DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114 was filed in this application after a decision by the Patent Trial and Appeal Board, but before the filing of a Notice of Appeal to the Court of Appeals for the Federal Circuit or the commencement of a civil action. Since this application is eligible for continued examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on 30 June 2026 has been entered.
Maintained Allowable Subject Matter Notice
The examiner maintains herein the allowable subject matter note provided in the previous office action under ‘Examiner’s Interview Summary” section. The examiner after properly reviewing the decision rendered by the Patent Trial and Appeal Board on October 02, 2025 affirming the rejections set forth in the final office action mailed on 06 September 2023 phoned Applicant’s attorney Michelle E. O’Brien on 16 December 2025 to discuss potential claim amendments to get the claims in condition for allowance. The board stated on page 12 of the decision that “We are not persuaded that the evidence supports a conclusion of non- obviousness. "The evidence presented to rebut a prima facie case of obviousness must be commensurate in scope with the claims to which it pertains." In re Dill, 604 F.2d 1356, 1361 (CCPA 1979). Of the Examples cited by Applicant and discussed by Mr. Lynch, only Example 7 in the Specification and the materials used in the Militana experiment discussed by Mr. Lynch contained the three elements required by the claims. See Appeal Br. 38-39. The microparticles were identified as D4 and D5. Id. The Specification teaches that D5 is a 50:50 DL-PLG copolymer with a molecular weight of 81,600 and D5 is a 50:50 DL-PGL copolymer with a molecular weight of 122,000. Spec. 18. Thus, the data relied upon by Applicant is limited to one set of molecular weights. Claim 91, however, is not so limited requiring only that the first and second set of particles comprise a 50:50 DL-PGL copolymer with different molecular weight. The evidence of allegedly unexpected results is not commensurate with the scope of the claims.”
In line with the above suggestion by the Board the examiner proposed to Applicant’s attorney to limit the molecular weights in claim 91 to a 50:50 DL-PLG copolymers to a molecular weight of 81,600 and a molecular weight of 122,000. Additionally, the examiner also suggested since the examples are drawn to lidocaine to amend the claims to recite lidocaine as the active agent and incorporate the limitations of claim 95 reciting “wherein the amount of local anesthetic in the composition is at least about 50% by weight, relative to the total weight of the composition.” into the independent claims 91, 112, and 119 to get the claims in condition for allowance. No response has been received regarding the examiner’s proposed claim amendments.
Note: Applicant did not comment about the examiner’s proposed amendments to reflect allowable subject matter in the claims except the new limitation added by amendment in claims 91, 112, and 119 reciting “the average amount of local anesthetic in the composition is at least about 50% by weight, relative to the total weight of the composition”. The recitation added would not make the claims commensurate in scope with the data.
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on 30 June 2026 are acknowledged. Claims 91-94, 97-100, and 111-121 are pending. Claims 91-94, 97-100, and 111-121 are under consideration in the instant office action. Claims 1-90, 95-96 and 101-110 are cancelled. Applicant’s amendments and arguments did not overcome the rejections set forth in the previous office action for the same reasons set forth in the previous office action; the rebuttal arguments provided by Patent Trial and Appeal Board on October 02, 2025 affirming the rejections; and additional rebuttal arguments set forth below.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
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 pre-AIA 35 U.S.C. 103(a) 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 91-94, 97-100, and 111-121 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chasin et al. (US 2003/0152637, IDS reference), Chasin et al. (II) (WO 96/41616, previously cited), Sackler et al. (US Patent 6699908, IDS reference), and Smith et al. (US Patent No. 6194000, previously cited).
Applicants’ claims
Applicants claim a composition for prolonged release of local anesthetic.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Chasin et al. teach a method for providing local analgesia, local anesthesia or nerve blockade in a human, comprising administering at a site in a human a formulation comprising a plurality of controlled release microspheres comprising bupivacaine free base and a biocompatible, biodegradable polymer comprising a 65:35 DL copolymer of lactic and glycolic acid having free carboxylic acid end groups, said copolymer having a molecular weight of about 40 kDa to about 120 kDa, said microspheres comprising from about 60% to about 85% bupivacaine free base, by weight, said microspheres being contained in a pharmaceutically acceptable medium for parenteral administration, said formulation having a concentration of bupivacaine free base from about 2.25 mg/ml to about 36.0 mg/ml and the formulation including a total amount of bupivacaine free base from about 45 mg to about 360 mg prior to administration, such that said formulation provides local analgesia, local anesthesia or nerve blockade at the site of administration less than about 2 hours after first administration, and a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about 1 day after first administration (see claim 1). In additional embodiments, the formulation comprises a plurality of controlled release microspheres containing the local anesthetic. In certain preferred embodiments, the formulation further comprises an augmenting agent in an amount effective to prolong the effect of the local anesthetic (paragraph 0014). Chasin et al. teach in other preferred embodiments, the formulations do not include an effective amount of an augmenting agent and provide a measurable change in sensory responses at the site of administration in a human patient for a time period from about 1 day to about 3 days after administration. Optionally the formulations contain no augmenting agent (paragraph 0021). Chasin et al. also teach wherein substantially the local anesthetic is preferably incorporated into the microspheres in a percent loading between 0.1% and 90% or more, by weight, preferably between 5% and 80%, or more, by weight and more preferably between 65 and 80%, or more, by weight. In an even more preferred embodiment, the local anesthetic is loaded at about 70-75% by weight (paragraph 0119). Chasin et al. also disclose a desired release profile can be achieved by using a given polymer molecular weight and hydrophilicity, a mixture of polymers having different release rates, and/or different percent loading of local anesthetic and/or augmenting agent, for example, local anesthetic and/or augmenting agent releasing in one day, three days, and one week. In addition, a mixture of microspheres having one or more different local anesthetic agents, having the same or different controlled release profile, can be utilized to provide the benefits of different potencies and spectrum of activity during the course of treatment (paragraph 0115). At least one of the anesthetic compounds is lidocaine (paragraph 0182). Various commercially available poly (lactide-co-glycolide) materials (PLGA) may be used in the preparation of the microspheres (paragraph 0106). The composition can be formulated as a dry powder (paragraph 0547). Commonly known local anesthetic agents include bupivacaine, levo-bupivacaine, ropivacaine, benzocaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, and xylocaine, as well as anesthetically active derivatives, analogs and mixtures thereof (paragraph 0028). Local anesthetics can be in the form of a salt, for example, the hydrochloride, bromide, acetate, citrate, carbonate or sulfate, or in the form of a free base. The free base generally provides a slower initial release and avoids an early "dumping" of the local anesthetic at the injection site (paragraph 0028). The polymers used in certain preferred embodiments of the present invention, particularly poly(lactide co-glycolide) (referred to herein as "PLGA"), preferably have a molecular weight from about 5 kilodaltons (kDa) to about 200 kDa (paragraph 0118)which clearly overlaps with claimed ranges of molecular weights. Chasin teaches the polymers used in certain preferred embodiments of the present invention, particularly poly(lactide co-glycolide) (referred to herein as "PLGA"), preferably have a molecular weight from about 5 kilodaltons (kDa) to about 200 kDa. Preferably the molecular weight is from about 20 kDa to about 50 kDa. The inherent viscosity of the preferred polymeric materials is from about 0.19 to about 0.7 dl/g, and most preferably from about 0.25 to about 0.43 dl/g. In certain preferred embodiments, these polymers are acid-terminated with carboxylic acid. In certain preferred embodiments, the polymer used in the microspheres is a poly(lactide co-glycolide) wherein the ratio of lactic acid to glycolic acid is from about 75:25 to about 50:50, preferably 65:35. In certain preferred embodiments, the polymer is a 65:35 DL copolymer of lactic and glycolic acid (inherent viscosity from about 0.25 to about 0.42 dL/g; molecular weight approximately 40 kDa with free carboxyl groups). In certain preferred embodiments, the local anesthetic incorporated in the polymer is bupivacaine base(paragraph 0118). The formulations of the present invention preferably provide an onset of effect in humans at the site of administration, which occurs less than about 2 hours after administration, and a duration of local analgesia which lasts for at least about 1 to about 7 days after administration. The duration of effect is at least 1 day, but may be at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or more (paragraph 0098).
