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 .
Response to Amendment and
Status of the Claims
2. Applicant’s amendment and response, submitted October 2, 2025, has been reviewed by the examiner and entered of record in the file. No claim is amended or canceled. Claim 20 is newly added.
3. The scope of the examined subject matter previously set forth is as follows:
a formulation comprising: (a) levobupivacaine or bupivacaine, (b) MgSO4 or ketamine, (c) meloxicam, and (d) tranexamic acid or dexmedetomidine.
4. The non-elected subject matter remains withdrawn from further consideration with traverse, pursuant to 37 CFR 1.142(b), as being drawn to nonelected species, there being no allowable generic or linking claim.
5. Claims 1-3, 10-12, 15-17 and 20 are under examination with the elected species and are the subject of this office action.
Previous Claim Rejections - 35 USC § 103
6. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
7. Claims 1-3, 10-12, and 15-17 remain rejected and claim 20 is newly rejected under 35 U.S.C. 103 as being unpatentable over Quart and Ottoboni, CA 3111570 A1 (cited on Applicant’s IDS of 9/7/23), in view of Abdel-Baky Mohamed et al., Pain Physician (2016), (cited on Applicant’s IDS of 9/7/23).
This rejection has been modified as a result of Applicant’s amendment to the claims.
It is noted that the disclosure of prior-filed Provisional Application No. 61/856,979, Application No. 14/337,819, Application No. 14/997,046, and Application No. 16/129,026 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for the limitations of:
the inclusion of any alpha agonist (claims 2, 3, 11, 12, 15, and 16); the antifibrinolytics of claims 2, 3, 11, 12, 15, and 16; steroids of claims 2, 3, 11, 12, 15, and 16.
Accordingly, this application is afforded the priority date of parent Application No. 16/834,863, filed March 30, 2020 (see above under “Priority).
Claims 1, 10 and 15 are drawn to a method of treating pain, comprising administering by injection an effective amount of a formulation to a mammal in need thereof, wherein the formulation comprises:
(a) about 0.01%- 0.5% of a local anesthetic comprising levobupivacaine or bupivacaine), and
(b) about 1.0-3.0 mg/cc of an NMDA receptor antagonist comprising MgSO4 or ketamine, and
(c) about 0.2-1.2 mg/cc of a COX inhibitor comprising meloxicam, and
(d) wherein the formulation additionally comprises an alpha agonist (more specifically, tranexamic acid or dexmedetomidine (claims 2, 3, 11, 12, 16 and 17)).
8. Quart and Ottoboni disclose a method of treating post-surgical pain in a patient in need thereof, comprising administering to said patient via injection, a pain medication comprising a local anesthetic and an NSAID, specifically a single composition comprising (a) 2.5% w/w bupivacaine and (c) 0.075% w/w meloxicam, that can be administered via intravenous injection (see Example 1, Table 3 at paragraphs [0408] and [0423], and see paragraph [0253]).
9. Quart and Ottoboni are silent to the inclusion of (b) an NMDA receptor antagonist, and (d), an alpha agonist.
10. Yet, Abdel-Baky Mohamed et al. teach a multimodal approach to postsurgical pain relief comprising the administration of (a) the local anesthetic bupivacaine, (b) the NMDA antagonist ketamine, and (d) the alpha2-agonist dexmedetomidine, and for the treatment of acute pain/ post-operative analgesia following major surgery (see E829, under “Objective”). Abdel-Baky Mohamed et al. demonstrate that the combination of intrathecally administered 5 µg dexmedetomidine and 0.1 mg/kg of ketamine co-administered with 0.05% bupivacaine provided superior postoperative analgesia in patients (see page E833, right column, first paragraph under “Discussion”).
11. As such, one skilled in the art before the effective filing date of the claimed invention would have been motivated to combine bupivacaine, meloxicam, ketamine and dexmedetomidine into a single pharmaceutical formulation and administer said formulation for postsurgical analgesia/ pain relief via injection to a mammal in need thereof, and would reasonably expect that said formulation would have an additive effect against pain, resulting in an improved method of treating/ reducing postsurgical pain in said mammal.
12. And, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law, please see In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings). Furthermore, MPEP 2144 teaches that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.
13. In the instant case, the combination of known caine local anesthetic, NMDA receptor antagonist, COX inhibitor and alpha agonist, which previously demonstrated post-surgical analgesic activity, could be combined in a single composition in order to achieve an additive effect in a method of treating pain in a patient in need thereof.
14. See Sundance, Inc. v. DeMonte Fabricated, Ltd., 550 F.3d 1356 (Fed. Cir. 2008): a claimed invention is obvious if it is a combination of known prior art elements that would reasonably have been expected to maintain their respective properties or functions after they had been combined. And, as stated by the Court in KSR International Co., v. Teleflex Inc., 127 US 1727 (2007), “when 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” (quoting Sakraida v. AG Pro, Inc., 425 US 273 (1976); see also: Merck v. Biocraft (874 F.2d 804, 807 (Fed. Cir. 1989), indicating that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands; Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327 (1945): indicating that “[r]eading a list and selecting a known component to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle.”
