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 24 August 2026 are acknowledged and have been fully considered. Claims 1-20 are pending. Claims 1-6 are under consideration in the instant office action. Claims 7-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking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.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-6, 8-16, and 18-20) in the reply filed on 24 August 2026 is acknowledged. Additionally, Applicant’s election of claims 1-6 for examination on the merits in the reply filed on 24 August 2026 is also acknowledged.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on August 24, 2024, October 01, 2024, December 12, 2024, April 09, 2025, July 01, 2025, October 17, 2025, May 14, 2026, September 01, 2026, and September 25, 2026 are noted and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Signed copies are attached herein.
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 1-6 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.
Claim 1 recites that each polymer microsphere comprises “(1) esketamine”, then immediately recites that each polymer microsphere has “a ketamine drug load of about 12 wt/wt% to about 17 wt/wt%.” Dependent claim 2 further recites release of “the ketamine.” Claim 4 also recites “a ketamine”. Esketamine is the S-enantiomer of racemic ketamine and is a distinct chemical entity. The claims therefore introduce “ketamine” (and “the ketamine”) without antecedent basis. It is unclear whether: the recited drug load and release limitations apply only to esketamine, the microspheres may contain racemic ketamine or the R-enantiomer in addition to esketamine, or “ketamine” is being used as a generic label for esketamine. A person of ordinary skill in the art cannot determine the metes and bounds of the claimed drug load or release profile with reasonable certainty. See MPEP § 2173.05(e). Claims 3 and 5–6 inherit the same defect.
Claim 1 requires that “each of the polymer microspheres comprises a plurality of internal macrovoids.” The term “macrovoids” is a relative term of degree. The claims and the claim language itself do not specify: any size threshold that distinguishes a “macrovoid” from a micropore, emulsion droplet remnant, or ordinary internal void, a minimum number constituting a “plurality,”, a method of observation or quantification (e.g., SEM cross-section, mercury porosimetry, specific magnification), or whether the limitation must be met by every individual microsphere in the formulation or by a representative population. Because the claim uses “each of the polymer microspheres,” the absence of an objective standard renders it unclear when the limitation is satisfied. A skilled artisan would not be able to determine, with reasonable certainty, whether a given microsphere batch falls inside or outside the claim. See MPEP §§ 2173.05(b), 2173.05(g). Dependent claims 2-6 do not address the issue.
Claim 2 characterizes the formulation of claim 1 by the functional result that “about 75% to 100% of the ketamine is released over a period of between about 25 to about 35 days of injection into a human subject, but not more than about 10% of the ketamine has been released within 24 hours of injection into the human subject.” The claim is a composition claim, yet its only additional limitation is an in vivo release profile that can be ascertained only after intramuscular or subcutaneous administration to a human. The claim does not identify: the injection site, dose, or vehicle, the patient population (body weight, metabolism, disease state), the bioanalytical method used to measure “released” ketamine, or whether the percentages are of the administered dose, of encapsulated drug, or of some other basis. Release in humans is subject to substantial inter-subject variability. The claim therefore fails to inform a skilled artisan, with reasonable certainty, of the structural or compositional boundaries of the product itself. Functional limitations of this type that depend on unrecited method steps and patient-specific variables render the claim indefinite. See MPEP § 2173.05(g); Halliburton Energy Servs., Inc. v. M-I LLC, 514 F.3d 1244 (Fed. Cir. 2008).
Claim 5 recites that the polymer microspheres have “a particle size of about 90 (D₅₀).” The unit of measure (µm) present in claim 1 is omitted. It is therefore unclear whether “90” refers to 90 µm, 90 nm, or some other scale. The claim is incomplete on its face and indefinite. See MPEP § 2173.05(c).
Claim 1 recites a biodegradable poly(lactide) polymer having an inherent viscosity of “about 0.6 dL/g to about 0.72 dL/g.” Inherent viscosity of PLA is known to vary with solvent, temperature, and polymer concentration. The claim does not specify the conditions under which the recited inherent viscosity is determined. While the specification of related family members identifies particular commercial PLA grades, the claim itself does not incorporate those conditions. In the absence of an objective measurement protocol, the precise scope of the inherent viscosity range is unclear. See MPEP § 2173.05(b).
Claim 6 is a pharmaceutical composition comprising the formulation of claim 1 and is indefinite for the same reasons as claim 1.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Meyer (US 2015/0250719, IDS reference, 08/06/2024) and Hobot (US 2011/0027331, IDS reference, 08/06/2024).
