DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on 20 May 2026 are acknowledged and have been fully considered. Claims 1-22 and 25-27 are pending. Claims 1-8, 10-11, and 26-27 are under consideration in the instant office action. Claims 9, 12-21 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claims. Claim 22 is withdrawn as being improper multiple dependent claims as indicated below (not further treated on the merits). Claims 23-24 are canceled. Claims 26-27 are newly added.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Note: The claims are examined with respect to the elected species wherein dexamethasone as the crystalline drug type and polylactic acid as the shell material.
Claims 1-8, 10-11, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Zanella et al. (US 2009/0263455) in view of Thote et al. (Nanomedicine: Nanotechnology, Biology, and Medicine 1 (2005) 85-90) and Pargaonkar et al. (Pharmaceutical Research, Vol. 22, No. 5, May 2005).
Applicants’ claims
Applicants claim a sustained-release composition comprising a plurality of microcapsules or microchambers, wherein the microcapsules or microchambers comprise a core and a shell, wherein the core comprises a crystalline drug and the shell comprises polylactic acid (PLA) or PLGA, and wherein the shell completely encapsulates the core. Dependent claims thereof recite further limitations defining various features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Zanella et al. teach effective treatments of acute pain for extended periods of time are provided. Through the administration of an effective amount of dexamethasone at or near a target site, one can relieve pain cause by diverse sources, including but not limited to spinal disc herniation (i.e. sciatica), spondilothesis, stenosis, discongenic back pain and joint pain as well as pain that is incidental to surgery. When appropriate formulations are provided within biodegradable polymers, this relief can be continued for at least twenty-five days. In some embodiments, the relief can be for at least fifty days, at least one hundred days, at least one hundred and thirty-five days or at least one hundred and eighty days (see abstract). An implantable drug depot for reducing, preventing or treating pain and/or inflammation in a patient in need of such treatment, the implantable drug depot comprising dexamethasone in an amount from about 2 wt. % to about 30 wt. % of the drug depot, and at least one biodegradable material, wherein the drug depot is capable of releasing dexamethasone over a period of at least three days (see claim 1). An implantable drug depot according to claim 1, wherein the at least one biodegradable polymer comprises one or more of poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone, D,L-lactide-glycolide-caprolactone or a combination thereof (see claim 5). A “depot” includes but is not limited to capsules, microspheres, microparticles, microcapsules, microfibers particles, nanospheres, nanoparticles, coating, matrices, wafers, pills, pellets, emulsions, liposomes, micelles, gels, or other pharmaceutical delivery compositions or a combination thereof. Suitable materials for the depot are ideally pharmaceutically acceptable biodegradable and/or any bioabsorbable materials that are preferably FDA approved or GRAS materials. These materials can be polymeric or non-polymeric, as well as synthetic or naturally occurring, or a combination thereof (paragraph 0032). In various embodiments, rather than directly admixing the therapeutic agent into the gel, microspheres may be dispersed within the gel, the microspheres being loaded with dexamethasone. In one embodiment, the microspheres provide for a sustained release of the dexamethasone (paragraph 0089). In some embodiments, the dexamethasone is encapsulated in a plurality of depots comprising microparticles, microspheres, microcapsules, and/or microfibers (paragraph 0115). The term “parenteral” as used herein refers to modes of administration that bypass the gastrointestinal tract, and include for example, intravenous, intramuscular, continuous or intermittent infusion, intraperitoneal, intrasternal, subcutaneous, intra-operatively, intrathecally, intradiskally, peridiskally, epidurally, perispinally, intraarticular injection or combinations thereof (paragraph 0041). In some embodiments, the dexamethasone is suitable for parenteral administration. In some embodiments, the injection is intrathecal, which refers to an injection into the spinal canal (intrathecal space surrounding the spinal cord). An injection may also be into a muscle or other tissue. In other embodiments, the dexamethasone is adminstered by placement into an open patient cavity during surgery itself (paragraph 0117). In various embodiments, the depot may comprise a bioabsorbable, a bioabsorbable, and/or a biodegradable biopolymer that may provide immediate release, or sustained release of the dexamethasone. Examples of suitable sustained release biopolymers include but are not limited to poly (alpha-hydroxy acids), poly (lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG), polyethylene glycol (PEG) conjugates of poly (alpha-hydroxy acids), polyorthoesters, polyaspirins, polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs, such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D,L-lactide, or L-lactide, caprolactone, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates, poly (N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate) or combinations thereof (see paragraph 0068).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Zanella et al. do not specifically teach dexamethasone in crystalline form. These deficiencies are cured by the teachings of Thote et al. and Pargaonkar et al.