With regard to the limitation reciting “A composition for providing a long-lasting local anesthetic effect, the composition comprising a suspension of a plurality of microparticles configured to provide pain relief lasting for a period of time ranging from more than 3 days up to 8 days in the substantial absence of an augmentation agent adapted to extend the pain relief of the local anesthetic,…” it must be recognized that Chasin et al. for instance in paragraph 0021 teach in other preferred embodiments, the formulations do not include an effective amount of an augmenting agent and provide a measurable change in sensory responses at the site of administration in a human patient for a time period from about 1 day to about 3 days after administration. Optionally the formulations contain no augmenting agent. Chasin et al. also teach in paragraph 0025 that in certain preferred embodiments, the local anesthetic is incorporated into a biocompatible, biodegradable polymer, preferably in the form of microspheres or microcapsules, which are in turn suspended in a pharmaceutically acceptable medium for administration (e.g., injection, trocar, or other means of infiltration) a desired site in the patient (e.g., subcutaneously). The local anesthetic loaded microspheres may be extended duration local anesthetic formulations ("EDLA") which extend the duration of the analgesia to, e.g., about 4 to about 5 days after administration. The prolonged duration of EDLA formulations may be made possible via the incorporation of an augmenting agent (e.g., a glucocorticosteroid such as dexamethasone). In other preferred embodiments, the local anesthetic loaded microspheres do not incorporate an augmenting agent, and the duration of analgesia lasts for about 1 to about 3 days after administration. Such formulations are referred to herein as an intermediate duration local anesthetic ("IDLA"). In preferred embodiments, the onset of measurable changes in sensory findings at the site of administration (indicative of analgesia) occur within about 2 hours with either the EDLA or the IDLA formulations. Based on the broadest reasonable interpretation afforded to claim 91 about 3 days clearly reads on from more than 3 days. Secondly, a careful review of applicant’s original specification as described above in the 112, second paragraph rejection Paragraph 0068 of Applicants US PG Pub 20200085732 states “In one embodiment, the compositions are substantially free of augmentation agents. For example, compositions which are substantially free include those where augmentation agent is present less than about 0.005%, as described in U.S. Pat. No. 5,922,340 already incorporated by reference above.” This recitation indicates that the phrase “substantially free of augmentation agents” or, as the limitation is phrased in claim 91, “in the substantial absence of an augmentation agent adapted to extend the pain relief of the local anesthetic” includes but is not limited to “an augmentation agent is present less than about 0.005%.” The examiner reminds applicant that in order to meet the newly added release profile limitation the inclusion of an augmentation agent in less than about 0.005% is permissible. Chasin et al. teach for instance In certain embodiments of the invention, the augmenting agent can be from one or more of the following general types or classes of agents, including glucocorticosteroid agents, alkalinizing agents, non-glucocorticoid steroids such as, e.g., neuroactive steroids and/or steroid or nonsteroid modulators of gamma amino butyric acid ("GABA") receptors, modulators of ionic transport across cell membranes, including, e.g., modulators of membrane transport of monovalent and divalent metal ions such as, for example, blockers or enhancers of sodium, potassium and/or calcium transport across cell membranes, antipyretic agents, adrenergic receptor agonists or antagonists, such as alpha-2 receptor agonists, tubulin binding agents, including, e.g., agents that are capable of either causing formation or disruption of intracellular microtubules, osmotic polysaccharides, agonists and antagonists of potassium ATP channels, i.e., able to open or close potassium ATP channels, Na, K-ATPase inhibitors and enhancers, neurokinin antagonists, PLC (i.e., phosphatidylinositol-specific phospholipase C) inhibitors, inhibitors of leukocyte glucose metabolism and anti-convulsants. The augmenting agent can also be an analeptic, a tranquilizing agent, an ataretic, an antidepressant, an anti-seizure agent, leukotriene and prostaglandin agonists and inhibitors, phosphodiesterase agonists and inhibitors, e.g., based on cAMP, and combinations of any of the foregoing. Vasoconstrictive agents provided in controlled release form also provide for unexpected and surprising augmentation of duration and potency of local anesthetics relative to immediate release forms of vasonstrictive agents heretofore known to the art. The aforementioned types of augmenting agents may to used alone or in any mixture or combination of each such agent to provide effective augmentation of local anesthesia where desired (paragraph 0191). When the augmenting agent is included in the sustained release substrates (e.g., microparticles) comprising local anesthetic, it has been found that useful loadings of augmenting agent are from about 0.001% to about 30% by weight of the substrate or preferably from about 0.01% to about 5% by weight of the substrate. When the augmenting agent is included in controlled release substrates (e.g., microspheres) without local anesthetic, it has been found that useful loadings of augmenting agent are from about 0.001% to about 90%, or more, by weight of the substrate, or preferably from about 0.001% to about 30% by weight of the substrate or more preferably from about 0.01% to about 5% by weight of the substrate. (see paragraph 0194). It is clear from the above teachings that the amounts of augmentation agent clearly overlaps with applicant’s disclosed description of Paragraph 0068 of Applicants US PG Pub 20200085732 which states that “In one embodiment, the compositions are substantially free of augmentation agents. For example, compositions which are substantially free include those where augmentation agent is present less than about 0.005%, as described in U.S. Pat. No. 5,922,340 already incorporated by reference above.” In addition to the explanation given above the examiner also provided Chasin et al. (II) to address the newly added release profile limitation.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP 2141.02)
Chasin et al. is silent about that third group of microparticles comprising microparticles of pure local anesthetic. This deficiency is cured by the teachings of Sackler et al. and Smith et al. Furthermore, the release profile property limitation is addressed by the teachings of Chasin et al. and Chasin et al. (II) as described in the prima facie explanation section below.
