DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is the national phase entry of International Application No. PCT/TR2020/050655, filed on July 25, 2020.
Claim Status
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on January 08, 2026. Claims 1-6 and 8-15 are pending. Claims 7 and 16-20 are canceled.
Action Summary
Claim 8 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of the claim amendment.
Claims 1-6 and 8-15 rejected under 35 U.S.C. 103 as being unpatentable over Berkheimer et al (US10,143,685 B2) in view of Gazelka et al (Pain Physician 2012; 15:87-93) Teva Canada (Product Monograph, June 21 2013, pages 1-41) and NCT01119079 (clinical trial.gov, 04/24/2015), are maintained, but modified and revisited in light of the claim amendment.
Claim 9 rejected under 35 U.S.C. 103 as being unpatentable over Berkheimer et al (US10,143,685 B2) in view of Gazelka et al (Pain Physician 2012; 15:87-93) Teva Canada (Product Monograph, June 21 2013, pages 1-41) and NCT01119079 (clinical trial.gov, 04/24/2015) as applied to claims 1-8 and 10-20, in further view of Xueqing et al (CN111481513A), is maintained.
Affidavit
The declaration by Ibrahim Turan under 37 CFR 1.132 filed 01/08/2026 is insufficient to overcome the rejection of claims 1-6 and -15. The declarant argues the following key points in the Affidavit:
1) The affidavit compares betamethasone (claim) and dexamethasone (prior art) formulations, converting concentrations between free base and salts form.
2) It presents AUC (area under the curve) values for ropivacaine HCl alone with water for injection (Reference 1) values with dexamethasone and clonidine HCL (reference 2), and with dexamethasone/clonidine HCL (D15).
3) It shows that the AUC differences are relatively small (e.g., 360 vs. 383).
4) The study also involves different dilutions (Groups 1-3), but does test the undiluted form (Group 3).
In response, the declarant’s arguments are not persuasive. First, While the declarant compares betamethasone sodium phosphate in the amount of 0.530 (calculated based on active substance quantification. Equivalent to 0.4 mg/ml betamethasone free base) with dexamethasone 21-phosphate disodium salt (calculated based on equivalent of 0.50 mg/ml dexamethasone free base). The free base and salts form can differ in solubility, bioavailability, or how they release the active ingredient. The claim covers both the free base and the salt forms. There does not appear to be any evidence that both the free base and the salts forms produce similar results. The facts that the salts were tested and not the free base, the affidavit leaves a gap in extrapolating to free bases. Without the evidence that both the free base and the salt forms yield comparable AUC and efficacy, the affidavit does not fully support the entire scope of the claim including both. The declarant does not address the full scope, leaving a gap in showing all variations yield similar results. Second, the slight difference in AUC (e.g., 360 vs. 383) does not appear to be a difference in degree. The declarant should demonstrate an unextend improvement or notable benefit beyond small numeric shifts. (See MPEP 2144.05 III(A).) Third, the declarant focuses on diluted forms, while the claim covers both diluted and undiluted compositions. However, these tests rely on very specific compositions including particular inactive ingredients-such as sodium chloride, hydrochloric acid, and sodium hydroxide in defined amounts-that are not recited in the claim. Since the claim covers a broader scope of ingredients and formulations without those specific excipients, the affidavit data does not demonstrate commensurate support for the full scope of the claim. Furthermore, altering one excipient for another may yield different outcomes in stability, solubility, or pharmacological performance, meaning that the specific benefit observed in the affidavit tested formulations may not extend to all possible formulations within the claim’s scope. Thus, the tested formulations advantages may not reflect the full breadth of the claimed invention. Fourth, while the declarant compares groups, it does not provide sufficient reasoning that tested forms represent the full concentrations claimed. Further justification or data spanning the claim’s breadth would be needed.
Moreover, the claim covers a broad range of parenteral routes, while the affidavit only tested an injectable route, the parenteral routes include various methods (e.g., intravenous, intramuscular, subcutaneous), not all of which were shown in the affidavit. The affidavit should justify why the tested injectable form adequately represents all parenteral possibilities.