Thote et al. teach our purpose was to produce nanoparticles of a hydrophilic drug with use of supercritical carbon dioxide (CO2), encapsulate the obtained nanoparticles into polymer microparticles with use of an anhydrous method and study their sustained in vitro drug release (see abstract, purpose). The hydrophilic drug, dexamethasone phosphate, is dissolved in methanol and injected in supercritical CO2 with an ultrasonic field for enhanced molecular mixing (supercritical antisolvent technique with enhanced mass transfer [SAS-EM]). Supercritical CO2 rapidly extracts methanol leading to instantaneous precipitation of drug nanoparticles. The nanoparticles are then encapsulated in poly(lactide-co-glycolide) (PLGA) polymer by use of the anhydrous solid-oil-oil-oil technique. This results in a well-dispersed encapsulation of drug nanoparticles in polymer microspheres (see abstract, methods). With supercritical CO2 used as an antisolvent, nanoparticles of dexamethasone phosphate were obtained in the range of 150 to 200 nm. On encapsulation in polylactide coglycolide, composite microspheres of ~70 Am were obtained. The in vitro drug release of these nanoparticles/ microparticles composites shows sustained release of dexamethasone phosphate over a period of 700 hours with almost no initial burst release (see abstract, results). Nanoparticles of dexamethasone phosphate can be produced with the SAS-EM technique. When microencapsulated, these particles can provide sustained drug release without initial burst release. Because the complete process is anhydrous, it can be easily extended to produce sustained release formulations of other hydrophilic drugs (see abstract, conclusion). Dexamethasone is a synthetic adrenocorticosteroid possessing basic glucocorticoid activity. A crystalline, water soluble salt of the same drug, disodium salt of dexamethasone phosphate, is used here. It is highly soluble in water and has been used in various drug delivery applications including ocular inserts , ocular injections, and polymer-lipid controlled-release devices (see page 86).
Pargaonkar et al. teach that in an effort to expand the application of core-shell structures fabricated by electrostatic layer-by-layer (LbL) self-assembling for drug delivery, this study reports the controlled release of dexamethasone from microcrystals encapsulated with a polyelectrolyte shell (see purpose). Pargaonkar et al. demonstrates sustained release of dexamethasone from core/shell microcapsules. Although the shell is polyelectrolyte rather than PLA, it shows that drug crystals can be encapsulated with a shell for controlled release.
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Zanella et al. by utilizing the dexamethasone in crystalline form because Thote et al. teach our purpose was to produce nanoparticles of a hydrophilic drug with use of supercritical carbon dioxide (CO2), encapsulate the obtained nanoparticles into polymer microparticles with use of an anhydrous method and study their sustained in vitro drug release (see abstract, purpose). The hydrophilic drug, dexamethasone phosphate, is dissolved in methanol and injected in supercritical CO2 with an ultrasonic field for enhanced molecular mixing (supercritical antisolvent technique with enhanced mass transfer [SAS-EM]). Supercritical CO2 rapidly extracts methanol leading to instantaneous precipitation of drug nanoparticles. The nanoparticles are then encapsulated in poly(lactide-co-glycolide) (PLGA) polymer by use of the anhydrous solid-oil-oil-oil technique. This results in a well-dispersed encapsulation of drug nanoparticles in polymer microspheres (see abstract, methods). With supercritical CO2 used as an antisolvent, nanoparticles of dexamethasone phosphate were obtained in the range of 150 to 200 nm. On encapsulation in polylactide coglycolide, composite microspheres of ~70 Am were obtained. The in vitro drug release of these nanoparticles/ microparticles composites shows sustained release of dexamethasone phosphate over a period of 700 hours with almost no initial burst release (see abstract, results). Nanoparticles of dexamethasone phosphate can be produced with the SAS-EM technique. When microencapsulated, these particles can provide sustained drug release without initial burst release. Because the complete process is anhydrous, it can be easily extended to produce sustained release formulations of other hydrophilic drugs (see abstract, conclusion). One of ordinary skill in the art would have been motivated to do so because Thote et al. teach that Dexamethasone is a synthetic adrenocorticosteroid possessing basic glucocorticoid activity. A crystalline, water soluble salt of the same drug, disodium salt of dexamethasone phosphate, is used here. It is highly soluble in water and has been used in various drug delivery