Sackler et al. teach controlled release local anesthetic formulations prepared, e.g., in the form of injectable microspheres, provide both immediate local anesthesia after administration, and provide greatly enhanced safety. Thus, the controlled release formulations according to the invention release enough local anesthetic, in vivo, to provide a normal onset of local anesthesia. However, in an unexpected benefit, the same controlled release local anesthetic formulations fail to cause the expected toxic results when injected into test animals in what would otherwise be toxic amounts (column 2, lines 56-67). Therefore, the present invention provides for safe regional local anesthesia at a site in a patient, by administering at the site a local anesthetic incorporated in a biocompatible, biodegradable, controlled release formulation where the site of administration is located at or adjacent to a nerve or nerves innervating a region of the patient to be so anesthetized. Further, the local anesthetic is present in a concentration effective to safely achieve sensory or motor local anesthesia with reduced toxicity, and the local anesthetic is released at a rate effective to safely achieve sensory or motor local anesthesia. In one aspect, the method of the invention provides for at least a portion of the local anesthetic in immediate release form. A method for providing local anesthesia at a site in a patient, comprising: administering at a site in a patient in need thereof a dose of biocompatible, biodegradable, controlled release microspheres consisting essentially of bupivacaine incorporated at a percent loading from about 60 to about 90% in a polymeric material selected from the group consisting of a polylactide, a polyglycolide, a poly (lactide-co-glycolide), a polyanhydride, a polyorthoester, a polycaprolactone, a polyphosphazene, a polysaccharide, a proteinaceous polymer, a soluble derivative of a polysaccharide, a soluble derivative of a proteinaceous polymer, a polypeptide, a polyester, a polyorthoester, and mixtures thereof contained in a pharmaceutically acceptable carrier, said dose providing local anesthesia to said site for a period of one day, said bupivacaine being present in said dose in an amount effective to induce a localized condition selected from the group consisting of sensory anesthesia, motor anesthesia and combinations thereof, and said dose providing local anesthesia having substantially improved safety relative to a formulation providing a pharmaceutically equivalent effect of bupivacaine administered in immediate release form (see claim 1). The method of claim 1, wherein at least a portion of the dose of said bupivacaine is in immediate release form (see claim 2). In other preferred formulations, the lipids containing the local anesthetic agent are dispersed in a pharmaceutically acceptable aqueous medium. In a further embodiment, a portion of the dose of the local anesthetic is incorporated into the aqueous medium in immediate release form to form an aqueous pharmaceutical suspension useful for administration at the desired site in the patient to be anesthetized (column 9, lines 24-28).
Smith et al. teach that a method for the therapeutic treatment of pain related to wind up in a human or animal (see abstract). A suitable immediate release (IR) form of the NMDA receptor antagonist which is a drug used to treat pain may simply be particles of the antagonist or particles of the antagonist admixed with soluble components for example (column 3, lines 29-30).
With regard to the newly added limitation reciting “A composition for providing a long-lasting local anesthetic effect, the composition comprising a suspension of a plurality of microparticles configured to provide pain relief lasting for a period of time ranging from more than 3 days up to 8 days in the substantial absence of an augmentation agent adapted to extend the pain relief of the local anesthetic,…” it must be recognized that Chasin et al. for instance in paragraph 0021 teach in other preferred embodiments, the formulations do not include an effective amount of an augmenting agent and provide a measurable change in sensory responses at the site of administration in a human patient for a time period from about 1 day to about 3 days after administration. Optionally the formulations contain no augmenting agent. Chasin et al. teach in paragraph 0025 that in certain preferred embodiments, the local anesthetic is incorporated into a biocompatible, biodegradable polymer, preferably in the form of microspheres or microcapsules, which are in turn suspended in a pharmaceutically acceptable medium for administration (e.g., injection, trocar, or other means of infiltration) a desired site in the patient (e.g., subcutaneously). The local anesthetic loaded microspheres may be extended duration local anesthetic formulations ("EDLA") which extend the duration of the analgesia to, e.g., about 4 to about 5 days after administration. The prolonged duration of EDLA formulations may be made possible via the incorporation of an augmenting agent (e.g., a glucocorticosteroid such as dexamethasone). In other preferred embodiments, the local anesthetic loaded microspheres do not incorporate an augmenting agent, and the duration of analgesia lasts for about 1 to about 3 days after administration. Such formulations are referred to herein as an intermediate duration local anesthetic ("IDLA"). In preferred embodiments, the onset of measurable changes in sensory findings at the site of administration (indicative of analgesia) occur within about 2 hours with either the EDLA or the IDLA formulations. Based on the broadest reasonable interpretation afforded to claim 91 about 3 days clearly reads on from more than 3 days. Secondly, a careful review of applicant’s original specification as described above in the 112, second paragraph rejection Paragraph 0068 of Applicants US PG Pub 20200085732 states “In one embodiment, the compositions are substantially free of augmentation agents. For example, compositions which are substantially free include those where augmentation agent is present less than about 0.005%, as described in U.S. Pat. No. 5,922,340 already incorporated by reference above.” This recitation indicates that the phrase “substantially free of augmentation agents” or, as the limitation is phrased in claim 91, “in the substantial absence of an augmentation agent adapted to extend the pain relief of the local anesthetic” includes but is not limited to “an augmentation agent is present less than about 0.005%.” The examiner reminds applicant that in order to meet the newly added release profile limitation the inclusion of an augmentation agent in less than about 0.005% is permissible. Chasin et al. teach for instance In certain embodiments of the invention, the augmenting agent can be from one or more of the following general types or classes of agents, including glucocorticosteroid agents, alkalinizing agents, non-glucocorticoid steroids such as, e.g., neuroactive steroids and/or steroid or nonsteroid modulators of gamma amino butyric acid ("GABA") receptors, modulators of ionic transport across cell membranes, including, e.g., modulators of membrane transport of monovalent and divalent metal ions such as, for example, blockers or enhancers of sodium, potassium and/or calcium transport across cell membranes, antipyretic agents, adrenergic receptor agonists or antagonists, such as alpha-2 receptor agonists, tubulin binding agents, including, e.g., agents that are capable of either causing formation or disruption of intracellular microtubules, osmotic polysaccharides, agonists and antagonists of potassium ATP channels, i.e., able to open or close potassium ATP channels, Na, K-ATPase inhibitors and enhancers, neurokinin antagonists, PLC (i.e., phosphatidylinositol-specific phospholipase C) inhibitors, inhibitors of leukocyte glucose metabolism and anti-convulsants. The augmenting agent can also be an analeptic, a tranquilizing agent, an ataretic, an antidepressant, an anti-seizure agent, leukotriene and prostaglandin agonists and