Applicant Claims
Applicant claims a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising (i) esketamine and (ii) a biodegradable poly(lactide) polymer, wherein the polymer has an inherent viscosity of about 0.6 dL/g to about 0.7 dL/g, each polymer microsphere has an esketamine drug load of about 12 wt/wt % to about 17 wt/wt %, the polymer microspheres have an average particle size of about 80 μm (D50) to about 110 μm (D50), and the polymer microspheres comprise a plurality of internal macrovoids (claim 1 and dependents as recited, including PK/release profile limitations).Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Meyer teaches a microsphere formulation (paras. [0032], [0052]: biocompatible polymer that can form gels which may be microsphere-based; creating a gel holding microspheres). Each polymer microsphere comprises (i) esketamine (para. [0020]: any derivative, analogue, and/or enantiomeric form of ketamine may be used as active agent; para. [0081]: S-(+)-ketamine hydrochloride at 2% w/w; S-(+)-ketamine is esketamine; see instant specification para. [0003]) and (ii) a biodegradable poly(lactide) polymer (paras. [0028]–[0029]: biodegradable polymer must be biocompatible; poly(esters) based on polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL) and their copolymers are useful).Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.012)
Meyer does not specifically teach that the biodegradable poly(lactide) polymer has an inherent viscosity of about 0.6 dL/g to about 0.7 dL/g; that each polymer microsphere has an esketamine drug load of about 12 wt/wt % to about 17 wt/wt %; that the polymer microspheres have an average particle size of about 80 μm (D50) to about 110 μm (D50); or that the polymer microspheres comprise a plurality of internal macrovoids. These deficiencies are cured by Hobot.Hobot teaches a similar microsphere formulation (para. [0161]: microspheres may be dispersed within the gel, the microspheres being loaded with at least one analgesic agent). Hobot teaches polymer inherent viscosity of about 0.6 dL/g to about 0.7 dL/g within a disclosed range of about 0.10 dL/g to about 1.2 dL/g (para. [0156]: gel molecular weight as shown by inherent viscosity from about 0.10 dL/g to about 1.2 dL/g; inherent viscosity is a measure of molecular weight and degradation time). Hobot teaches microsphere diameters ranging from about 10 microns to about 200 microns (para. [0162]; diameter interpreted as average particle size, which overlaps the claimed 80–110 μm D50 range). Hobot teaches that the drug depot has pores that allow release of the drug and that fluid in the depot displaces the drug (para. [0052]; “pores” in the microspheres interpreted as internal macrovoids). Pore size of less than 10–50 microns is taught to prevent cell infiltration (para. [0052]).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious before the effective filing date to modify Meyer’s esketamine/PLA microsphere formulation by selecting a polylactide having an inherent viscosity of about 0.6–0.7 dL/g as taught by Hobot in order to increase degradation time and matrix strength (Hobot para. [0156]: a gel with higher inherent viscosity has higher molecular weight and longer degradation time). It would have been obvious to select an average particle size of about 80–110 μm (D50) because Meyer expressly teaches that active-agent release rates depend strongly on microsphere size and that larger microspheres generally release encapsulated compounds more slowly and over longer periods (Meyer para. [0053]). Hobot’s 10–200 μm range overlaps the claimed range. Overlapping ranges support a prima facie case of obviousness. In re Wertheim, 541 F.2d 257 (CCPA 1976); In re Woodruff, 919 F.2d 1575 (Fed. Cir. 1990). Even close ranges support obviousness. Titanium Metals Corp. v. Banner, 778 F.2d 775 (Fed. Cir. 1985). Optimization of particle size to control release is routine. In re Aller, 220 F.2d 454 (CCPA 1955). It would have been obvious to include a plurality of internal macrovoids/pores as taught by Hobot to permit drug release while preventing cell infiltration (Hobot para. [0052]).Drug load of about 12–17 wt/wt % is an overlapping or close concentration within the general conditions disclosed by the combination. Differences in concentration do not support patentability absent evidence of criticality. In re Aller, supra. A skilled artisan would have had a reasonable expectation of success because both references are directed to polylactide-based microspheres for delivery of drugs such as ketamine/analgesics. With regard to the pharmacokinetic/release profile recited in claims 2 and 8 (and analogous dependents), the combination of Meyer and Hobot meets the claimed microsphere formulation; the recited PK profile would necessarily follow. Inherency may supply a missing claim limitation in an obviousness analysis. PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1185, 1194–95 (Fed. Cir. 2014); Endo Pharms. Sols. v. Custopharm Inc., 894 F.3d 1374 (Fed. Cir. 2018). Mere recitation of a newly discovered function or property inherently possessed by things in the prior art does not distinguish the claim. In re Oelrich, 666 F.2d 578 (CCPA 1981); Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 (Fed. Cir. 2012); In re Kao, 639 F.3d 1057 (Fed. Cir. 2011). An obvious formulation does not become nonobvious merely by administering it and claiming the resulting serum concentrations or release rates. Inherency is a high standard and requires that the limitation be necessarily present or the natural result of the combination of elements explicitly disclosed. PAR, 773 F.3d at 1195–96. Here the combination of the same polymer class, overlapping IV, overlapping particle size, porous structure, and ketamine/esketamine loading produces the claimed formulation; the recited release/PK properties are the natural result.The skilled artisan would have had a reasonable expectation of success. Therefore the invention as a whole would have been obvious.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12, 233,165.