applications including ocular inserts , ocular injections, and polymer-lipid controlled-release devices (see page 86). Furthermore, Pargaonkar et al. teach that in an effort to expand the application of core-shell structures fabricated by electrostatic layer-by-layer (LbL) self-assembling for drug delivery, this study reports the controlled release of dexamethasone from microcrystals encapsulated with a polyelectrolyte shell (see purpose). Pargaonkar et al. demonstrates sustained release of dexamethasone from core/shell microcapsules. Although the shell is polyelectrolyte rather than PLA, it shows that drug crystals can be encapsulated with a shell for controlled release. With regard to the limitations of claim 3 and claim 6, Zanella et al. teach the same drug dexamethasone and the same polymer PLA. Therefore, the solubility of the drug and the melting point of the shell are inherently the same respectively. "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty."). The combination teachings of Zanella et al., Thote et al., and Pargaonkar et al. met the claimed structure as described above. Moreover, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Furthermore, in the case where any measurable parameters" overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Furthermore, differences in concentration or measurable parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of Zanella et al., Thote et al, and Pargaonkar et al. because all of the references are drawn to microcapsules for the delivery of dexamethasone.
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. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 20 May 2026 have been fully considered but they are not persuasive.
Applicant argues none of the cited references, whether taken alone or in combination, teach or motivate the claimed combination of a true core-shell microchamber architecture with a thick, largely impermeable PLA/PLGA shell; crystalline drug (dexamethasone) as the cargo; and a solvent free / dry loading approach. The methods described in Pargaonkar are not compatible with PLA and PLGA shells as they lack the necessary water solubility and have no ionic charge. Whilst a core shell structure is formed by this approach, a person with ordinary skill in the art following the teaching of Pargaonkar would not achieve the thicker (from about 0.05 to about 2 microns) and impermeable core-shell structure of the present invention.
The above assertions are not found persuasive because 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., the claim does not require specific shell thickness, permeability values, microchamber geometry beyond the recited core-shell relationship, loading process, or performance metrics (release rate and permeability)) 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). The examiner indeed provided a proper motivation explaining why one of ordinary skill in the art would combine the references.
Applicant submits Zanella discloses broadly formulated dexamethasone delivery systems (e.g. pellets, gels, emulsions), but does not disclose a core-shell architecture, use of a crystalline drug, or dry loading. The reported release data of Zanella are tied to structurally different formats. More specifically, Zanella discloses data concerning the in vitro release of dexamethasone from melt extrusion and hand mix formulations. Melt extrusion produces pellets, whilst hand mix produces injectable gels. Release data is shown for both formulations, with less than 50% release after 150 days with the slowest release formulation. In the formulation table (Fig 3), Zanella also discloses a melt extrusion in the form of a strand and a double emulsion hand mix that is a microparticle suspension in POE gel. There is no matching release data for these formulations. As mentioned above, a difference between the present application and the disclosure of Zanella is that Zanella is absent of any mention of a core-shell structure, nor a structure in which the shell completely encapsulates the core, in contrast to the present invention. The core shell structure is essential for the providing the surprising advantage of an improved sustained release profile of the present invention, compared to polymeric microspheres of Zanella. In contrast to the polymeric microspheres of Zanella, complete encapsulation of the crystalline drug as described in the present application provides much more precise and sustained release. There is no suggestion in Zanella to provide a microsphere with a core-shell structure, wherein the shell completely encapsulates the core. Furthermore, there is no suggestion to comprise a crystalline drug. A person with ordinary skill in the art could not reach the present invention even with the disclosure of Zanella without exercising inventive skill.
