wODETAILED 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 .
Election/Restrictions
Applicant’s election of Group (I) with the election of ropivacaine and/or bupivacaine as the elected first anesthetic agent, a lipid phase comprising triglyceride as the elected lipid phase species, and an aqueous phase comprising a polyol and/or a thickener as the elected aqueous phase species. in the reply filed on 06/10/2026 is 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)).
During a telephone conversation with Rachel Kahler on 07/09/2026 a provisional election was made without traverse to prosecute glyceryl tristearate as the elected lipid phase species, glycerol and hyaluronic acid as the elected aqueous phase species, Affirmation of this election must be made by applicant in replying to this Office action. Claims 4, 8, 10-14, 17, 22-24 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 4, 8, 10-14, 17, 22-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/invention, there being no allowable generic or linking claim.
Priority
This application claims priority to U.S. Provisional Application No. 63/458,316,
filed April 10, 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/25/2025 has been considered by the examiner.
Status of Claims
Claims 1 and 4-27 are pending. Claims 2-3 are canceled. Claims 4, 8, 10-14, 17, 22-27 are withdrawn. Claims 1, 6-7, 9, 15-16, 18-21 are examined in accordance to the elected species.
Claim Objections
Claim 7 is objected to because to as being informal. Claim 7 recites that “the aqueous carrier further comprises a thickener and a polyol.” However, parent claim 1 merely recites “an aqueous carrier” and does not positively recite any constituents of the aqueous carrier to which the recited thickener and polyol are added. Accordingly, the phrase “further comprises” is imprecise. Appropriate correction is required. For example, claim 7 may be amended to recite “the aqueous carrier comprising a thickener and a polyol… “or equivalent language that clearly sets forth the additional limitation of the aqueous carrier.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6-7, 9, 15-16, and 18-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 recites a composition comprising an aqueous carrier, a lipid carrier dispersed into droplets within the aqueous carrier, and a first anesthetic comprising a first plurality of anesthetic crystal within the lipid phase.
Independent claim 20 recites a composition comprising an aqueous carrier, a lipid carrier phase and an aqueous phase dispersed into droplets within the lipid carrier phase, and a first anesthetic comprising a first plurality of anesthetic crystal within the aqueous phase.
Dependent claims further limit the anesthetic to ropivacaine and/or bupivacaine.
Although the specification broadly states that anesthetic crystals may be formed during manufacture of the emulsion (see, e.g., paragraphs [0072]-0075]), and the specification does not reasonably demonstrate possession of the claimed crystalline anesthetic formulation itself. Specifically, the specification only discloses an integrated emulsion manufacturing process in which the anesthetic is dissolved in a triglyceride phase and subsequently cooled or subjected to solvent removal during preparation of the emulsion. The specification does not disclose:
preparation of ropivacaine crystals independent of emulation manufacture;
preparation of bupivacaine crystals independent of emulation manufacture;
characterization of the resulting anesthetic crystals;
crystal morphology selection;
crystal polymorph selection;
crystal habit control;
crystal size control;
crystal nucleation control; or
method demonstrating that the disclosed process reproducibly produces the claimed first plurality of anesthetic crystals within the lipid phase.
Rather, the specification merely states that crystals are present after preparation of the
emulsion.
The specification repeats substantial identical language (paragraph [0075]) but provides no working example demonstration formation of such other plurality of crystals, no description of how such crystals population is prepared, and no description by which a person of ordinary skill would recognize or distinguish such other crystal preparation from the first crystal preparation.
Accordingly, the originally-filed disclosure does not reasonably convey possession of the full scope of the claimed crystalline anesthetic formulations recited in the claims.
Claims 1, 6-7, 9, 15-16, and 18-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an emulsion preparation where anesthetic crystals may be formed during manufacture of the emulsion in which the anesthetic is dissolved in a triglyceride phase followed by cooling or solvent removal, does not reasonably provide enablement for a composition comprising an emulsion having plurality of anesthetic crystals, a lipid phase and an aqueous phase. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The enablement required under 35 U.S.C. 112(a) is satisfied only when specification teaches those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. Whether undue experimentation would be required is evaluated under the factors set forth in in re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988), including (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of the ordinary skill in the art; (5) the level of predictability in the art; (6) the amount of direction or guidance presented in the specification; (7) the present or absence of working examples; and (8) the quantity of experimentation necessary to practice the full scope of the claimed invention.
(1) Breadth of the claims
The claims are broad. Independent claims 1 and 4 broadly encompass plethora of crystal populations, including ropivacaine and/or bupivacaine, multiple lipid systems, multiple aqueous systems, numerous excipients.
