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
2. Applicant's amendment and response, submitted October 2, 2025 has been reviewed by the examiner and entered of record in the file.
3. Claim 9 is canceled. No claim is amended or added.
Status of the Claims
4. Claims 11-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), with traverse, as being drawn to a nonelected invention, there being no allowable generic or linking claim.
5. Claims 2-4, 7, 8, 10 and 21, drawn to non-elected species, also remain withdrawn from consideration with traverse.
6. Claims 1, 5, and 6 are under examination and are the subject of this office action.
Previous Claim Rejections - 35 USC § 112
7. Claim 9 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as lacking antecedent basis.
8. In view of Applicant’s cancelation of claim 9, the previous indefiniteness rejection is withdrawn.
Previous Claim Rejections - 35 USC § 103
9. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
10. Claims 1, 5, and 6 remain rejected under 35 U.S.C. 103 as being unpatentable over Mahabir et al., (Plastic and Reconstructive Surgery 2004),in view of McCartney et al., (Anesth Analg 2004), and ClinicalTrials.gov (Record History of NCT03364569, 2017), and further in view of Sawynok et al., (Eur J of Pharm 2002).
Claim 1 is drawn to a multimodal infiltrative opioid sparing analgesic composition that is formulated for infiltrative injection in or around a therapeutic site of action, for use in treating or preventing pain in a subject in need thereof, wherein the composition comprises:
(a) about 0.01%-0.5% of a local anesthetic comprising bupivacaine hydrochloride;
(b) about 0.01-3.0 mg/cc of an NMDA receptor antagonist comprising Dextromethorphan;
(c) about 0.01-1.5 mg/cc of a COX inhibitor comprising Ketorolac;
(d) tranexamic acid (claim 5); and
(e) epinephrine (claim 6);
wherein the therapeutic site of action comprises a source of peripheral nociceptive transduction or inflammation in the subject.
11. Mahabir et al. teach a multimodal approach to postoperative pain relief comprising the administration of (a) the local anesthetic bupivacaine, (c) the COX inhibitor ketorolac, and (e) the alpha agonist epinephrine, for post-operative analgesia following breast augmentation surgery (see Abstract). Mahabir et al. demonstrate that the combination of 30 mg of ketorolac co-administered with 150 mg bupivacaine and epinephrine “significantly reduced pain in the postoperative period” (see page 1912, Table 1, page 1914, Figure 3 and pages 1915, right column- page 1916, left column, under “Conclusions”).
12. Mahabir et al. do not teach the administration of (b), dextromethorphan.
13. Yet, McCartney et al. disclose the analgesic effects of NMDA antagonists on postoperative pain, in particular the significant beneficial effects of (b) dextromethorphan in the reduction of acute postoperative pain in dozens of different surgical procedures (page 1385, abstract and left column, first paragraph, see Table 4 page 1394-1396). McCartney et al. teach dosage amounts of dextromethorphan of 10 mg, 20 mg, 40 mg, 45 mg, 60 mg, 90 mg, and 0.5 mg/kg and 1.0 mg/kg.
14. ClinicalTrials.gov evaluates the results of administering (d) tranexamic acid for improving surgical outcome in breast augmentation surgical patients.
15. As such, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention that combining bupivacaine, ketorolac, dextromethorphan, tranexamic acid, and epinephrine into a single pharmaceutical composition for postsurgical analgesia would have an additive effect and would result in an improved composition for treating/ reducing postsurgical pain in a subject in need thereof.
16. 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.
17. In the instant case, the combination of Bupivacaine, Dextromethorphan and Ketorolac with tranexamic acid and epinephrine, each having previously demonstrated post-surgical analgesic activity could be combined in a single composition in order to achieve an additive effect for use in treating/preventing postoperative pain in a patient in need thereof.
18. 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.
19. Regarding the recited dosage amounts per cc of dextromethorphan (0.01-3.0 mg/cc), and ketorolac (0.01-1.5 mg/cc), it would have been obvious for one of ordinary skill in the art to use the starting point of ketorolac (i.e., 30 mg), disclosed by Mahabir et al. and dextromethrophan (i.e., 10 mg, 20 mg, 40 mg, 45 mg, 60 mg, 90 mg, and 0.5 mg/kg and 1.0 mg/kg) disclosed by McCartney et al., and optimize these amounts in a composition for intraperitoneal administration, 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.