The above assertions are not found persuasive because Zanella et al. expressly defines “depot” to include capsules, microspheres, microparticles, microcapsules, microfiber particles, nanospheres, nanoparticles, coating, matrices, wafers, pills, pellets, emulsions, liposomes, micelles, gels, or other pharmaceutical delivery compositions or a combination thereof. It contemplates solid, semi-solid, or solidifying implants that release dexamethasone over extended periods (at least 25 days, and in preferred embodiments 50, 100, 135, or 180 days or longer). Although Zanella’s primary examples emphasize matrix type de[pots in which drug is dispersed throughout the polymer, the reference is not limited to homogenous dispersions. Its explicit inclusion of microcapsules, microspheres, and microparticles as suitable depot forms encompasses structures in which a polymeric shell or continuous polymer phase surrounding drug containing regions. A “depot” includes but is not limited to capsules, microspheres, microparticles, microcapsules, microfibers particles, nanospheres, nanoparticles, coating, matrices, wafers, pills, pellets, emulsions, liposomes, micelles, gels, or other pharmaceutical delivery compositions or a combination thereof. Suitable materials for the depot are ideally pharmaceutically acceptable biodegradable and/or any bioabsorbable materials that are preferably FDA approved or GRAS materials. These materials can be polymeric or non-polymeric, as well as synthetic or naturally occurring, or a combination thereof (paragraph 0032). An implantable drug depot for reducing, preventing or treating pain and/or inflammation in a patient in need of such treatment, the implantable drug depot comprising dexamethasone in an amount from about 2 wt. % to about 30 wt. % of the drug depot, and at least one biodegradable material, wherein the drug depot is capable of releasing dexamethasone over a period of at least three days (see claim 1). An implantable drug depot according to claim 1, wherein the at least one biodegradable polymer comprises one or more of poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone, D,L-lactide-glycolide-caprolactone or a combination thereof (see claim 5). In various embodiments, rather than directly admixing the therapeutic agent into the gel, microspheres may be dispersed within the gel, the microspheres being loaded with dexamethasone. In one embodiment, the microspheres provide for a sustained release of the dexamethasone (paragraph 0089). In some embodiments, the dexamethasone is encapsulated in a plurality of depots comprising microparticles, microspheres, microcapsules, and/or microfibers (paragraph 0115). A person of ordinary skill in the art reading Zanella would understand that PLGA/PLA, PLA, or PLGA microcapsules, microspheres, or microparticles loaded with dexamethasone clearly encompass core-shell or encapsulated systems as recited.
Regarding the crystalline drug Zanella teaches dexamethasone and its pharmaceutically acceptable salts. Dexamethasone is routinely available and used in crystalline form; nothing in Zanella requires or prefers an amorphous or dissolved state. Additionally, Pargaonkar goes further and expressly uses crystalline dexamethasone microcrystals as the solid core that is then encapsulated. Thote likewise start with particulate (nanoparticulate) drug that s subsequently encapsulated. It would indeed have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Zanella et al. by utilizing the dexamethasone in crystalline form because Thote et al. teach our purpose was to produce nanoparticles of a hydrophilic drug with use of supercritical carbon dioxide (CO2), encapsulate the obtained nanoparticles into polymer microparticles with use of an anhydrous method and study their sustained in vitro drug release (see abstract, purpose). The hydrophilic drug, dexamethasone phosphate, is dissolved in methanol and injected in supercritical CO2 with an ultrasonic field for enhanced molecular mixing (supercritical antisolvent technique with enhanced mass transfer [SAS-EM]). Supercritical CO2 rapidly extracts methanol leading to instantaneous precipitation of drug nanoparticles. The nanoparticles are then encapsulated in poly(lactide-co-glycolide) (PLGA) polymer by use of the anhydrous solid-oil-oil-oil technique. This results in a well-dispersed encapsulation of drug nanoparticles in polymer microspheres (see abstract, methods). With supercritical CO2 used as an antisolvent, nanoparticles of dexamethasone phosphate were obtained in the range of 150 to 200 nm. On encapsulation in polylactide coglycolide, composite microspheres of ~70 Am were obtained. The in vitro drug release of these nanoparticles/ microparticles composites shows sustained release of dexamethasone phosphate over a period of 700 hours with almost no initial burst release (see abstract, results). Nanoparticles of dexamethasone phosphate can be produced with the SAS-EM technique. When microencapsulated, these particles can provide sustained drug release without initial burst release. Because the complete process is anhydrous, it can be easily extended to produce sustained release formulations of other hydrophilic drugs (see abstract, conclusion). One of ordinary skill in the art would have been motivated to do so because Thote et al. teach that Dexamethasone is a synthetic adrenocorticosteroid possessing basic glucocorticoid activity. A