Accordingly, the claims encompass numerous crystalline pharmaceutical formulations having different crystallization behaviors and physiochemical properties.
(2) Nature of the Invention
The claimed invention concerns the preparation of pharmaceutical crystalline formulation of lipid emulsions. Pharmaceutical crystallization is a technologically complex field in which crystal formation depends upon nucleation, crystal growth, thermodynamic stability, kinetic effects, solvent selection, cooling conditions, formulation composition, and numerous other interesting variables.
Braga et al. (Int J Mol Sci. 2022 Aug 12;23(16):9013, pages 1-29) teaches that crystal forms of pharmaceutical active ingredients exhibit different physiochemical properties and that crystal formation represents a significant aspect of pharmaceutical development because crystal form selection and crystallization behavior cannot be reliably predicted. (See Abstract and page 5.)
(3) State of the Prior Art
The prior art demonstrates the crystal formation requires substantial investigation and characterization. Braga et al. explains that pharmaceutical development routinely includes crystal screening because multiple crystal forms may exist, and because crystallization behavior depends upon numerous thermodynamic and kinetic variables. Braga et al. further explains that unexpected crystal forms may arise throughout pharmaceutical development and that crystal form assessment has become an integral component of pharmaceutical quality control. (See Section 4 and conclusion section.) Accordingly, the prior art establishes that pharmaceutical crystallization is not considered routine or inherently predictable.
(4) Level of Ordinary Skill in the Art
A person of ordinary skill in the art would possess knowledge of pharmaceutical formulation, emulsion preparation, and crystallization techniques. However, a high level of skill does not eliminate the statutory enablement requirement. Even highly skilled artisan would require sufficient guidance where the technology itself is unpredictable.
(5) Predictability of the Art
This factor weight heavily against enablement. Braga et al. explains that crystal formation depends upon numerous thermodynamic and kinetic variables and that new crystal forms frequently arise unexpectedly despite extensive pharmaceutical development efforts. (See page 10.)
Hoerner et al. (Regional Anesthesia & Pain Medicine 2022; 47:625-629) specifically investigated the crystallization behavior of the presently claimed anesthetics, namely ropivacaine and bupivacaine. The study demonstrates that crystallization behavior varies depending upon concentration, formulation, components, pH, and admixture conditions. Variables crystallization behavior was observed under different formulation conditions, demonstrating that crystallization of these anesthetics is formulation-dependent rather than predictable. (See Abstract.)
Yang et al. (Molecules 2024, 29, 1847, pages 1-22) further demonstrate that lipid crystallization itself depends upon numerous internal variables including triacylglycerol composition, fatty acid structure, molecular interactions, nucleation, crystal growth, polymorphic transition, liquid oil compositions, and minor components. (See Abstract and Title.)
Accordingly, both pharmaceutical crystallization and lipid crystallization are highly unpredictable.
(6) Amount of Guidance Presented
The specification provides only limited guidance. Although paragraph [0093]-[0095] broadly describe dissolving an anesthetic in a triglyceride phase followed by solvent removal or cooling, the specification does not disclose the crystallization conditions necessary to reproducibly obtain the claimed crystalline anesthetic formulation.
The specification does not teach:
conditions governing crystal nucleation;
crystal growth parameters;
cooling profiles required for particular anesthetic agents;
crystal morphology control;
crystal polymorph selection;
crystal characterization;
confirmation that crystals reside within the claimed lipid phase;
preparation of ropivacaine crystals independent of emulsion manufacture;
preparation of bupivacaine crystals independent of emulsion manufacture; or
processes parameters necessary to reproducibly obtain the claimed crystalline formulations across the scope of the claims. Rather, the specification generally
describes preparation of an emulsion in which crystallization is broadly stated to occur during cooling or solvent removal.
(7) Presence or Absence of Working Examples
The specification contains working exampled directed primarily to preparation of a soybean oil emulsion using ropivacaine. However, no working examples demonstrates:
preparation of ropivacaine crystals independent of emulsion manufacture;
preparation of bupivacaine crystals independent of emulsion manufacture;
preparation of alternative triglyceride systems recited in the claims;
characterization of the claimed crystals populations;
verification that the claimed crystal population reside within the lipid phase as required by the claims; or
preparation of the full scope of crystalline anesthetic formulations encompassed by the claims.
Accordingly, the working examples do not enable the entire scope of the claims.
