W/O/W) emulsion process, and the particle size and porous structure could be decoupled. Section 2.2 describes PLGA and BSA were dissolved in methylene chloride (3 ml) and deionized water (0.6 ml), respectively. Both solutions were emulsified using a probe type sonicator (Branson Digital Sonifier®) for 10 s in an ice bath. A 4% aqueous PVA solution (15 ml) was poured into the resultant emulsion (w/o), and the emulsion was emulsified again to form double emulsion (w/o/w) using a homogenizer (Ultra-Turrax® T25 basic, IKA®-Werke) for 5 min at 6000 rpm. The double emulsion was poured into a 0.4% aqueous PVA solution (300 ml) and mixed thoroughly using a mechanical stirrer at 800 rpm for 3 h at room temperature to evaporate organic solvent. The solidified microspheres were washed with deionized water five times and lyophilized. Porous microspheres with different particle sizes and pore sizes were prepared by varying either polymer concentration (5, 8, and 10%) or BSA content (0.1, 0.2, 0.4, and 0.6, BSA/PLGA = w/w). Section 2.5 teaches incorporating VEGF or insulin proteins in the internal water phase, during the preparation of porous microspheres.
Lee teaches that controlling the concentration of BSA and PLGA provides a control over the pore size and particle size (section 3.2 & fig. 3). Lee teaches administering proteins and peptide-based drugs via injection may reduce patient compliance and acceptance for treatment, and that pulmonary delivery has been attractive over the past decades for systemic drug administration due to large surface area, high permeability, and slow mucociliary clearance of lung tissues, and refers to porous microparticles for inhalable delivery systems (2nd para on page 61). Section 3.3 describes that the highest deposit efficiency of porous microspheres with homogenous distribution in the lungs (fig. 5) and the active agent (VEGF) released in a sustained release for two weeks.
Lee does not teach the instant claimed freezing and lyophilization.
Benny teaches a process of water-in-oil emulsion, in preparing porous microspheres, in paragraph [0210, fig.6]. Benny teaches PLGA (72:25 polymer) is dissolved in DCM (organic phase) [0199]. BSA or drugs were 100 mg PEG-PLGA were dissolved in 1800 μl DCM (organic phase)[0210-0211]. B. The two phases were mixed using homogenizer for one min at max speed (22000 rpm) on ice [0210]. The emulsion was then transferred to 4 ml saturated PVA 5% and mix again using homogenizer for 40 seconds at 40% max speed on ice. The double emulsion dropped into 50 ml PVA 5% under stirring (800 rpm). After five minutes stirring 2.5 ml cold isopropanol were added and the solution was stirred for an additional hour. The microspheres were centrifuged at 5000 rpm for 10 min and pellet was re-suspended into 50 ml DDW to washes the microspheres.
Benny teaches homogenizing on ice. Instant claim step 1 does not limit the temperature of homogenization to any specific temperature and therefore allows for homogenization on ice. Instant step 1 states 10000 rpm whereas Benny teaches 22000 rpm. However, [0205] teaches preparation of porous microparticles homogenized at 11000 rpm for 3 min to form the primary elusion, and thus suggests optimization of the homogenization in step 1.
The microspheres solution was then frozen and lyophilized. The powder obtained was submitted to SEM for imaging. The porous microparticles are collapsible has a size range between 10 to 500 microns or 40-50 microns (0029-0030). The microparticles are typically polymeric particles made of poly(lactic-co-glycolic) acid (PLGA) [0041, 0173].
For claim 3, A total of three washes were made, each one using 50 ml DDW. Aliquot was removed for size and zeta determination.
Thus, it would have been obvious for one of an ordinary skill in the art before the effective filing date to modify the method of preparing relaxin-2 microspheres (of Kirsch) by further subjecting the double emulsion to freezing and lyophilizing, and thus arrive at the instant claimed inhalable porous microspheres. One of an ordinary skill in the art would have been able to optimize the conditions, such as the amounts of PLGA, BSA and PVA, centrifugation speed, temperature and time for freezing and lyophilization, with an expectation to provide porous microspheres that would be suitable for different routes of administration including inhalation. One of an ordinary skill in the art would have been motivated because Lee teaches double emulsification carried out under cooling conditions (ice bath), centrifugation for homogenization at 6000 rpm, and further optimizing the amounts of BSA for controlling the porosity and particle size of the microspheres. Further, Benny suggests that the double emulsion method involving the additional steps of freezing and lyophilization form porous microparticles with void features that allow continuous flow of liquid through the channels that extends a distance between the pores [0058]. Benny teaches that the process enables drug present in the microsphere and release therefrom to distally and selectively reach the tumor bed due to the porous mesh and the enlarged surface-volume ratio [0197].
Even though Benny does not state freezing performed at -20ºC for 4-6 hrs and -80ºC and maintaining for 8 hours, one of an ordinary skill in the art would have been motivated to choose the appropriate time and temperature with an expectation to provide porous microparticles having desired size range, porosity and density, and thus provide the release of relaxin-2 from the said modified microspheres for a sustained period of time. For claim 3, Lee teaches that the microspheres were washed with deionized water several times and lyophilized, and Benny teaches washing three times. For the centrifugation in claim 1 and 2, the cited references teach centrifuging at speeds that are within or close to the claimed ranges. Accordingly, one of an ordinary skill in the art would have been able to determine the variables to prepare porous microspheres of desired porosity and density, with an expectation to achieve a sustained release of relaxin-2.