inhibitors, phosphodiesterase agonists and inhibitors, e.g., based on cAMP, and combinations of any of the foregoing. Vasoconstrictive agents provided in controlled release form also provide for unexpected and surprising augmentation of duration and potency of local anesthetics relative to immediate release forms of vasonstrictive agents heretofore known to the art. The aforementioned types of augmenting agents may to used alone or in any mixture or combination of each such agent to provide effective augmentation of local anesthesia where desired (paragraph 0191). When the augmenting agent is included in the sustained release substrates (e.g., microparticles) comprising local anesthetic, it has been found that useful loadings of augmenting agent are from about 0.001% to about 30% by weight of the substrate or preferably from about 0.01% to about 5% by weight of the substrate. When the augmenting agent is included in controlled release substrates (e.g., microspheres) without local anesthetic, it has been found that useful loadings of augmenting agent are from about 0.001% to about 90%, or more, by weight of the substrate, or preferably from about 0.001% to about 30% by weight of the substrate or more preferably from about 0.01% to about 5% by weight of the substrate. (see paragraph 0194). It is clear from the above teachings that the amounts of augmentation agent clearly overlaps with applicant’s disclosed description of Paragraph 0068 of Applicants US PG Pub 20200085732 which states that “In one embodiment, the compositions are substantially free of augmentation agents. For example, compositions which are substantially free include those where augmentation agent is present less than about 0.005%, as described in U.S. Pat. No. 5,922,340 already incorporated by reference above.” In addition to the explanation given above the examiner also provided Chasin et al. (II) to address the newly added release profile limitation.
Chasin et al. (II) teach a formulation and methods for inducing sustained regional local anesthesia in a patient comprising a substrate comprising a local anesthetic and an effective amount of a biocompatible, biodegradable, controlled release material prolonging the release of the local anesthetic from the substrate to obtain a reversible local anesthesia when implanted or injected in a patient, and a pharmaceutically acceptable, i.e., non-toxic, non-glucocorticoid augmenting agent effective to prolong the duration of the local anesthesia for a time period longer than that obtainable from the substrate without the augmenting agent (see abstract). Chasin et al. (II) teach the substrates of the presently described formulations in certain preferred embodiments are manufactured using a method that evenly disperses the local anesthetic throughout the formulation, such as emulsion preparation, solvent casting, spray drying or hot melt, rather than a method such as compression molding. A desired release profile can be achieved by using a mixture of polymers having different release rates and/or different percent loading of local anesthetic and/or augmenting agent, for example, polymers releasing in one day, three days, and one week. In addition, a mixture of microspheres having one or more different local anesthetic agents, having the same or different controlled release profile, can be utilized to provide the benefits of different potencies and spectrum of activity during the course of treatment (see page 23, lines 12-22).
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 at the time the present invention was made to include a third group of microparticles comprising microparticles of pure local anesthetic because Sackler et al. teach controlled release local anesthetic formulations prepared, e.g., in the form of injectable microspheres, provide both immediate local anesthesia after administration, and provide greatly enhanced safety. Thus, the controlled release formulations according to the invention release enough local anesthetic, in vivo, to provide a normal onset of local anesthesia. However, in an unexpected benefit, the same controlled release local anesthetic formulations fail to cause the expected toxic results when injected into test animals in what would otherwise be toxic amounts. (column 2, lines 56-67). Therefore, the present invention provides for safe regional local anesthesia at a site in a patient, by administering at the site a local anesthetic incorporated in a biocompatible, biodegradable, controlled release formulation where the site of administration is located at or adjacent to a nerve or nerves innervating a region of the patient to be so anesthetized. Further, the local anesthetic is present in a concentration effective to safely achieve sensory or motor local anesthesia with reduced toxicity, and the local anesthetic is released at a rate effective to safely achieve sensory or motor local anesthesia. In one aspect, the method of the invention provides for at least a portion of the local anesthetic in immediate release form. A method for providing local anesthesia at a site in a patient, comprising: administering at a site in a patient in need thereof a dose of biocompatible, biodegradable, controlled release microspheres consisting essentially of bupivacaine incorporated at a percent loading from about 60 to about 90% in a polymeric material selected from the group consisting of a polylactide, a polyglycolide, a poly (lactide-co-glycolide), a polyanhydride, a polyorthoester, a polycaprolactone, a polyphosphazene, a polysaccharide, a proteinaceous polymer, a soluble derivative of a polysaccharide, a soluble derivative of a proteinaceous polymer, a polypeptide, a polyester, a polyorthoester, and mixtures thereof contained in a pharmaceutically acceptable carrier, said dose providing local anesthesia to said site for a period of one day, said bupivacaine being present in said dose in an amount effective to induce a localized condition selected from the group consisting of sensory anesthesia, motor anesthesia and combinations thereof, and said dose providing local anesthesia having substantially improved safety relative to a formulation providing a pharmaceutically equivalent effect of bupivacaine administered in immediate release form (see claim 1). The method of claim 1, wherein at least a portion of the dose of said bupivacaine is in immediate release form (see claim 2). In other preferred formulations, the lipids containing the local anesthetic agent are dispersed in a pharmaceutically acceptable aqueous medium. In a further embodiment, a portion of the dose of the local anesthetic is incorporated into the aqueous medium in immediate release form to form an aqueous pharmaceutical suspension useful for administration at the desired site in the patient to be anesthetized (column 9, lines 24-28). One of ordinary skill in the art would have been motivated to include the pure local anesthetic in immediate release form in order to achieve an immediate relief of pain as described by Sackler et al. and one of ordinary skill in the art would have been motivated to include the immediate release of the pure drug just by adding the pure drug particles because as an alternative Smith et al. teach that a method for the therapeutic treatment of pain related to wind up in a human or animal (see abstract). A suitable immediate release (IR) form of the NMDA receptor antagonist which is a drug used to treat pain may simply be particles of the antagonist or particles of the antagonist admixed with soluble components for example (column 3, lines 29-30). An ordinary skill artisan would have had a reasonable chance of success in combining the teachings of Chaisin et al, Stackler et al. and Smith et al. because all of the reference teach compositions for the treatment of pain. Furthermore, in the case where the claimed ranges for particle size and amount of ingredients "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 temperature, size or concentration 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). With regard to the newly added limitation reciting “A