(8) Quantity of Experimentation Required
A person of ordinary skill would be required to perform substantial experimentation to determine appropriate crystallization conditions for each claimed formulation. Such experimentation would include, at a minimum:
selecting appropriate lipid compositions;
determining suitable solvent systems;
determining appropriate anesthetic concentrations;
optimizing heating and cooling conditions;
determining nucleation conditions;
determining crystal growth conditions;
characterizing crystal morphology;
confirming crystal localization within the lipid phase;
confirming crystal localization within the aqueous phase; or
verifying stability and reproducibility of the resulting crystalline formulations.
The cited references demonstrate that these variables materially influence crystallization
behavior and are not predictable. Consequently, substantial experimentation would be required before the full scope of the claimed invention could be practiced.
Conclusion
When the Wand factors are considered as a whole, the evidence demonstrates that the claims encompass a broad genus of crystalline anesthetic lipid emulsions in an unpredictable technological field, while the specification only provides limited guidance and limited working examples. The cited literature further establishes that pharmaceutical crystallization, crystallization of ropivacaine and bupivacaine, and lipid crystallization each depend upon numerous interacting variables that significantly affect crystal formation and cannot be reliably predicted. Therefore, one of ordinary skill in the art would be required to engage in undue experimentation to make and use the full scope of the claimed invention. Accordingly, the specification fails to satisfy the enablement of 35 U.S.C. 112(a).
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.
Claim 7 is 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 7 recites in pertinent part, “…. Wherein the aqueous carrier further comprises a thickener and a polyol wherein the thickener is hyaluronic acid and wherein the polyol is glycerol and is present in an amount of from about 0.25 to about 2.5% (w/v) of the composition….” As drafted, it is unclear to which claim element the recited concentration of “from about 0.25 to about 2.5% *w/v) of the composition” applies. Specifically, because the concentration limitation immediately follows a series of coordinated “wherein” clauses identifying both the thickener and the polyol, it is unclear from the claim language alone whether the phrase “is present in an amount of from about 0.25 to about 2.5% (w/v) of the composition” modifies only the glycerol, another antecedent, or more than one recited component.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 6-7, 9, 15-16, and 18-21 are rejected under 35 U.S.C. 103 as being obvious over Davis et al. (Int. J. Phamr., 2020, Vol. 588, 119703) as evidenced by FDA “Intralipid® in view Davis et al. (WO2023/147480 A1) cited herein as “Davis-WO”, Hoerner et al. (Regional Anesthesia & Pain Medicine 2022; 47:625-629), Fita et al. (US8,609,722 B2), and Olejnik et al. (International Journal of Cosmetic Science, 2015, 37, 401–407).
Davis teaches a bupivacaine-loaded emulsion (BLE) made by combining Intralipid® 20%, bupivacaine freebase, glycerol, and deionized water to form a 15% w/v Intralipid®, 2.25% w/v glycerol, and 1.5% w/v bupivacaine and then homogenized with a Tissue-Tearor high-speed rotor stator homogenizer. Davids further teaches the BLEs were dispersed and entrapped within a crosslinked-HA hydrogel to create an emulsion hydrogel composite system (HA-BLE) to create a solution with final concentrations of 1.25% w/v HA, 0.833% w/v PEGDA, 1.5% w/v bupivacaine, 15% w/v Intralipid®, and 2.25% w/v glycerol for postoperative pain. (See Abstract and Section 2.2.) Davis teaches a crosslinked hyaluronic acid hydrogel matrix into which the previously prepared bupivacaine-loaded emulsion is dispersed and entrapped, thereby providing a continuous aqueous hydrogel phase containing dispersed lipid emulsion droplets. The 15% (w/v) intralipid is considered to meet the limitation that “the lipid phase is from about 10% to about 40% (w/v). As evidenced by FDA, Intralipid® comprising soybean oil which is a refined natural product consisting of triglycerides. Therefore, the teaching of intralipid® meets the limitation of triglyceride claimed in claim 6. Davis demonstrates the formulation architecture.
Davis does not teach plurality of anesthetic crystals. Davis does not further teach the emulsion is stable for at least six months.