Furthermore, according to MPEP 716.02(d), evidence must address the full breadth of the claim. Here, the affidavit focuses only on specific salt forms, a narrow range of concentrations, specific inactive ingredients, and an injectable route. Since the claim encompasses a broader set of parenteral forms and wider concentration ranges and no inactive ingredients, the affidavit does not demonstrate that the entire claim scope provides the same effect. Thus, evidence is not commensurate with the full scope of the claim, and further data or reasoning covering all forms and ranges and inactive ingredients is necessary.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-6 and 8-15 are rejected under 35 U.S.C. 103 as being unpatentable over Berkheimer et al (US10,143,685 B2) in view of Gazelka et al (Pain Physician 2012; 15:87-93) Teva Canada (Product Monograph, June 21 2013, pages 1-41) and NCT01119079 (clinical trial.gov, 04/24/2015).
Berkheimer teaches a parenteral pharmaceutically acceptable medicament comprising
ropivacaine, bupivacaine, ketorolac, dexamethasone, clonidine, and ketamine., the concentration of ropivacaine is 0.1125 mg/ml to 12.5 mg/ml; the concentration of bupivacaine is 0.1125 mg/ml to 12.5 mg/ml, the concentration of ketorolac is 10 μg/ml to 2,000 μg/ml; the concentration of dexamethasone is 2 μg/ml to 500 μg/ml, the concentration of clonidine is 0.05 μg/ml to 10 μg/ml; the concentration of ketamine is 5 μg/ml to 2,500 μg/ml, and optionally the medicament further comprises epinephrine at a concentration of 0.1 μg/ml to 15 μg/ml.(See Title and claims 1 and 4.) Berkheimer teaches the pharmaceutically acceptable medicament is for treating post-operative pain in a nerve block procedure and anesthetic procedure, wherein the nerve block procedure comprises one or more members of the group consisting of a peripheral nerve block, an extradural nerve block, a neuraxial nerve block, a retrobulbar nerve block, and a transversus abdominis plane block, and field block anesthesia, regional anesthesia, peripheral nerve block, plexus anesthesia, epidural anesthesia, extradural anesthesia, spinal anesthesia, local anesthesia, or transincision catheter anesthesia. (See claims 9-13) Berkheimer also teaches the parenteral route is selected from the group of routes consisting of periarticular, intra-articular, intrabursal, interscalene, intradiscal, transdermal, intradermal, transmucosal, subcutaneous, intrathecal, epidural, caudal, periodontal, and intramuscular. (See claim 18.) The pharmaceutical composition can include a pharmaceutically acceptable carrier. (See lines 22-24 of column 9.) Berkheimer teaches the pharmaceutical composition is useful for treating osteomoty. (See lines 21-22 of column 10.) osteomoty is the same as osteotomy. Moreover, Berkheimer teaches tvolume for the nerve block may range from 5 ml to 30 ml. (See lines 3-4 of column 10.) Additionally, Berkheimer teaches the preferred solution is formulation 002:
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where the components are combined (. See table 1.) The combination of the components implies mixing the components, reading on claim 15. Buffer and saline solution are taught on Tables 6 and 7. For the high dose, If the nerve block volume is 10 ml, then the amount of ropivacaine would be 25 mg, 100 µg/ml dexamethasone would be 1,000 µg which can be converted to 1.0 mg, and 2 µg of clonidine would be 20 µg. For the low dose, If the nerve block volume is 10 ml, then the amount of ropivacaine would be 11.25 mg, the 20 µg/ml dexamethasone would be 200 µg which can be converted to 0.2 mg, and the 0.5 µg of clonidine would be 5 µg.
In sum, for a 10 ml nerve block volume, ropivacaine ranges from 11.25 to 25 mg, dexamethasone ranges from 0.2-1.0 mg, and clonidine ranges from 5-20 µg. These ranges overlap and obvious over the ranges claimed in claim 1. Lastly, Berkheimer teaches several routes of administration including intradermal, transmucosal, subcutaneous, intrathecal, epidural, caudal, periodontal, or intramuscular administration. (See paragraph [0026].)
Berkheimer does not teach betamethasone and 10 ml saline solution comprising sodium and water. Additionally, Berkheimer does not teach the S-enantiomer of ropivacaine hydrochloride monohydrate and clonidine hydrochloride.