15. Both Quart and Ottoboni and Abdel-Baky Mohamed et al. disclose administration via injection. Regarding dosage amount, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to use the starting point of each ingredient as disclosed by Quart and Ottoboni and Abdel-Baky Mohamed et al. and optimize these amounts in a single composition to administer via injection with a reasonable expectation of success. The optimization of known effective amounts of known active agents to be administered, is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. It has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980). It is also noted that "[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 optimization with a reasonable expectation of success. Thus one skilled in the art would have been be motivated before the effective filing date of the claimed invention to combine bupivacaine, meloxicam, ketamine and dexmedetomidine in the recited concentrations, into a single pharmaceutical formulation and administering said composition for postsurgical analgesia/ pain relief via injection to a mammal in need thereof, and would reasonably expect that said formulation would have an additive effect against pain, resulting in an improved method of treating/ reducing postsurgical pain in said mammal.
As such, claims 1-3, 10-12, and 15-17 are prima facie obvious.
Claims 20 is drawn to a method of treating pain, comprising administering by injection an effective amount of a formulation to a mammal in need thereof, wherein the formulation comprises:
(a) about 0.01%- 0.5% of a local anesthetic comprising levobupivacaine), and
(b) about 1.0-3.0 mg/cc of an NMDA receptor antagonist (more specifically, MgSO4 ), and
(c) about 0.2-1.2 mg/cc of a COX inhibitor, (more specifically, meloxicam), and
(d) at least one other pharmaceutical agent selected from tranexamic acid or dexmedetomidine, or dexamethasone.
16. Quart and Ottoboni additionally teach that the local anesthetic in the composition belongs to the caine type class of anesthetics, in particular the amide-type, specifically naming bupivacaine and levobupivacaine in a class of eight amide-type anesthetics (paragraph [0168]). Although Quart and Ottoboni do not specifically disclose a multimodal composition comprising levobupivacaine, as recognized by In re Schaumann, 572 F.2d 312 (CCPA 1978), claims to a species are anticipated where the prior art teaches a genus embracing a limited number of members closely related to each other such that one of ordinary skill in the art could immediately envisage each member. Notably, in In re Petering, 301 F.2d 676 (CCPA 1962) the court determined that a prior art genus containing only 20 compounds anticipated a claimed species within the genus because "one skilled in [the] art would... envisage each member" of the genus (emphasis in original)). Thus, considering that the genus of amide-type caine anesthetics disclosed by Quart and Ottoboni only eight compounds, the skilled artisan would have immediately envisaged substituting levobupivacaine for bupivacaine as the caine local anesthetic to employ in the formulation of Example 1. One skilled in the art would be motivated to combine levobupivacaine, meloxicam, ketamine and dexmedetomidine into a single pharmaceutical formulation and administering for postsurgical analgesia/ pain relief via injection, and would reasonably expect that said formulation would have an additive effect against pain, resulting in an improved method of treating/ reducing postsurgical pain in a subject in need thereof.
As such, claim 20 is prima facie obvious.
Response to Arguments
17. Applicant traverses the obviousness rejection, arguing the following points:
(i) Applicant argues that Quart teaches a concentration of 2.5% w/w bupivacaine (e.g., paragraph [0423]), which is a five-fold greater concentration of bupivacaine than is encompassed at the upper range (i.e., 0.5%) of instant claim 1. Applicant alleges that one of skill in the art would not be motivated to combine the lower concentration of bupivacaine with meloxicam, because Quart teaches a much higher concentration.
18. Applicant's arguments have been fully considered but they are not persuasive. While Quart teaches a concentration of 2.5% w/w bupivacaine in Example 1, Quart additionally teaches that the caine type local anesthetic can be employed at concentration of from about 0.01 wt% to about 7.5 wt% (paragraphs [0170]-[0171]), which range fully embraces the amount of “about 0.01 to 0.5% of a local anesthetic,” as required by claim 1. As such, one of skill in the art would have been motivated before the effective filing date of the claimed invention to combine the caine local anesthetic at any concentration of from about 0.01 wt% to about 7.5 wt% as taught by Quart, in the instantly claimed formulation, with a reasonable expectation of success.
(ii) Applicant argues that Mohamed teaches away from the present invention:
“Mohamed teaches three combinations: Group I (hyperbaric bupivacaine plus intrathecal dexmedetomidine); Group II (hyperbaric bupivacaine plus intrathecal ketamine); and Group III (hyperbaric bupivacaine plus intrathecal dexmedetomidine and ketamine). Mohamed teaches away from the present invention by indicating that Group II (bupivacaine plus ketamine) experienced 16.7% nausea and 13.3% vomiting, and Group III (bupivacaine plus dexmedetomidine and ketamine) experienced 13.3% nausea and 13.3% vomiting. Mohamed therefore teaches that combinations involving bupivacaine and ketamine (and dexmedetomidine), as required by Claim 1, induce nausea and vomiting.”