composition for providing a long-lasting local anesthetic effect, the composition comprising a suspension of a plurality of microparticles configured to provide pain relief lasting for a period of time ranging from more than 3 days up to 8 days in the substantial absence of an augmentation agent adapted to extend the pain relief of the local anesthetic,…” it must be recognized that Chasin et al. for instance in paragraph 0021 teach in other preferred embodiments, the formulations do not include an effective amount of an augmenting agent and provide a measurable change in sensory responses at the site of administration in a human patient for a time period from about 1 day to about 3 days after administration. Optionally the formulations contain no augmenting agent. Chasin et al. teach in paragraph 0025 that in certain preferred embodiments, the local anesthetic is incorporated into a biocompatible, biodegradable polymer, preferably in the form of microspheres or microcapsules, which are in turn suspended in a pharmaceutically acceptable medium for administration (e.g., injection, trocar, or other means of infiltration) a desired site in the patient (e.g., subcutaneously). The local anesthetic loaded microspheres may be extended duration local anesthetic formulations ("EDLA") which extend the duration of the analgesia to, e.g., about 4 to about 5 days after administration. The prolonged duration of EDLA formulations may be made possible via the incorporation of an augmenting agent (e.g., a glucocorticosteroid such as dexamethasone). In other preferred embodiments, the local anesthetic loaded microspheres do not incorporate an augmenting agent, and the duration of analgesia lasts for about 1 to about 3 days after administration. Such formulations are referred to herein as an intermediate duration local anesthetic ("IDLA"). In preferred embodiments, the onset of measurable changes in sensory findings at the site of administration (indicative of analgesia) occur within about 2 hours with either the EDLA or the IDLA formulations. Based on the broadest reasonable interpretation afforded to claim 91 about 3 days clearly reads on from more than 3 days. Secondly, a careful review of applicant’s original specification as described above in the 112, second paragraph rejection Paragraph 0068 of Applicants US PG Pub 20200085732 states “In one embodiment, the compositions are substantially free of augmentation agents. For example, compositions which are substantially free include those where augmentation agent is present less than about 0.005%, as described in U.S. Pat. No. 5,922,340 already incorporated by reference above.” This recitation indicates that the phrase “substantially free of augmentation agents” or, as the limitation is phrased in claim 91, “in the substantial absence of an augmentation agent adapted to extend the pain relief of the local anesthetic” includes but is not limited to “an augmentation agent is present less than about 0.005%.” The examiner reminds applicant that in order to meet the newly added release profile limitation the inclusion of an augmentation agent in less than about 0.005% is permissible. Chasin et al. teach for instance In certain embodiments of the invention, the augmenting agent can be from one or more of the following general types or classes of agents, including glucocorticosteroid agents, alkalinizing agents, non-glucocorticoid steroids such as, e.g., neuroactive steroids and/or steroid or nonsteroid modulators of gamma amino butyric acid ("GABA") receptors, modulators of ionic transport across cell membranes, including, e.g., modulators of membrane transport of monovalent and divalent metal ions such as, for example, blockers or enhancers of sodium, potassium and/or calcium transport across cell membranes, antipyretic agents, adrenergic receptor agonists or antagonists, such as alpha-2 receptor agonists, tubulin binding agents, including, e.g., agents that are capable of either causing formation or disruption of intracellular microtubules, osmotic polysaccharides, agonists and antagonists of potassium ATP channels, i.e., able to open or close potassium ATP channels, Na, K-ATPase inhibitors and enhancers, neurokinin antagonists, PLC (i.e., phosphatidylinositol-specific phospholipase C) inhibitors, inhibitors of leukocyte glucose metabolism and anti-convulsants. The augmenting agent can also be an analeptic, a tranquilizing agent, an ataretic, an antidepressant, an anti-seizure agent, leukotriene and prostaglandin agonists and inhibitors, phosphodiesterase agonists and inhibitors, e.g., based on cAMP, and combinations of any of the foregoing. Vasoconstrictive agents provided in controlled release form also provide for unexpected and surprising augmentation of duration and potency of local anesthetics relative to immediate release forms of vasonstrictive agents heretofore known to the art. The aforementioned types of augmenting agents may to used alone or in any mixture or combination of each such agent to provide effective augmentation of local anesthesia where desired (paragraph 0191). When the augmenting agent is included in the sustained release substrates (e.g., microparticles) comprising local anesthetic, it has been found that useful loadings of augmenting agent are from about 0.001% to about 30% by weight of the substrate or preferably from about 0.01% to about 5% by weight of the substrate. When the augmenting agent is included in controlled release substrates (e.g., microspheres) without local anesthetic, it has been found that useful loadings of augmenting agent are from about 0.001% to about 90%, or more, by weight of the substrate, or preferably from about 0.001% to about 30% by weight of the substrate or more preferably from about 0.01% to about 5% by weight of the substrate. (see paragraph 0194). It is clear from the above teachings that the amounts of augmentation agent clearly overlaps with applicant’s disclosed description of Paragraph 0068 of Applicants US PG Pub 20200085732 which states that “In one embodiment, the compositions are substantially free of augmentation agents. For example, compositions which are substantially free include those where augmentation agent is present less than about 0.005%, as described in U.S. Pat. No. 5,922,340 already incorporated by reference above.” In addition to the explanation given above the examiner also provided Chasin et al. (II) to address the newly added release profile limitation. Chasin et al. (II) teach a formulation and methods for inducing sustained regional local anesthesia in a patient comprising a substrate comprising a local anesthetic and an effective amount of a biocompatible, biodegradable, controlled release material prolonging the release of the local anesthetic from the substrate to obtain a reversible local anesthesia when implanted or injected in a patient, and a pharmaceutically acceptable, i.e., non-toxic, non-glucocorticoid augmenting agent effective to prolong the duration of the local anesthesia for a time period longer than that obtainable from the substrate without the augmenting agent (see abstract). Chasin et al. (II) teach the substrates of the presently described formulations in certain preferred embodiments are manufactured using a method that evenly disperses the local anesthetic throughout the formulation, such as emulsion preparation, solvent casting, spray drying or hot melt, rather than a method such as compression molding. A desired release profile can be achieved by using a mixture of polymers having different release rates and/or different percent loading of local anesthetic and/or augmenting agent, for example, polymers releasing in one day, three days, and one week. In addition, a mixture of microspheres having one or more different local anesthetic agents, having the same or different controlled release profile, can be utilized to provide the benefits of different potencies and spectrum of activity during the course of treatment (see page 23, lines 12-22). It should be noticed that even in the absence of augmenting agent release can be achieved for one week.