Gazelka concludes that clonidine was noted not to increase particulate matter or aggregation when combined with a combination of corticosteroids such as dexamethasone, triamcinolone, or betamethasone. (See Abstract and Conclusion Section of page 91.) Gazelka teaches four mL each of clonidine (100 μg/ mL), clonidine (100 μg/mL) + dexamethasone sodium phosphate injection (4 mg/mL), clonidine (100 μg/mL) + triamcinolone acetonide injectable suspension (40 mg/mL), and clonidine (100 μg/mL) + betamethasone sodium phosphate and betamethasone acetate injectable suspension (6 mg/mL). (See Abstract.)
Teva Canada teaches parenteral solution formulation for injection comprising 2 mg/ml of the S-enantiomer of ropivacaine hydrochloride monohydrate, sodium chloride, sodium hydroxide, hydrochloric acid, and water for injection for acute pain management in connection with continuous epidural infusion or intermittent bolus administration e.g. postoperative or labor pain and field block e.g. infiltration. (See pages 1 and 30) Moreover, Teva Canada teaches Ropivacaine hydrochloride injection is chemically and physically compatible with clonidine hydrochloride in the amount of 5.0-50.0 µg/ml. (See page 28)
NCT01119079 suggests that 10 ml normal saline to improve analgesia during labor. (See Title.) Moreover, NCT01119079 teaches using 10 mL of saline as compared to two mL in patients undergoing elective surgery during lumbar epidural anesthesia with 2% mepivacaine resulted in a greater extent of anesthesia. (See fifth paragraph of page 2.) Normal saline consists of 0.9% sodium chloride in water for injection.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the pharmaceutical composition taught by Berkheimer by substituting dexamethasone with betamethasone and further by including ropivacaine hydrochloride monohydrate in the S-enantiomer and clonidine hydrochloride as taught by Teva Canada and by choosing a volume of 10 ml normal saline that consists of sodium chloride and water as taught by NCT01119079 to give Applicant’s claimed invention. One would have been motivated to do so, because not only Berkheimer teaches the components of the pharmaceutical composition include any of the useful forms of the components such as polymorphs, crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers), enantiomers, salts, solvates and complexes thereof and solvates and complexes of salts thereof (see paragraph [0010], but also because ropivacaine and clonidine are commercially available as ropivacaine hydrochloride monohydrate in the S-enantiomer and clonidine hydrochloride as taught by Teva Canada, and because NCT01119079 teaches using 10 mL of saline as compared to two mL in patients undergoing elective surgery during lumbar epidural anesthesia with 2% mepivacaine resulted in a greater extent of anesthesia as taught by NCT01119079, and lastly because Gazelka concludes that clonidine was noted not to increase particulate matter or aggregation when combined with a combination of corticosteroids such as dexamethasone, triamcinolone, or betamethasone. One would reasonably expect the modified parenteral composition to be an effective for use in anesthesia, post-operative pain, and osteotomy with success.
With respect to claim 8; the obvious teaching of 10 mg saline with the 25 mg ropivacaine hydrochloride monohydrate would necessarily be equivalent to 25 mg of the ropivacaine and the obvious teaching of 10 mg saline with 5-50 µg/ml clonidine hydrochloride would also be equivalent to 50-500 µg/10 ml that encompasses 75 µg/ml, and the 10 mg saline with 0.02-0.1 mg/ml to the 6 mg/ml betamethasone would be equivalent to 0.2-60 mg/10ml that includes 2 mg.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Berkheimer et al (US10,143,685 B2) in view of Gazelka et al (Pain Physician 2012; 15:87-93) Teva Canada (Product Monograph, June 21 2013, pages 1-41) and NCT01119079 (clinical trial.gov, 04/24/2015) as applied to claims 1-8 and 10-20, in further view of Xueqing et al (CN111481513A).
The teachings of Berkheimer, Gazelka, Teva Canada, and NCT01119079 have been discussed in the rejection set forth above.
Berkheimer, Gazelka, Teva Canada, and NCT01119079 collectively do not teach the pharmaceutical medicament is in the form of an extended-release dosage form comprising a carrier selected from the group consisting of liposome, nanocapsule, and microcapsule.