Claim 1 of U.S. Patent No. 12,233,165 recites a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: esketamine in a concentration of about 10 wt/wt % to about 30 wt/wt %; and a biodegradable poly(lactide) polymer in a concentration of about 70 wt/wt % to about 90 wt/wt %, wherein the biodegradable poly(lactide) polymer has an inherent viscosity from about 0.6 dL/g to about 0.7 dL/g; wherein the polymer microspheres have a particle size greater than 60 μm (D50); wherein the polymer microspheres are characterized in that each of the polymer microspheres comprises an internal polymer phase, a plurality of internal macrovoids dispersed within the internal polymer phase, and an outer surface substantially free of voids; and wherein the polymer microspheres are prepared by a method that does not include the use of a porogen, the method comprising: (i) contacting the esketamine with the biodegradable poly(lactide) polymer in the presence of a solvent to form an organic component; (ii) emulsifying an inner aqueous component comprising water with the organic component to form a primary emulsion; (iii) emulsifying the primary emulsion with a continuous phase comprising water to form a secondary emulsion; (iv) removing the solvent from the secondary emulsion to form the polymer microspheres; and (v) subjecting the polymer microspheres to dehydration.
Claim 2 of the patent recites a particle size of about 70 μm (D50) to about 110 μm (D50).
Claim 3 of the patent recites an esketamine concentration of about 12 wt/wt % to about 17 wt/wt % and a poly(lactide) concentration of about 83 wt/wt % to about 88 wt/wt %.
Claim 4 of the patent recites that about 75% to 100% of the esketamine is released over a period of between about 25 to about 35 days of injection into a human subject, but not more than about 10% of the esketamine has been released within 24 hours of injection.
Claim 5 of the patent recites a pharmaceutical composition comprising the microsphere formulation of claim 1.
Claim 6 of the patent recites that the esketamine is dispersed within the internal polymer phase.
Instant claim 1 recites a microsphere formulation comprising polymer microspheres, each comprising esketamine and a biodegradable poly(lactide) polymer having an inherent viscosity of about 0.6 dL/g to about 0.7 dL/g, each polymer microsphere having an esketamine drug load of about 12 wt/wt % to about 17 wt/wt %, the polymer microspheres having an average particle size of about 80 μm (D50) to about 110 μm (D50), and the polymer microspheres comprising a plurality of internal macrovoids. Instant dependent claims recite the corresponding in vivo release/PK profile and related formulation features. The patented claims and the instant claims are directed to the same invention or an obvious variant thereof. Both sets of claims require:• polymer microspheres containing esketamine and a biodegradable poly(lactide) polymer;• the same polymer inherent-viscosity range (about 0.6–0.7 dL/g);• overlapping (and in claim 3 of the patent, identical) esketamine load of about 12–17 wt/wt % within the patented 10–30 wt/wt % range;• overlapping particle-size ranges (instant 80–110 μm D50 lies inside patented “greater than 60 μm” and patented claim 2’s 70–110 μm); and• a plurality of internal macrovoids.
The patented claim further specifies an internal polymer phase, an outer surface substantially free of voids, dispersion of esketamine in the internal polymer phase, and a double-emulsion/dehydration process that does not use a porogen. Those additional limitations do not patentably distinguish the claimed product. Product-by-process limitations are limited to the product itself; the process is relevant only insofar as it defines the product. MPEP § 2113; In re Thorpe, 777 F.2d 695, 227 USPQ 964 (Fed. Cir. 1985). The product obtained by the patented process is the same esketamine/PLA microsphere having internal macrovoids that instant claims 1–6 recite. Any difference in claim scope (e.g., instant claims omitting the explicit process steps or the “outer surface substantially free of voids” language) is an obvious variation of the patented product. A person of ordinary skill in the art would have recognized that the microspheres defined by patented claims 1–6 necessarily possess, or obviously would be formulated to possess, the load, size, IV, and internal-macrovoid features of instant claims 1–6. The release profile recited in instant claim 2 (and analogous dependents) is the same or an obvious variant of the release profile in patented claim 4; such pharmacokinetic properties add no patentable distinction when the underlying formulation is not patentably distinct. See In re Kao, 639 F.3d 1057 (Fed. Cir. 2011); Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 (Fed. Cir. 2012).The inventions are not patentably distinct. Allowance of instant claims 1–6 without a terminal disclaimer would improperly extend the right to exclude granted by U.S. Patent No. 12,233,165.A terminal disclaimer is required to overcome this rejection.
Conclusion
No claim is allowed.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