The specific combination of features such as molecular weight of polymer, ratio of monomeric units within the polymer, ratio of first and second particles claimed are disclosed within the broad generic teachings taught by the Chasin et al. but such "picking and choosing" within several variables does not necessarily give rise to anticipation. Corning Glass Works' v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989). Where, as here, the reference does not provide any motivation to select this specific combination of variables (such as the water insoluble polymers or pore formers), anticipation cannot be found. That being said, however, it must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." KSR v. Teleflex, 127 S. Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273,282 (1976)). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious," the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR at 1741. The Court emphasized that "[a] person of ordinary skill is... a person of ordinary creativity, not an automaton." Id. at 1742. Consistent with this reasoning, it would have been obvious to have selected various combinations of various disclosed ingredients (molecular weight of polymer, ratio of monomeric units within the polymer, ratio of first and second particles) from within a prior art disclosure, to arrive compositions "yielding no more than one would expect from such an arrangement." The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) In the case where the claimed range for amounts of ingredients "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). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775,227 USPQ 773 (Fed. Cir. 1985). Furthermore, differences in concentration 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).
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.
Response to Arguments
Note: The rebuttal arguments which are provided in the previous office action along with the Patent Trial and Appeal Board decision mailed on October 02, 2025 affirming the rejections are maintained and are incorporated herein by reference in their entirety. The examiner addresses herein below Applicant’s newly presented arguments.
Applicant argues none of Chasin, Chasin II, Sackler, or Smith teach a composition made up of distinct groups of microparticles let alone two encapsulated groups differing in encapsulating polymer molecular weight plus a third group of pure local anesthetic. The Office Action relies on isolated, general statements in Chasin that "a mixture of polymers having different release rates" may be used, or that "a mixture of microspheres having one or more different local anesthetic agents" may be used. Neither describes the claimed structure. A "mixture of polymers" within a microsphere is not a composition of distinct groups of microparticles; and a "mixture of microspheres having different local anesthetic agents" refers to different drugs, not to groups of the same drug encapsulated in polymers of different molecular weight, and says nothing of a third group of pure anesthetic. Critically, Chasin never prepared, exemplified, or otherwise enabled any such multi-group composition. Its working examples are single-population bupivacaine formulations, with or without dexamethasone. A passing mention of a possibility, untethered to any working example, does not teach or suggest the specific claimed combination. As the M.P.E.P. recognizes, the disclosure relied upon "must provide an enabling disclosure of the desired subject matter; mere naming or description of the subject matter is insufficient, if it cannot be produced without undue experimentation." M.P.E.P. § 2121.01. And where, as here, the rejection assembles the asserted elements from three references directed to different problems, the primary reference must still teach every claimed element for the secondary references to supply only confirmation of public possession; secondary references cannot be used to supply elements the primary reference never taught. See M.P.E.P. § 2131.01. Chasin does not teach groups of microparticles or a pure- anesthetic group, and the deficiency cannot be cured by Sackler or Smith. Applicant also argues no reference achieves the claimed multi-day block in the absence of an augmentation agent.
This is not found persuasive because the combination teachings of Chasin, Chasin II, Sackler, and Smith indeed met the claimed composition as described in detail above. The rejection is not based on the teachings of a single reference. 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). First, the primary reference (Chasin’637) expressly teaches controlled release local anesthetic formulations based on biodegradable polymer microparticles/microspheres (including PLGA) that deliver prolonged analgesia. The reference teaches high drug loadings, suspensions of microparticles, the use of local anesthetics as free base or salt, and the ability to achieve mulit-day sensory blockade. Critically, Chasin’637 and the closely related Chasin II teach that release kinetics can be modulated by polymer molecular weight, polymer composition (including 50:50 lactide: glycolide ratios), particle size, and drug loading. Both references further recognize that mixtures of particles having different release rates can be used to tailor the overall duration and profile of analgesia. A person of ordinary skill in the art seeking a continuous multi-day effect (more than 3 days up to about 6.5 days) in the substantial absence of augmentation agent would therefore have had a clear motivation to combine populations of microparticles that differ in polymer molecular with averages. Chasin teaches the formulations of the present invention preferably provide an onset of effect in humans at the site of administration, which occurs less than about 2 hours after administration, and a duration of local analgesia which lasts for at least about 1 to about 7 days after administration. The duration of effect is at least 1 day, but may be at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or more (paragraph 0098). Chasin teaches pharmaceutical formulations administered via parenteral methods, which provide a prolonged localized analgesic effect. More particularly, the present invention concerns a pharmaceutically acceptable biocompatible biodegradable carrier containing a local anesthetic and the parenteral administration of such carrier in a manner such that a localized analgesic effect is attained for a prolonged period of time (abstract). Chasin teaches in other preferred embodiments, the formulations do not include an effective amount of an augmenting agent and provide a measurable change in sensory responses at the site of administration in a human patient for a time period from about 1 day to about 3 days after administration. Optionally the formulations contain no augmenting agent (see paragraph 0021). Chasin teaches any of the foregoing embodiments, where the local anesthetic is incorporated into the controlled release form at a percent loading of ranging from about 60% to about 85% by weight (paragraph 0267).
Furthermore, Sackler reinforces similar teachings Sackler teaches methods and compositions for safe, prolonged local anesthesia using controlled release microspheres of local anesthetics (including bupivacaine) encapsulated in biodegradable polymers such as PLGA. Sackler explicitly discusses variation of polymer molecular weight and composition to control release duration, high loadings, and administration as suspensions. It further contemplates the inclusion of immediate-release (pure/unencapsulated local anesthetic fraction with one or more polymer encapsulated fractions therefore demonstrating Applicant’s inclusion of pure anesthetic unencapsulated is not a novel or unobvious concept which is an art recognized strategy for achieving a desired onset-plus-duration profile. Furthermore, Smith while directed more broadly to immediate and controlled release analgesic compositions, supplies additional teaching that pharmaceutical compositions may contain distinct populations of particles or units having different release characteristics (immediate-release and sustained release fractions) in order to produce a continuous effect. One of ordinary skill in the art based on the teachings of Smith would have readily applied this general principle to the local-anesthetic microspheres or microparticles systems of Chasin, Chasin II, and Sackler. Collectively indeed the combination teachings of the references rendered obvious the recited combinations for reasons described in detail above. Differences in polymer molecular weights are expressly taught as a means of differentiating release rates; the addition of pure anesthetic fraction is an obvious way to supply immediate release onset component; and the recited ratios and loadings fall within the ranges taught by the references and are routinely optimized by one of ordinary skill in the art once the multi-population approach is adapted absent a showing of criticality. Applicant’s argument amount to an assertion that the precise combination of three named groups is not identically disclosed in a single reference. Under 35 USC 103(a), however, the question is whether the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art in view of the combined teachings. The cited prior art supplies both the individual elements and the motivation to assemble them for the purpose of obtaining a continuous, multi-day local anesthetic effect free or (substantially free of ) augmentation agents.