crystalline, water soluble salt of the same drug, disodium salt of dexamethasone phosphate, is used here. It is highly soluble in water and has been used in various drug delivery applications including ocular inserts , ocular injections, and polymer-lipid controlled-release devices (see page 86). Furthermore, Pargaonkar et al. teach that in an effort to expand the application of core-shell structures fabricated by electrostatic layer-by-layer (LbL) self-assembling for drug delivery, this study reports the controlled release of dexamethasone from microcrystals encapsulated with a polyelectrolyte shell (see purpose). Pargaonkar et al. demonstrates sustained release of dexamethasone from core/shell microcapsules. Although the shell is polyelectrolyte rather than PLA, it shows that drug crystals can be encapsulated with a shell for controlled release. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The examiner also reminds Applicant regarding the dry anhydrous loading argument that the claims are drawn to a composition not a process claim. The claim does not recite any loading method. Even if the specification describes a solvent free dry loading process, that process is not a claimed limitation and cannot be used to distinguish the art. Neverthless, the combination renders dry or anhydrous loading obvious. Thote expressly teaches an anhydrous solid-oil-oil-oil technique to encapsulate pre formed drug nanoparticles into PLGA microparticles, deliberately avoiding aqueous solvents that would dissolve hydrophilic drug and produce burst release. The stated purpose is to achieve well dispersed encapsulation with minimal initial burst and sustained release over hundreds of hours. One of ordinary skill in the art combining Zanella’s PLGA/PLA dexamethasone depots with Thote’s anhydrous encapsulation method would arrive at solvent minimized or dry loading of particulate/crystalline dexamethasone into PLA/PLGA shells with reasonable expectation of success. Physical loading of crystals into pre-formed polymer cavities or wells is a natural extension of the dry handling techniques already known for preserving crystallinity.
Applicant’s observation that Zanella’s reported release data are associated with matrix type or other depot format does not negate the rejection. Obviousness does not require that every reference disclose every claim element in identical structural form or with identical release profiles. Zanella establishes that PLGA/PLA formulations of dexamethasone provide multi-week to multi-month sustained release suitable for local pain/inflammation therapy. Pargaonkar demonstrates that core-shell encapsulation of crystalline dexamethasone modulates release in a layer number and composition dependent manner. Thote shows that anhydrous encapsulation of particulate dexamethasone (phosphate) into PLGA yields sustained release with essentially no burst. One of ordinary skill in the art would combine these teachings because the secondary references address recognized limitations of simple matrix systems (burst release, incomplete control of crystallinity, solvent induced changes) while retaining the biodegrdable polyester platform of Zanella. Any difference in absolute release kinetics are expected and optimizable.; they do not demonstrate non-obviousness of the claimed structure.
Thote teaches crystalline dexamethasone nanoparticles in the context of solvent based encapsulation leading to dispersion throughout polymer microspheres (including surface exposure), rather than spatially isolated cores within a shell (as provided by the present invention). More specifically, on page 87, Thote discloses a method of preparing the microspheres involving the crushing of crystalline dexamethasone to nanosizes, followed by microencapsulation using solid-oil-oil-oil dispersion technique. During this method of preparation, the nanoparticles of dexamethasone are mixed with polymer in solvent (dichloromethane and use of hexane is mentioned), and therefore the dexamethasone drug cargo is exposed to the solvent. In contrast, the compositions of the presently claimed invention are preparable by a dry loading method where there is not contact between cargo and solvent. This is particularly important for cargo that would be denatured by solvent. Again, the microspheres of Thote have no core-shell structure since dexamethasone nanoparticles are dispersed throughout the polymer in microspheres and would also be exposed on the surface of the microspheres. A person with ordinary skill in the art would not be motivated to produce an encapsulated drug in the microspheres according to the present invention. For at least these reasons, the disclosure of Thote does not remedy the deficiencies of Zanella.
The above assertions are not found persuasive because Applicant is claiming a composition of matter or a product not a method of making the composition or the product. The process of making does not carry any patentability weight. Additionally, as indicated above such process limitations are not recited in the claims as well.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIGABU KASSA whose telephone number is (571)270-5867. The examiner can normally be reached on 8 AM-5 PM.
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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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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