20. Regarding the preamble statement in claim 1 reciting that the opioid-sparing analgesic composition is “…for infiltrative injection in or around a therapeutic site of action for use in treating or preventing pain in a subject in need thereof,” [emphasis added] a “mere statement of a new use for an otherwise old or obvious composition cannot render a claim to the composition patentable.” In re Zierden, 411 F.2d 1325, 1328 (CCPA 1969). Rather, a preamble is not limiting ‘where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention.” Catalina Marketing Int’l, Inc. v. Coolsavings.com, Inc. 298 F.3d 801,808 (Fed. Cir. 2002).
21. Likewise, claim 1 is drawn to a product (i.e., an analgesic composition comprising components a., b, and c.), and while the use of a descriptive clause pertaining to the process of formulating and/or using the composition is permitted, i.e., “formulated for infiltrative injection,” Applicant is reminded that a recitation of the intended administration/use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. As such, the claimed method by which the composition is formulated and intended for use does not carry patentable weight.
22. Assuming for the sake of argument that Applicant’s recitation that the composition “formulated for infiltrative injection in or around a therapeutic site of action… wherein the therapeutic site of action comprises a source of peripheral nociceptive transduction or inflammation in the subject,” carries patentable weight, Sawynok et al. demonstrate the peripheral analgesic action of dextromethorphan when administered via local delivery in a murine pain model:
“In the present study, dextromethorphan was the only agent to produce a peripheral antinociception against flinching behaviors. Dextromethorphan can block NMDA receptors in a noncompetitive manner by actions within the ion channel (Tortella et al., 1989; Fisher et al., 2000). It can also block voltage-gated Ca2+ channels (Carpenter et al., 1988), and this action might contribute to antinociception at peripheral sites (cf. White and Cousins, 1998),”
(page 158, right column, first full paragraph).
23. Therefore, one of skill in the art before the effective filing date of the claimed invention would have been motivated to combine Bupivacaine, Dextromethorphan and Ketorolac with tranexamic acid and epinephrine, each having previously demonstrated post-surgical analgesic activity, into a single composition in order to achieve an additive effect for use in treating/preventing postoperative pain in a patient in need thereof, with a reasonable expectation of success.
As such, claims 1, 5, and 6 are prima facie obvious.
Response to Arguments
24. Applicant traverses the previous obviousness rejection over claims 1, 5 and 6 and argues that the prior art and industry standard teach away from the claimed invention. Applicant refers to Wadhwa et al., (Anesth Analg. 2001), arguing that Wadhwa teaches that dextromethorphan is a "weak N-methyl-d-aspartate (NDMA) receptor antagonist," and that "previous studies with dextromethorphan that have used small doses have shown only a modest reduction in morphine requirements with no or minimal changes to the postoperative pain experience." Applicant contends that Wadhwa teaches that "large dose[s]" of dextromethorphan are needed to achieve "significant improvement in the management of the postoperative pain experience."
(Applicant’s Remarks, page 6). Applicant alleges that Wadhwa teaches away from the present invention for at least two reasons:
(i) Applicant argues that Wadhwa teaches even "large dose[s]" of dextromethorphan result in "no reduction in postoperative pain levels," concluding that "dextromethorphan does not improve pain scores in a manner expected of a drug with NDMA antagonist properties." Applicant alleges that Wadhwa teaches away from the present invention first by teaching that dextromethorphan is an ineffective agent in treating postoperative pain, wherein Wadhwa states that, in these studies, "there was no report of significant reduction in the pain experienced... and no or minimal opioid sparing." Applicant alleges that the present invention achieves a surprising result by effectively utilizing dextromethorphan in the treatment of postoperative pain.