Xueqing teaches an extended-release microsphere formulation comprising an organic stabilizer, a drug, a biodegradable material, an organic solvent, and a narcotic analgesic that can be ropivacaine hydrochloride, said drug being a pharmaceutically effective amount of a local anesthetic encapsulated in microspheres, wherein each microsphere has a diameter of 0.5 μm to 5 μm, preferably 1 μm to 2 μm. (See claims 1-10 and 14). Moreover, Xueqing teaches ropivacaine or a pharmaceutically acceptable salt thereof can be encapsulated in a variety of pharmaceutical formulations comprising microparticles, microspheres, microcapsules and/or microfibers suspended in a gel preparation. (See 28th paragraph of page 4.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to formulate the pharmaceutical medicament taught by Berkheimer in the form of microcapsule to give Applicant’s claimed invention. The motivation to do so is because Xueqing ropivacaine can be formulated in microcapsule in the form of an extended release in order to release the therapeutic agent in this case ropivacaine continuously or discontinuously over a predetermined period of time and at therapeutic levels sufficient to achieve a desired therapeutic effect throughout the predetermined period of time with success.
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on January 08, 2026.
Applicant’s argument
Applicant argues that the prior art (like Berkheimer) does not provide a reasonable expectation of success for achieving their specific three-drug combination and simultaneous concentration ranges. They emphasize that multi-component interactions are complex and unpredictable. They argue that substituting dexamethasone with betamethasone, while adjusting the other components, would not have been predictable due to differences in particle aggregation and compatibility. In short, they claim a skilled person wouldn’t expect their claimed combination to work.
Examiner’s response
In response, Applicant’s argument is not persuasive. While Applicant highlights unpredictability, the cited art teaches each component’s known effects. A person of ordinary skill could reasonably expect that substitutions or adjustments would yield workable solutions, especially since each ingredient and range is known in the art. The combinations of known agents at known ranges, even if requiring routine optimization, would be predictable to one skilled in the field. First, ropivacaine is a well-known local anesthetic, and its use in the claimed concentration range has precedent in the art. Second, clonidine, a known adjuvant, is also taught for enhancing analgesic effects, and the cited art provides overlapping or adjustable ranges. Third, while the prior art mentions dexamethasone, the substitution of betamethasone, another corticosteroid, would have been a predictable choice to a person of ordinary skill. Both steroids are known to be used in similar contexts, and routine optimization would guide their interchange. Thus, combining ropivacaine, clonidine, and a corticosteroid at known ranges would have been within the ordinary skill in the art, providing a reasonable expectation of success. Berkheimer directly teaches a medicament combining ropivacaine, dexamethasone, and clonidine, with overlapping or closely related concentration ranges. Given that dexamethasone and betamethasone are both known corticosteroids, a skilled artisan would have found it predictable to substitute one for the other, Thus, Berkheimer’s teaching provides a reasonable expectation that adjusting such components within the taught ranges would success.
Furthermore, the Examiner points out that differences in particle behavior between dexamethasone and betamethasone, both are well-established corticosteroids used in injectable formulations. Pharmaceutical development routinely addresses particle size, and known techniques-such as proper excipients or formulations-would mitigate aggregation risks. Thus, a person of ordinary skill could reasonably expect that substituting one known corticosteroid for another could be managed to ensure safety and efficacy, without creating unpredictable outcomes that would negate a reasonable expectation of success.
Applicant reiterates arguments already addressed in the Affidavit Section. Accordingly, the same reasoning and response provided in that context apply equally here.
Applicant’s argument
Applicant argues that dependent claims 2-6 and 8-15 are nonobvious because the limitations of claim 1-particularly the simultaneous concentration ranges of ropivacaine, clonidine, and betamethasone-are not taught or suggested by the cited prior art, and therefore the dependent claims recite additional non-obvious subject.
Examiner’s answer
In response, Applicant’s argument is not persuasive. While applicant asserts that the dependent claims are non-obvious due to the simultaneous ranges, the prior art, including Berkheimer and Xueqing, already suggests overlapping ranges and forms of administration. Xueqing teaches encapsulated ropivacaine formulations, which would make the inclusion of microcapsules in claim 9 obvious when combined. Thus, the additional element do not amount to non-obvious subject matter, and the rejection stands.
Conclusion
Claims 1-6, 8-15 are not allowed.
THIS ACTION IS MADE FINAL. 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.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628