In response to the amendment, the following rejection has been withdrawn:
Claim Rejections - 35 USC § 112
Claims 1-4 are 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.
Response to Arguments
Applicant's arguments filed 8/18/25 have been fully considered, with respect to the rejection under 35 USC 103, but they are not persuasive.
Applicants argue that Kirsch’s method teaches non-porous microspheres, based on the process steps, and fails to teach the microspheres for inhalation. Applicants’ arguments are not found persuasive because the rejection relies on the teachings of Lee to show that employing BSA at an optimum amount provides porosity to the microspheres. Even though Kirsch fails to teach porous microspheres, one of an ordinary skill in the art would have recognized that the process of Kirsch results in porous microspheres. Applicants’ argument that that Kirsch does not suggest porosity would be beneficial is not persuasive because the rejection relies on Lee reference to show the same.
It is argued that Lee form porous microspheres using BSA as an osmotic agent but not the freezing/lyophilization step to create pores, whereas instant microspheres are rendered porous not with BSA but with a specific programed cooling process, and that the specification avoids pore forming agents. Applicants argue that Lee used lyophilization to dry the microspheres but not for forming pores. Therefore, it is argued that Lee teaches away from the claimed method. The argument that instant claims result in porous microspheres without BSA (which is an osmagent according to Lee) is not found persuasive because the claimed process positively recites BSA, and a chemical compound and its properties are inseparable. If the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Further, it is noted that instant claims are silent regarding the absence of porous microspheres after performing step 2) of the instant claims.
It is argued that Benny does not teach the claimed freezing/lyophilization step for creating pores but for SEM imaging. It is argued that Benny teaches porosity is formed by emulsification not by freeze drying/lyophilization. Hence, it is argued that there is no motivation to arrive at the claimed invention. The argument that Benny uses the freezing and lyophilization for SEM imaging and not for creating pores is not persuasive because Benny (analogous to Lee and Kirsch) suggests that the double emulsion method, involving the additional steps of freezing and lyophilization, form porous microparticles with void features that allow continuous flow of liquid through the channels that extends a distance between the pores [0058]. Benny teaches that the process enables drug present in the microsphere and release therefrom to distally and selectively reach the tumor bed due to the porous mesh and the enlarged surface-volume ratio [0197]. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Applicants argue that the claimed specific condition of freezing is to achieve high porosity and resulting in inhalable properties. It is argued that instant claims require specific emulsification at 10000 rpm and programmed cooling , not taught by Kirsch, Lee or Benny references. It is argued that Lee used 6000 rpm and Benny used 22000 that is outside the claimed range. It is argued that the claimed two-step freezing protocol (-20°C 4-6h to 80°C 8h) exploits differential ice crystal nucleation kinetics. Slow freezing at -20°C forms macroporous scaffolds, while rapid — 80°C freezing locks the structure achieving 95% porosity without porogens.
Applicants’ argument has been considered but not found persuasive because the method of preparing porous microspheres includes formation of emulsion and further step of freezing and lyophilization conditions [0207 & 0210]. The combined teachings of Lee and Benny provides the motivation to modify the teachings of Kirsch because while Lee teaches control of porosity for controlling the release of the drug, Benny also teaches homogenizing at a high speed ( a maximum speed of 22000) for the preparation of emulsion. Moreover, Lee also teaches a homogenization speed of 8000 rpm for the emulsification Thus, the combined teachings of Lee and Benny suggests a range of homogenization speed of 8000-22000 (maximum limit) for emulsification in preparation of porous microspheres, and therefore one of an ordinary skill in the art before the effective filing date of the instant invention would have recognized that the
homogenizer speed of emulsification (of instant step 1) can be optimized to arrive at the claimed 10000 rpm with an expectation to provide an effective emulsification. With respect to the argument that the claimed method unexpectedly produces microspheres with 95% porosity and sustained release over 24 days without using pore- forming agents that are unexpected over Kirsch, Benny and Lee. Kirsch’s microspheres and that Lee's porous microspheres release VEGF for only two weeks and require a pore-forming agent (BSA)., the argument has been considered but not found persuasive because Lee explains the relationship between porosity and the released of VEGF, that the formation of pores reduced the initial burst of the protein and provided sustained release. Instant claims do not recite a particular release of any drug, protein or active agents or the amounts of the active agent and on the other hand, Kirsch discloses the preparation of RLX-loaded slow-release microspheres. Moreover, Lee also teaches pulmonary delivery and hence one of an ordinary skill in the art would have expected that the modification of the method of preparing microspheres, with that of Lee and Benny renders inhalable porous microparticles of the instant claims.
THIS ACTION IS MADE FINAL. 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.
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/LAKSHMI S CHANNAVAJJALA/Primary Examiner, Art Unit 1611