(ii) Applicant argues that Wadhwa also teaches away from the present invention by teaching that dextromethorphan is a weak antagonist of the NMDA receptor, such that doses of dextromethorphan needed to reduce postoperative pain are consequently large, and result in "severe dose-limiting side effects" that led to termination of the "first part of... [Wadhwa's] trial." Applicant argues that in Wadhwa's second phase study, with a modified dosing (i.e., reduced) regimen, at least five patients were excluded from the study because they experienced "adverse effects such as...nausea and vomiting," even before receiving the complete modified (i.e., reduced) dosing regimen. Applicant alleges that even among the patients who completed Wadhwa's second phase study and received the modified (i.e., reduced) dosing regimen, Wadhwa concluded that "[d]extromethorphan treatment caused a significant increase in nausea scores." Applicant argues that prior studies cited by Wadhwa concluded that, "the incidence of side effects [among patients receiving dextromethorphan for post-operative pain] was very frequent-42% suffering from dose-related side effects such as... nausea, and vomiting." Wadhwa teaches that, "when the full [first part of Wadhwa's] trial was started, 50% of the patients experienced severe pruritus or nausea after the initial 400-mg dose. This necessitated a further dose reduction... Despite this, the results show clearly that 200 mg of dextromethorphan given eight hourly [i.e., a reduced dosing regimen] still leads to a significant increase in postoperative nausea." Applicant argues that Wadhwa concludes that dextromethorphan is ineffective at reducing postoperative pain, and that its use is "at a cost of increased nausea," leading the authors to "conclude that...dextromethorphan is not clinically useful in the treatment of postoperative pain..." (Applicant’s Remarks, pages 6-7).
Applicant argues that conversely, the present invention 1) effectively (and surprisingly) utilizes dextromethorphan for the treatment of postoperative pain; and 2) does so (surprisingly) without significant increases in nausea and/or vomiting.
25. Applicant's arguments have been fully considered but they are not persuasive. Regarding the argument that the Wadhwa et al. rebuttal reference (Anesth Analg. 2001) teaches away from the claimed invention, it is noted that rebuttal evidence must be reasonably commensurate in scope with the claimed invention. See, e.g., In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990); In re Grasselli, 713 F.2d 731, 743, 218 USPQ 769, 777 (Fed. Cir. 1983). In other words, objective evidence of nonobviousness must be attributable to the claimed invention. See MPEP 2145. In this case, Wadhwa et al. summarize the effects of the administration of dextromethorphan when administered “as an adjunct to patient-controlled analgesia with morphine after knee surgery,” [emphasis added] (Applicant’s Remarks, page 6), for example at doses of 400 mg or 200 mg (Applicant’s Remarks, page 7). Wadhwa et al. do not discuss the effects of dextromethorphan when administered as a component in a multimodal opioid-free analgesic composition, as instantly claimed.
26. And, King et al. (Anesthesiology 2016, published after Wadhwa) teach that N-methyl-D-aspartate (NMDA) receptor antagonists have been shown to reduce perioperative pain and opioid use, wherein the NMDA receptor antagonist dextromethorphan is employed as an adjunct for postoperative analgesia. King et al. go on to report the side effects of dextromethorphan, wherein no patients reported severe nausea:
“Eighteen out of 21 trials included in our meta-analyses tracked the incidence of side effects, which for both opioids and dextromethorphan primarily consist of nausea, vomiting, dizziness, and lightheadedness. Ten studies reported either no side effects or a nonsignificant difference between groups.9-10,13-14,16,19- 20,22,24,27,29. Five studies did, however, did report a decrease in side effects in groups receiving dextromethorphan.15,17-18,25-26. One study23 found a higher incidence of nausea in the dextromethorphan group, with rating mild to moderate nausea reported by patients at 31 time points in the dextromethorphan group compared to 20 time points in the control group, although no patients reported severe nausea at any time.” [emphasis added].
(Page 5 under “incidence of side effects”). As such, one of skill in the art at the time of filing would have reasonably considered employing dextromethorphan as an adjunct in a multimodal composition for reducing perioperative pain and opioid use.
Conclusion
27. In conclusion, claims 1-8 and 21 are present in the application. Claims 2-4, 7, 8 and 10-21 are presently withdrawn from consideration. Claims 1, 5, and 6 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 Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628