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 response in the reply filed on 17 November 2025 are acknowledged and have been fully considered. Claims 1-25 are pending. Claims 1-8 Claims 9, 12-21 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking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. Claims 22-24 are withdrawn as being improper multiple dependent claims as indicated below (not further treated on the merits).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05 June 2024 is noted and the submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the references. A signed copy is attached herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d).
Election/Restrictions
Applicant's election of Group I (claims 1-11 and 22-24) in the reply filed on 17 November 2025 is acknowledged. Additionally, Applicant’s election of dexamethasone as the crystalline drug and polylactic acid as the shell material in the reply filed on 17 November 2025 is also acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Objections
Claim 22 is objected to as depending from a withdrawn base claim.
Appropriate correction is required.
Claims 22-24 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot serve as the basis of any other multiple dependent claim. Claims 22-24 are not further been treated on the merits. See MPEP § 608.01(n). Accordingly, claims 22-24 are not been further treated on the merits and are withdrawn from further consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 and 10 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 4 recites the broad recitation “the drug is a corticosteroid”, and the claim also recites “optionally wherein the corticosteroid is selected from the group consisting of dexamethasone, prednisolone, betamethasone, prednisone, methylprednisolone, budesonide, hydrocortisone, triamcinolone and fludrocortisone” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 4 recites the broad recitation “or wherein the drug is a protein”, and the claim also recites “optionally wherein the protein is a growth factor, an enzyme, a cytokine, a chemokine or a biological therapeutic” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 10 recites the broad recitation “one or more pharmaceutically acceptable excipients or diluents”, and the claim also recites “optionally wherein the sustained-release composition comprises PBS” which is the narrower statement of the range/limitation. PBS is a pharmaceutically acceptable excipient. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 24 recites the broad recitation “the disease or disorder is an anti-inflammatory disease or disorder”, and the claim also recites “for example arthritis” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7 recites “wherein the shell comprises PLA homopolymer, PLGA, or a PLA/PLGA blend, and optionally polycaprolactone.” Claim 1 already recites “the shell comprises polylactic acid or PLGA.” Therefore, the PLA and PLGA are already recited in claim 1. Although the comprising language of claim 1 does not preclude a PLA/PLGA blend it does not explicitly recite that embodiment. Claim 1 does not recite a PLA/PLGA blend; rather, it recites polylactic acid and PLGA as alternative embodiments. As such claim 7 does not further limit claim 1. The PLA/PGA blend recited in claim 7 does not further limit claim 1 because the required limitation of claim 1 recites polylactic or PLGA but not both. If Applicants wish to include a PLA/PLGA blend as one of the potential embodiments, it should be included in the list in claim 1 and claim 7 should be rephrased to actually further limit claim 1. Additionally, claim 1 does not recite polycaprolactone. Therefore, selection of polycaprolactone cannot further limit the limitation of claim 1 reciting “the shell comprises polylactic acid or PLGA.” However, claim 7 may recite “optionally further comprising polycaprolactone.” Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 and 10-11 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).
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.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Gai et al. (Nanoscale, 2017, 9, 7063-7070).
Gai et al. teach long term encapsulation combined with spatiotemporal release for a precisely defined quantity of small hydrophilic molecules on demand remains a challenge in various fields ranging from medical drug delivery, controlled release of catalysts to industrial anti-corrosion systems. Free-standing individually sealed polylactic acid (PLA) nano- and microchamber arrays were produced by one-step dip-coating a PDMS stamp into PLA solution for 5 s followed by drying under ambient conditions. The wall thickness of these hydrophobic nano–microchambers is tunable from 150 nm to 7 µm by varying the PLA solution concentration. Furthermore, small hydrophilic molecules were successfully in situ precipitated within individual microchambers in the course of solvent evaporation after sonicating the PLA@PDMS stamp to remove air-bubbles and to load the active substance containing solvent. The cargo capacity of single chambers was determined to be in the range of several picograms, while it amounts to several micrograms per cm2 . Two different methods for sealing chambers were compared: microcontact printing versus dip-coating whereby microcontact printing onto a flat PLA sheet allows for entrapment of micro-air-bubbles enabling microchambers with both ultrasound responsiveness and reduced permeability. Cargo release triggered by external high intensity focused ultrasound (HIFU) stimuli is demonstrated by experiment and compared with numerical simulations (see abstract). We demonstrate the fabrication of sealed, biocompatible and biodegradable PLA nano- and microchamber arrays by one-step dip-coating and microcontact printing. In order to examine the feasibility of small molecule encapsulation in situ within individual microchambers and further investigate their release behaviour under HIFU treatment, the fluorescent dye Rhodamine B (RhB) (Mw = 479) and sodium chloride were chosen as model cargo substances. Furthermore, two different methods for chamber sealing were employed: dip-coating and microcontact printing, respectively, whereby microcontact printing offers cargo sealing within entrapped micro-air bubbles. Air bubbles support encapsulation of the cargo up to 14 days under submerged conditions and enhance ultrasound responsiveness, allowing for spatiotemporal release upon HIFU exposure. Experimental demonstrations are compared with numerical defined finite element (DFE) simulation (see page 7064). Cargo loading into PLA (m% = 2%) microchambers was performed via sonication within NaCl solution (3 M), and drying in air (shown in Fig. 3). The said treatment allows chamber in situ NaCl crystal growth (Fig. 3B). Utilizing 1% PLA solution, several dozens of nanometer thin PLA membranes which are vacuum stable (Fig. 3D) and mainly electron transparent (despite a 10 nm gold conduction layer) are formed. The electrons penetrate through the PLA sealing layer, arrive at the underlying NaCl crystal and stimulate X-ray emission, which escapes the chamber, reaching the detector.45 Fig. 3E is the resulting EDX mapping micrograph, proving successfully the presence of sealed NaCl crystals within microchambers (see page 7066).
Conclusion
No claims are allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619