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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114.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 04 December 2025 has been entered.
Advisory Note
According to MPEP section 2190 (II) a patent owner or applicant may be precluded from seeking a claim that is not patentably distinct from a claim that was finally refused or canceled during an administrative trial or federal court proceeding under the doctrine of res judicata. Similarly, a patent owner may be precluded from seeking an amendment of a specification or drawing that was denied entry during a trial if the application or patent for which the amendment is sought has the same written description as the patent or application that was the subject of the administrative trial or federal court proceeding. See 37 CFR 42.73(d)(3). A patent owner or applicant may be precluded from seeking a claim that is not patentably distinct from a claim that was previously rejected if the rejection was affirmed on appeal and the decision on appeal became final. A res judicata rejection should be applied only when the earlier decision was a decision of the Patent Trial and Appeal Board (or its predecessor Board) or any one of the reviewing courts and when there is no opportunity for further court review of the earlier decision. See In re Hitchings, 342 F.2d 80, 85, 144 USPQ 637, 641 (CCPA 1965) (holding that unappealed rejections from examiners cannot have a preclusive effect). When making a rejection on res judicata, any prior art rejection under 35 U.S.C. 102 or 35 U.S.C. 103 should ordinarily be made on the basis of the same prior art, especially in continuing applications. In most situations, the same prior art which was relied upon in the earlier decision would again be applicable.
In the instant case, the instantly filed claims in the reply filed on 04 December 2025 are the same claims that were previously rejected under pre-AIA 35 USC 103(a) wherein the rejections were affirmed on appeal and the decision on appeal became final based on the decision rendered by the Patent Trial and Appeal Board on October 02, 2025. Applicant filed request for continued examination after the decision rendered by the Patent Trial and Appeal Board on October 02, 2025 without making any amendments to the claims. It is determined that it is an improper filing and the examiner request applicant to comply and properly amend the claims for further prosecution.
Examiner’s Interview Summary
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.
Formal Matters
Applicant’s arguments in the reply filed on 04 December 2025 are acknowledged. Claims 91-95, 97-100, and 111-121 are pending. Claims 91-95, 97-100, and 111-121 are under consideration in the instant office action. Claims 1-90, 96 and 101-110 are cancelled. Applicant’s arguments did not overcome the rejections set forth in the previous office action for the same reasons set forth in the previous office action and the rebuttal arguments provided by Patent Trial and Appeal Board on October 02, 2025 affirming the rejections.
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 91-95, 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. 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. disclose wherein the composition is totally free of augmentation agent (paragraph 0021). Chasin et al. also disclose 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. 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. Chasin et al. disclose wherein the plurality of microparticles comprise a mixture of at least two groups of microparticles (paragraph 0114) each group having an average polymer molecular weight (paragraph 0118) and an average drug loading percentage (paragraph 0115 and an average particle size which may be different from the other groups (paragraph 0116). The composition further comprises a suspension medium for the microparticles (paragraph 0011). At least one of the anesthetic compounds is a water-insoluble compound or class 1B drug (paragraph 0160). At least one of the anesthetic compounds is lidocaine (paragraph 0182). The composition when formulated into a suspension and injected for local pain relief demonstrates performance of polymer being absorbed in body in 2-4 weeks (paragraph 0103) 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 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.
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
Applicant argues the Examiner’s unclear/incorrect statements with regard to paragraphs 0103, 0114-0116, 0118, 0160, and 0547. Applicant further argues none of the cited references mention any dry powder of local anesthetic. They mention an "immediate release form" of the local anesthetic (which the Examiner stated was a dry powder) but the only immediate release form that will release in under 5 minutes, as Chasin states in " [0013] and [0022], is a liquid form. Skilled artisans know that solid local anesthetics release in 30 minutes. Chasin added dexamethasone as his augmentation agent. A skilled person would know that dexamethasone (Chasin's only augmentation agent – a glucocorticosteroid) takes about 4 hours to drop to 50% of its biological half-life and is mostly cleared from the body in about 20 hours so it is not going to extend the bupivacaine from 3 days to 7 days. Applicant further argues In summary, Chasin never mentioned or showed any examples of any groups or mixtures of microspheres, microcapsules, or capsules in his 204-page application. Chasin never mentioned "groups" of anything except, free radical, carboxylic acid end, treatment, 40K, dose, EDLA and IDLA groups. Additionally, since Chasin imposed a 5-minute limitation on his "immediate release form," it could not have been a solid. So, since Chasin never demonstrated the groups of microcapsules and solid local anesthetic invention, Applicant could not have modified or optimized something that was never taught.