Applicant continues to argue about the examiner’s incorrect statements with regard to paragraphs 0103, 0114-0116, 0118, 0160, and 0547.
The examiner appreciates Applicant pointing to any potential errors of citations of the teachings within the references. The examiner made the utmost effort to correct any alleged errors on the listed paragraphs. However, the question is whether the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art in view of the combined teachings of the references, which the examiner maintains that is indeed the case as per the above detailed teachings. The teachings do not negate the fact that the claims are still obvious based on the combined teachings of the references. In most cases. the examiner also summarized the teachings based on the clear understandings of what the references teach. It may not be verbatim or the same as what each paragraph teaches. It is not clear to the examiner how a listing of alleged paragraph errors is related to the rejected claims or how the combined teachings of the references failed to render the claims obvious. Applicant does not explain the correlations to the current claims. Arguendo if the examiner erred in specific citations, Applicant should look the reference as whole whether other teachings still render the claims obvious. A prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). Prior art is not limited just to the references being applied, but includes the understanding of one of ordinary skill in the art. The prior art reference (or references when combined) need not teach or suggest all the claim limitations. However, Office personnel must explain why the difference(s) between the prior art and the claimed invention would have been obvious to one of ordinary skill in the art. The "mere existence of differences between the prior art and an invention does not establish the invention’s nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art." Id. In determining obviousness, neither the particular motivation to make the claimed invention nor the problem the inventor is solving controls. The proper analysis is whether the claimed invention would have been obvious as of the relevant time to one of ordinary skill in the art after consideration of all the facts. See 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a). Factors other than the disclosures of the cited prior art may provide a basis for concluding that it would have been obvious to one of ordinary skill in the art to bridge the gap. The rationales discussed below outline reasoning that may be applied to find obviousness in such cases. The Examiner agrees with Applicant that paragraph 0160 is drawn to in certain other formulations, such as those described in U. S. Pat. No. 5,747,058, a composition for the controlled release of substances is provided that includes: (i) a non-polymeric, non-water soluble high-viscosity liquid carrier material (HVLCM) of viscosity of at least 5,000 cP at 37.degree. C. that does not crystallize neat under ambient or physiological conditions; and (ii) a substance to be delivered. The Examiner brings to Applicant’s attention that the above citation does not negate the fact that the combined teachings of the references clearly render the claimed invention obvious as described above. With regard to the second argument, Chasin et al. on paragraph 0103 teach a wide variety of biocompatible materials may be utilized as a controlled release carrier to provide the controlled release of the local anesthetic. Any pharmaceutically acceptable biocompatible polymer known to those skilled in the art may be utilized. It is preferred that the biocompatible controlled release material degrade in vivo within about one year, preferably within about 3 months, more preferably within about two months. More preferably, the controlled release material will degrade significantly within one to three months, with at least 50% of the material degrading into non-toxic residues, which are removed by the body, and 100% of the drug being released within a time period within about two weeks, preferably within about 2 days to about 7 days. A degradable controlled release material should preferably degrade by hydrolysis, either by surface erosion or bulk erosion, so that release is not only sustained but also provides desirable release rates. However, the pharmacokinetic release profile of these formulations may be first order, zero order, bi- or multi-phasic, to provide the desired reversible local anesthetic effect over the desired time period. The examiner takes the position that paragraph 103 strongly supports the Examiner’s position regarding the pharmacokinetic profiles of such formulations. It is relevant teaching applicable to the current claims. Applicant has not provided any objective evidence why the teaching on paragraph 103 is incorrect. With regard to the third and fourth points the examiner maintains that the references of record do address the claimed invention. With regard to the final point the examiner indeed summarized the teachings and also the fact that Chasin et al. teach a plurality of microspheres, microparticles, or microcapsules made from polymers with different molecular weights have been clearly established. Chasin et al. teach a method for providing local analgesia, local anesthesia or nerve blockade in a human, comprising administering at a site in a human a formulation comprising a plurality of controlled release microspheres comprising bupivacaine free base and a biocompatible, biodegradable polymer comprising a 65:35 DL copolymer of lactic and glycolic acid having free carboxylic acid end groups, said copolymer having a molecular weight of about 40 kDa to about 120 kDa, said microspheres comprising from about 60% to about 85% bupivacaine free base, by weight, said microspheres being contained in a pharmaceutically acceptable medium for parenteral administration, said formulation having a concentration of bupivacaine free base from about 2.25 mg/ml to about 36.0 mg/ml and the formulation including a total amount of bupivacaine free base from about 45 mg to about 360 mg prior to administration, such that said formulation provides local analgesia, local anesthesia or nerve blockade at the site of administration less than about 2 hours after first administration, and a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about 1 day after first administration (see claim 1). In additional embodiments, the formulation comprises a plurality of controlled release microspheres containing the local anesthetic. In certain preferred embodiments, the formulation further comprises an augmenting agent in an amount effective to prolong the effect of the local anesthetic (paragraph 0014). In other preferred embodiments, the formulations do not include an effective amount of an augmenting agent and provide a measurable change in sensory responses at the site of administration in a human patient for a time period from about 1 day to about 3 days after administration. Opionally the formulations contain no augmenting agent (paragraph 0021). Chasin et al. teach in certain preferred embodiments, the local anesthetic formulations are prepared during the manufacture of microcapsules containing the drug. In certain preferred embodiments, the local anesthetic is incorporated into a biocompatible, biodegradable polymer, preferably in the form of microspheres or microcapsules, which are in turn suspended in a pharmaceutically acceptable medium for administration (e.g., injection, trocar, or other means of infiltration) a desired site in the patient (e.g., subcutaneously). The local anesthetic loaded microspheres may be extended duration local anesthetic formulations ("EDLA") which extend the duration of the analgesia to, e.g., about 4 to about 5 days after administration. The prolonged duration of EDLA formulations may be made possible via the incorporation of an augmenting agent (e.g., a glucocorticosteroid such as dexamethasone). Chasin et al. also disclose a desired release profile can be achieved by using a given polymer molecular weight and hydrophilicity, a mixture of polymers having different release rates, and/or different percent loading of local anesthetic and/or augmenting agent, for example, local anesthetic and/or augmenting agent releasing in one day, three days, and one week. In addition, a mixture of microspheres having one or more different local anesthetic agents, having the same or different controlled release profile, can be utilized to