Davis-WO teaches a pharmaceutical composition, comprising: a lipophilic oil; a therapeutic agent, salt, ion pair thereof, or prodrug thereof dispersed in the lipophilic oil; and a structuring agent at least a portion of which is not dissolved in the lipophilic oil and forms a gel, wherein the structuring agent comprises glycerol monostearate, glyceryl distearate, tristearin, glycerol monopalmitin, glycerol dipalmitin, tripalmitin, glycerol monomyristin, glycerol dimyristin, trimyristin, or a mixture thereof, and wherein the structuring agent is present in a concentration in a range of from about 0.1 % (w/v) to about 25 % (w/v) of the pharmaceutical composition based on the volume of the lipophilic oil. (See claims 1, 12-13.) Moreover, Davis teaches method of manufacturing a pharmaceutical composition, the method comprising: a) mixing the lipophilic oil and the analgesic agent, anesthetic agent under stirring at a temperature above 25 °C to form a first mixture; b) mixing the structuring agent with the first mixture under stirring and heating at a temperature above 25 °C to form a second mixture; and c) cooling the second mixture to form the pharmaceutical composition. (See paragraph [0006].) David further teaches at least a portion of the structuring agent is phase separated in the lipophilic oil. Thus, for example, a portion of the structuring agent can be partially dissolved in the lipophilic oil (first phase), while a second portion is not dissolved in the lipophilic oil (second phase). The phase separation of the structuring agent allows the structuring agent to help the pharmaceutical composition achieve the supramolecular gel within the lipophilic oil. (See paragraph [0033].) In sum, Davis-WO teaches heating following cooling, structuring agents including glyceryl tristearate, phase separation, and crystallization behavior of the formulation.
Hoerner showed that crystallization is present in pure local anesthetics and may be increased or decreased by admixture of adjuvants. Higher pH of mixtures was weakly associated with more crystallization. (See Abstract.) Hoerner’s crystallization necessarily results in multiple crystal particles, i.e., a plurality of anesthetic crystals. In sum, Hoerner teaches that bupivacaine and ropivacaine undergo crystallization and demonstrates crystal deposition by microscopic evaluation, thereby evidencing the known crystalline physical form of these anesthetics.
Fita discloses compositions having a mixture of lidocaine, prilocaine and tetracaine, or their pharmaceutically acceptable salts comprising approximately w/w percentages: 1.5% lidocaine base; 1.5% prilocaine base; 4% tetracaine base and water and further teaches that such compositions exhibit a high concentration on skin, a deep anesthetic effect and a significantly more rapid onset of the anesthetic effect than comparable transdermal anesthetics. (Abstract.) Fita is used for the motivation to include additional local anesthetics.
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify the bupivacaine-loaded emulsion of Davis in view of Davis-WO, Hoerner, and Fita. Davis teaches an injectable sustained-release local anesthetic emulsion comprising an aqueous hyaluronic acid carrier, glycerol, intralipid®, and bupivacaine for postoperative pain management. David-WO teaches that glyceryl tristearate (tristearin) is a suitable structuring agent for lipophilic pharmaceutical compositions and further teaches heating followed by cooling to produce structure lipid phase exhibiting phase separation and crystallization behavior. Hoerner that local anesthetics, including bupivacaine and ropivacaine, are known to exist in crystalline form and that crystallization is affected by conventional formulation variables such as pH and the presence of formulation additives. Fita teaches that pharmaceutical compositions comprising combinations of local anesthetics provide improved anesthetic performance, including a more rapid onset of anesthetic effect than comparable formulations. Accordingly, it would have been obvious to employ the known crystalline physical form of the anesthetic taught by Hoerner while incorporating the known formulation components and processing techniques by Davis and Davis-WO, and, where appropriate, to include an additional local anesthetic as taught by Fita, in order to obtain a sustained-release local anesthetic formulation having predictable anesthetic properties taught by the prior art.
One of ordinary skill in the art would have had a reasonable expectation of success in making the above modifications because each reference is directed to pharmaceutical local anesthetic formulations and teaches compatible formulation variables, including anesthetic selection, lipid structuring agents, aqueous carrier, processing conditions, and the known crystalline physical form of local anesthetics. The proposed combination merely applied known formulation techniques to known local anesthetics for their intended purpose of providing effective postoperative analgesia and therefore, would have predicably yielded the claimed composition.
With respect to claim 18, Olejnik teaches that hyaluronic acid-containing emulsions are conventionally evaluated for long-term storage stability and specifically reports characterization of such emulsions after six months storage room temperature. (See Synopsis; Table II; Figures; and page 403.) The study demonstrates that moisturizing HA emulsion remained stable over the six-month storage period and that stability can be assessed using particle-size distribution and multiple light scattering techniques. Accordingly, one of ordinary skill in the art would have been motivated to formulate the HA-containing emulsion of Davis to possess commercially useful long-term storage stability. Moreover, because the combined teachings of Davis, Davis-WO, Hoerner, and Fita render obvious the claimed pharmaceutical emulsion comprising a local anesthetics crystal, including ropivacaine and bupivacaine, hyaluronic acid, glycerol, and glyceryl tristearate, prepared using conventional formulation techniques, the recited six-month stability is considered an inherent property of the otherwise obvious pharmaceutical composition. Claim 18 merely recites a property of the resulting composition, namely that the emulsion is stable for at least six-months. Because the claimed composition does not differ structurally from the composition rendered obvious by the combined teachings of the prior art, the recited stability is considered an inherent property of the otherwise obvious composition.