19. Applicant's arguments have been fully considered but they are not persuasive. Regarding Applicant’s argument that Mohamed teaches away from the claimed invention, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." 27 F.3d at 554, 31 USPQ2d at 1132.). Thus, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed...." In re Fulton, 391 F.3d 1195,1201,73 USPQ2dii4i, 1146 (Fed. Cir. 2004).
20. And, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.").
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21. In this case, Mohamed teaches in Table 3 that out of 30 patients in Group III (bupivacaine plus dexmedetomidine and ketamine), 4 experienced nausea, and 4 experienced vomiting. However, this data in Group III is an improvement over Group I (bupivacaine plus dexmedetomidine) wherein out of 30 patients, 6 patients experienced nausea and 4 patients experienced vomiting; and improvement over Group II (bupivacaine plus ketamine), wherein out of 30 patients, 5 patients experienced nausea, and 4 patients experienced vomiting. That is, the number of patients with postoperative nausea actually decreased in Group III relative to Group I or Group II.
(iii) Applicant argues that: “[by contrast, the present invention produced the following surprising result: related US Patent No. 11,559,521 [Exhibit A] teaches that over 92% of patients receiving bupivacaine, ketorolac and ketamine had no nausea and vomiting whatsoever, with less than 8% having some nausea and vomiting, and only 0.18% having severe nausea and vomiting. This represents a dramatic improvement in nausea and vomiting rates in patients treated with bupivacaine, ketorolac, and ketamine.”
(Applicant’s Remarks, page 7).
Applicant argues that this result is further reinforced by Kathirvel, et al., Anaesthesia (2000), wherein Kathirvel specifically states that, "Because of the increased incidence of side-effects in the ketamine group, the study was abandoned when 30 patients had been evaluated. We performed a post hoc power analysis based on the incidence of adverse effects in both groups to validate our results. Our study has 90% power to demonstrate an increase in the incidence of adverse events with the addition of spinal ketamine (86.7% in the7
ketamine group vs. 26.7% in the bupivacaine-only group, with a relative risk of
3.24)." Applicant contends that Kathivrel teaches away from the present invention, because Kathivrel teaches that such a combination results in increased nausea and vomiting.
22. Applicant's arguments have been fully considered but they are not persuasive. According to MPEP 716.02(d), the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." Applicant relies on the alleged unexpected results demonstrated in US Patent No. 11,559,521 [Exhibit A], which are for the administration of BKK: bupivacaine, ketorolac and ketamine. However, the instant claims are presently limited to the combination of levobupivacaine or bupivacaine, ketamine or MgSO4, and meloxicam, which combination is not commensurate in scope with the “surprising result” produced in U.S. Patent No. 11,559,521. Furthermore, the effective minimal concentration for each of the components in the formulation: (a) 0.048 to 0.5% of the local anesthetic, (b) 0.12 mg/kg to 3 mg/kg of the N-methyl-D-aspartate (NMDA) receptor, (c) 0.4 mg/kg to 1.5 mg/kg of the cyclooxygenase (COX) inhibitor, and (d) the alpha agonist concentration is from 0.001 to 0.5 mg/ccm, 1 to 10 mg/kg, are not recited in the claims, which presently recite a broader range for each ingredient. It is recommended to incorporate the critical amount for each component into the claims (i.e., not a broader range).
Terminal Disclaimer
23. The terminal disclaimer filed on October 2, 2025, disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of the full statutory term of any patent granted on pending reference Application Numbers 18/543,991 and 18/543,781, and beyond the expiration date of the full statutory term of prior patent number U.S. Pat. No. 11,992,485, has been reviewed and is accepted. The terminal disclaimer has been recorded.
Previous Double Patenting Rejections
24. Claims 1, 2, 10, 11, 15 and 16 were previously rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Pat. No. 11,992,485.
25. Claims 1-3, 10-12, and 15-17 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/543,991 (reference application).
26. Claims 1-3, 10-12, and 15-17 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 18/543,781 (reference application).
In view of Applicant’s submission of the terminal disclaimer on October 2, 2025 (see above), disclaiming the terminal portion of the statutory term of any patent granted on the instant application which would extend beyond the expiration date of the full statutory term of any patent granted on pending reference Application Numbers 18/543,991 and 18/543,781, and beyond the expiration date of the full statutory term of prior patent number U.S. Pat. No. 11,992,485, the previous double patenting rejections are overcome and are withdrawn.
Conclusion
27. In conclusion, claims 1-3, 10-12, 15-17 and 20 are pending. Claims 1-3, 10-12, 15-17 and 20 are rejected. No claim is currently allowable.
28. 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.
29. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached on Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628