provide the benefits of different potencies and spectrum of activity during the course of treatment. The polymers used in certain preferred embodiments of the present invention, particularly poly(lactide co-glycolide) (referred to herein as "PLGA"), preferably have a molecular weight from about 5 kilodaltons (kDa) to about 200 kDa (paragraph 0118)which clearly overlaps with claimed ranges of molecular weights. Chasin teaches the polymers used in certain preferred embodiments of the present invention, particularly poly(lactide co-glycolide) (referred to herein as "PLGA"), preferably have a molecular weight from about 5 kilodaltons (kDa) to about 200 kDa. Preferably the molecular weight is from about 20 kDa to about 50 kDa. The inherent viscosity of the preferred polymeric materials is from about 0.19 to about 0.7 dl/g, and most preferably from about 0.25 to about 0.43 dl/g. In certain preferred embodiments, these polymers are acid-terminated with carboxylic acid. In certain preferred embodiments, the polymer used in the microspheres is a poly(lactide co-glycolide) wherein the ratio of lactic acid to glycolic acid is from about 75:25 to about 50:50, preferably 65:35. In certain preferred embodiments, the polymer is a 65:35 DL copolymer of lactic and glycolic acid (inherent viscosity from about 0.25 to about 0.42 dL/g; molecular weight approximately 40 kDa with free carboxyl groups). Chasin et al. teach that in certain preferred embodiments of the invention, the substrate comprises a plurality of microcapsules laden with the local anesthetic agent with or without an augmenting agent (paragraphs 0113 and 0147). In other embodiments, the formulation includes a mixture of microspheres utilizing polymers of different molecular weights, e.g., from about 20 kDa to about 120 kDa (paragraph 0171). In certain embodiments, the invention is directed to a method for providing local analgesia, local anesthesia or nerve blockade in a human, comprising administering at a site in a human a formulation comprising a plurality of microspheres comprising a biocompatible, biodegradable carrier and a local anesthetic effective to provide local analgesia, local anesthesia or nerve blockade at the site of administration in a human which occurs less than 2 hours after first administration, and a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about 1 day after first administration, wherein the level of local anesthetic at the site of administration is at least 100 times, 150 times, 175 times or 200 times the level of local anesthetic in the systemic blood plasma. The present invention is also directed to formulations utilized in this method (paragraph 0232). It is very clear from all of the above teachings a plurality or a mixture of microspheres, microcapsules, or microparticles with different polymer molecular weights that overlap with the molecular weights of the first and second group of particles are taught by Chasin et al. Chasin et al. then goes on to teach that the rate of drug release can be controlled by the particular polyanhydride polymer utilized and its molecular weight (paragraph 0107). A desired release profile can be achieved by using a given polymer molecular weight and hydrophilicity, a mixture of polymers having different release rates, and/or different percent loading of local anesthetic and/or augmenting agent, for example, local anesthetic and or augmenting agent releasing in one day, three days, and one week. In addition, a mixture of microspheres having one or more different local anesthetic agents, having the same or different controlled release profile, can be utilized to provide the benefits of different potencies and spectrum of activity during the course of treatment (paragraph 0115). Diffusional release of the local anesthetic from the microspheres of the present invention can be altered in a number of ways including modification of polymer properties (molecular weight (MW), comonomer ratio and hydrophilicity), increasing matrix porosity via altering process parameters or through the addition of porosogens (inorganic salts and polyethylene glycol), and increasing dissolution rate/solubility of the drug (paragraph 0120). Polymer properties such as molecular weight (MW), comonomer ratio and type of polymer end group can all play a role in determining the structure of the encapsulating shell and in drug diffusion through the shell. As hydration of the encapsulating shell matrix increases, so does the rate of diffusion through decreased tortuosity (diffusional resistance) in the swollen matrix and increased dissolution and transport (paragraph 0127). Polymer MW can be used to manipulate the release profiles. In general, polymers with lower MW produce increased release due to formation of an encapsulating shell having greater porosity (decreased tortuosity) and increased flux (paragraph 0128).
Applicant further argues the claims require a third group of pure local anesthetic, exemplified in the specification as solid lidocaine free base that is ground and admixed with the encapsulated groups (Examples 7 and 9; Table 2). The Office Action attempts to supply this element from Sackler's and Smith's disclosures of a portion of drug in "immediate release form." That is a different thing. Sackler describes a portion of bupivacaine dispersed in an aqueous medium for rapid release; Smith describes an NMDA antagonist (not a local anesthetic at all) as particles admixed with soluble components for rapid, sub-five-minute release. Neither describes a discrete group of solid, pure local anesthetic combined with two encapsulated groups of differing molecular weight.
The above assertions are not found persuasive because Smith indeed teaches a suitable immediate release (IR) form of the NMDA receptor antagonist may simply be particles of the antagonist or particles of the antagonist admixed with soluble components for example, sugars (eg sucrose, lactose, fructose, mannitol etc.), polymers (eg polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc) (column 3, lines 30-52). The particle sizes of the IR and SR components in the dosage form depends on the technology used. The particle sizes component range from submicron to 500 μm for powder technologies (mixtures, spray drying, dispersions etc), 5-1700 μm for coating technologies (wurster, top spray, bottom spray, spray drying, extrusion, layering etc), to 1-40 mm for tabletting technologies (column 4, line 66-67 and column 5, lines 1-5). The fact that drug particles in powder form can be included in the immediate release form is well established by Smith. The claimed invention as described above is rendered obvious by the combination teachings of the references.
Applicant argues the proposed combination is improper and rests on hindsight. There is no basis to require single molecular-weight values; the art and the supplier characterize these polymers by ranges. Applicant then continues to argue about unexpected results which were presented before the board during appeal. Applicant asserts that Applicant's two encapsulated groups use high-molecular-weight 50:50 DL-PLG (the D4 and D5 materials, on the order of about 81,600 and about 122,000), so that their primary and delayed secondary bursts overlap and interleave; the third group of pure local anesthetic supplements the early phase. The combination produces the continuous, multi-day release seen in Figures 7-8 and Examples 9 and 11, with the day 3-4 secondary burst that the mechanism predicts for higher-molecular-weight matrices. By contrast, a single-population, lower-molecular-weight system of the kind Chasin prefers-approximately 40 kDa-exhibits a single dominant burst and an early (about twelve-hour) plateau, and cannot reproduce the claimed multi-day profile. The claimed result is therefore a consequence of the specific, molecular-weight-dependent autocatalytic behavior of paired high-molecular-weight groups, not an obvious optimization of any single-population prior-art formulation, which is neither taught nor suggested by the cited art.
This is not found persuasive because first in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). With regard to the unexpected results whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). Applicant’s data as pointed by the Board is not commensurate in scope with the claims.
Conclusion
No claims are allowed.
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/TIGABU KASSA/ Primary Examiner, Art Unit 1619
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