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 non-statutory 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.
Claim 1, 6-7, 9, 15-16, and 18-21 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 15-17 and 19-21 of copending Application No. 17/965,738 in view of Hoerner et al. (Regional Anesthesia & Pain Medicine 2022; 47:625-629), Fita et al. (US8,609,722 B2), and Olejnik et al. (International Journal of Cosmetic Science, 2015, 37, 401–407).
The copending claims teach an echogenic composition for the treatment of pain comprising: a continuous aqueous phase comprising an emulsifier and a polyol; a lipid phase dispersed into droplets having an average diameter of about 500 nm to about 5 um within the aqueous carrier comprising a triglyceride, wherein the triglyceride is liquid at 25°C and wherein an undissolved crystalline anesthetic agent within the lipid phase droplets; and wherein the lipid phase is emulsified within the continuous aqueous phase, wherein the lipid phase is present in an amount from about 10% to about 40% (w/v) of the composition, and wherein the polyol is glycerol and is present in an amount of from about 0.25 to about 2.5% (w/v) of the composition. (See claims 15 and 19-20.)
The copending claims do not teach plurality of ropivacaine and bupivacaine.
Hoerner showed that crystallization is present in pure local anesthetics and may be increased or decreased by admixture of adjuvants. Higher pH of mixtures was weakly associated with more crystallization. (See Abstract.) Hoerner’s crystallization necessarily results in multiple crystal particles, i.e., a plurality of anesthetic crystals. In sum, Hoerner teaches that bupivacaine and ropivacaine undergo crystallization and demonstrates crystal deposition by microscopic evaluation, thereby evidencing the known crystalline physical form of these anesthetics.
Fita discloses compositions having a mixture of lidocaine, prilocaine and tetracaine, or their pharmaceutically acceptable salts comprising approximately w/w percentages: 1.5% lidocaine base; 1.5% prilocaine base; 4% tetracaine base and water and further teaches that such compositions exhibit a high concentration on skin, a deep anesthetic effect and a significantly more rapid onset of the anesthetic effect than comparable transdermal anesthetics. (Abstract.) Fita is used for the motivation to include additional local anesthetics.
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify composition taught by the copending claims to include a first plurality of anesthetics crystal, including bupivacaine crystals and ropivacaine crystals to give Applicant’s claimed composition. One would have been motivated to do so, because Hoerner that local anesthetics, including bupivacaine and ropivacaine, are known to exist in crystalline form and that crystallization is affected by conventional formulation variables such as pH and the presence of formulation additives. Fita teaches that pharmaceutical compositions comprising combinations of local anesthetics provide improved anesthetic performance, including a more rapid onset of anesthetic effect than comparable formulations. One of ordinary skill in the art would have had a reasonable expectation of success in making the above modifications because each reference is directed to pharmaceutical local anesthetic formulations and teaches compatible formulation variables, including anesthetic selection, and the known crystalline physical form of local anesthetics. The proposed combination merely applied known formulation techniques to known local anesthetics for their intended purpose of providing effective analgesia and therefore, would have predicably yielded the claimed composition.
With respect to claim 18, Olejnik teaches that hyaluronic acid-containing emulsions are conventionally evaluated for long-term storage stability and specifically reports characterization of such emulsions after six months storage room temperature. (See Synopsis; Table II; Figures; and page 403.) The study demonstrates that moisturizing HA emulsion remained stable over the six-month storage period and that stability can be assessed using particle-size distribution and multiple light scattering techniques. Accordingly, one of ordinary skill in the art would have been motivated to formulate the HA-containing emulsion of Davis to possess commercially useful long-term storage stability. Moreover, because the combined teachings of Davis, Davis-WO, Hoerner, and Fita render obvious the claimed pharmaceutical emulsion comprising a local anesthetics crystal, including ropivacaine and bupivacaine, hyaluronic acid, glycerol, and glyceryl tristearate, prepared using conventional formulation techniques, the recited six-month stability is considered an inherent property of the otherwise obvious pharmaceutical composition. Claim 18 merely recites a property of the resulting composition, namely that the emulsion is stable for at least six-months. Because the claimed composition does not differ structurally from the composition rendered obvious by the combined teachings of the prior art, the recited stability is considered an inherent property of the otherwise obvious composition.
This is a provisional non-statutory double patenting rejection.
Conclusion
Claims 1, 6-7, 9, 15-16, and 18-21 are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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