The above assertions are not found persuasive because Chasin teach on paragraph 0103 that 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. With regard to different populations of microspheres 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 wherein the composition is totally free of augmentation 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). 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 (paragraph 0025). Chasin et al. also disclose 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. 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. Chasin et al. teach wherein the plurality of microparticles comprise a mixture of at least two groups of microparticles (paragraph 0114) each group having an average polymer molecular weight (paragraph 0118) and an average drug loading percentage (paragraph 0115 and an average particle size which may be different from the other groups (paragraph 0116). The composition further comprises a suspension medium for the microparticles (paragraph 0011). At least one of the anesthetic compounds is a water-insoluble compound or class 1B drug (paragraph 0160). At least one of the anesthetic compounds is lidocaine (paragraph 0182). The composition when formulated into a suspension and injected for local pain relief demonstrates performance of polymer being absorbed in body in 2-4 weeks (paragraph 0103) 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). In certain preferred embodiments, the formulations of the present invention comprise microcapsules in which the local anesthetic (e.g., bupivacaine base) with or without optional augmenting agent (e.g.,dexamethasone) is not uniformly distributed throughout the controlled release carrier (e.g., PLGA). In certain preferred embodiments, the microcapsules comprise a "shell" and a "core", the bulk of the drug(s) being found in the core (e.g., about 60-100%, preferably about 70-90%), and the remainder of the drug(s) is found in the shell of the microcapsules. In further preferred embodiments, such microcapsules have a mean particular size preferably smaller than 200 microns, and preferably have a particular size distribution from about 5 to about 150 microns, more preferably from about 25 to about 125 microns. In further preferred embodiments, the "shell" of the microcapsule is from about 1 to about 10 microns in mean thickness, and more preferably to about 3 to about 5 microns in mean thickness (paragraph 0026). The microspheres are preferably manufactured in a size distribution range suitable for local infiltration or injection. The diameter and shape of the microcapsules, microspheres or other particles can be manipulated to modify the release characteristics. For example, larger diameter microcapsules or microspheres will typically provide slower rates of release and reduced tissue penetration and smaller diameters of microcapsules or microspheres will produce the opposite effects, relative to microspheres of different mean diameter but of the same composition. The mean diameter of injectable microcapsules or microspheres is in a size range, for example, from about 5 microns to about 200 microns in diameter. In a more preferred embodiment, the microcapsules or microspheres range in mean diameter from about 20 to about 130 microns (paragraph 0116). 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). Chasin et al. teach The product combines bupivacaine free base, a local anesthetic of the amide class, and dexamethasone, a synthetic adrenocorticoid included in DURAIN® solely for its observed ability to prolong the duration of action of bupivacaine. The two active ingredients are encapsulated in a slightly porous shell composed of polylactic-co-glycolic acid polymers (MW=40 kD) in a 65:35 ratio. 120K EDLA, a previously studied formulation, differed from DURAIN® in that it employed polymer with a molecular weight of 120 kD. Bupivacaine (free base) comprises approximately 72% of total microcapsule mass and dexamethasone comprises 0.04%. Bupivacaine-loaded microspheres without dexamethasone are referred to as 40K IDLA (Intermediate Duration Local Analgesic). In both products, the sterile, ingredient-loaded microcapsules are formed into a dry powder for storage and shipment. When suspended in a specialized aqueous diluent, they form a fine suspension, suitable for injection (paragraph 0928). The above teachings are in line with Chasin’s relevance in reaching to Applicant’s claims.. 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 the Board’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). Chasin et al. teach wherein the composition is totally free of augmentation 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).
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIGABU KASSA whose telephone number is (571)270-5867. The examiner can normally be reached on 8 AM-5 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on 571-272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIGABU KASSA/ Primary Examiner, Art Unit 1619