DETAILED ACTION
Previous Rejections
Applicant’s arguments, filed 02/26/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Response to Arguments
Applicant’s arguments with respect to the instant claims have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Claim Rejections - 35 USC § 103 - Obviousness
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.
Claim(s) 1, 7, 9, 11-12, 16-18, 22, 24-25, 26, 28, 29, 33-34, 45 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al (Int J Clin Exp Med, 2015, 8(9), 15630-15638), in view of Kim et al (US 2006/0078606 A1), further in view of Ferrillo et al (Clinical Case Reports, 2016, 4(9), 861-865) and further in view of Lipov et al (Military Medicine, 178, 2:e260, 2013).
Yang taught the administration of the anesthetic bupivacaine as stellate ganglion block (SGB) treatment of traumatic brain injury patients (TBI) [abstract and page 15631, last paragraph bridging to the adjoining paragraph of page 15632]. As per Yang, SGB is a known treatment method against pain-related diseases, generally, wherein SGB is widely used clinically, and has achieved good results [page 15630, 2nd paragraph].
Yang did not teach multivesicular liposomes; treating an anxiety disorder, as recited in claim 1.
Kim provided a method for obtaining local anesthetics encapsulated in multivesicular liposomes, with high encapsulation efficiency and slow release in vivo. When the encapsulated anesthetic was administered, the duration of anesthesia and half-life of the drug at the local injection site was increased, as compared to injection of unencapsulated anesthetic. The maximum tolerated dose of the encapsulated anesthetic was also markedly increased in the liposomal formulation, over injection of unencapsulated anesthetic. These results showed that the liposomal formulation of local anesthetic was useful for sustained local infiltration, and nerve block anesthesia [abstract]. The anesthetic was bupivacaine [see claims 35 and 37].
Since Yang taught bupivacaine for nerve block procedures (e.g., SGB), it would have been prima facie obvious to one of ordinary skill in the art to substitute Yang’s bupivacaine with Kim’s multivesicular liposomal bupivacaine. The ordinarily skilled artisan would have been motivated to use a formulation with high encapsulation efficiency and slow release in vivo, as taught by Kim [abstract]. Additionally, the ordinarily skilled artisan would have been motivated to use a formulation with a markedly increased maximum tolerated dose, as compared with the unencapsulated bupivacaine, as taught by Kim
The combined teachings of Yang and Kim did not teach multivesicular liposomal bupivacaine administered in a stellate ganglion block procedure.
However, Ferrillo taught the use of both traditional bupivacaine HCl and multivesicular liposome bupivacaine in stellate ganglion blocks, for the treatment of complex regional pain syndrome, with liposome bupivacaine observed to provide improved treatment, over an extended duration [abstract; page 862, Case Presentation, bridging to page 863].
Furthermore, Lipov taught that the use of bupivacaine in stellate ganglion block procedures substantially improved post-traumatic stress disorder (PTSD) symptom severity and memory dysfunction, indicating SGB’s clinical utility as a treatment for PTSD [abstract; see also page e261, Methods, SGB Treatment Procedure].
And so, it would be prima facie obvious to one of ordinary skill in the art to administer multivesicular liposomal bupivacaine in a stellate ganglion block procedure, as taught by Ferrillo. Since Yang generally taught that SGB is a known treatment method against pain-related diseases, generally, with wide clinical usage and good results, the ordinarily skilled artisan would be motivated to provide improved treatment, over an extended duration, with multivesicular liposomal bupivacaine, versus the unencapsulated bupivacaine, as taught by Ferrillo [abstract; page 862, Case Presentation].
Since the combined teachings of Yang, Kim and Ferrillo taught bupivacaine administered via stellate ganglion block, it would be prima facie obvious to one of ordinary skill in the art to include, within the combined teachings of the art, the treatment of PTSD, as taught by Lipov. The ordinarily skilled artisan would be motivated to substantially improve PTSD symptom severity and memory dysfunction, indicating SGB’s clinical utility as a treatment for PTSD, as taught by Lipov [abstract; see also page e261, Methods, SGB Treatment Procedure].
It appears that the methods and compositions of the instant claims (administering bupivacaine MVL to SGB to treat anxiety disorder) and those of the combined teachings of the prior art (administering bupivacaine MVL to SGB) would reasonably be expected to have substantially the same physical and chemical properties (treatment of PTSD).
Inherent features need not be recognized at the time of the invention. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2112 II. It should be noted that a chemical composition (bupivacaine MVL administered by SGB) and its properties (treatment of PTSD) are inseparable. If the prior art teaches the identical chemical compounds, then the properties that the Applicant discloses and/or claims are necessarily present.
Yang, in view of Kim, Ferrillo and Lipov, read on claims 1 and 45.
Claims 7 and 11 are rendered prima facie obvious because Lipov taught PTSD treatment via the SGB.
Claim 16 is rendered prima facie obvious because Yang taught that 5 ml venous blood was extracted from the right internal carotid of both the SGB treatment and the control group at five designed time points, namely before-SGB-treatment (T1), 1 h-after SGB-treatment (T2), 2 d-after-SGB-treatment (T3), 4 d-after-SGB-treatment (T4) and 7 d-after SGB-treatment (T5) (e.g., reads on measuring or receiving information on a baseline level of markers in the blood prior to administration) [page 15632, left column, last paragraph] .
Claims 17-18 are rendered prima facie obvious because Yang taught that SGB reduced IL-6, IL-1β and TNF-α in the serum [abstract].
The instant claim 22 recites that the method causes a temporary reduction in the ability of the sympathetic nervous system to release norepinephrine. The instant claims 24-25 recite that the method results in at least a 6-point decrease on HIT-6 Test or 10-point decrease on PCL-5 Checklist, 4, 6 or 8 weeks after administration. The instant claim 1, from which claims 22 and 24-25 depend, recite that the method comprises administering an effective amount of bupivacaine MVLs to one or more nerves of the stellate ganglion of the patient.
The combined teachings of the prior art taught: Yang (administering bupivacaine to SGB of TBI patients), Kim (administering bupivacaine MVL) and Ferrillo (administering 13.3 mg/mL bupivacaine MVL to SGB; [page 863, left column, 1st and 2nd full paragraphs]). It appears that the compositions of the instant claims (effective amount of bupivacaine MVL) and those of the combined teachings of the prior art (13.3 mg/mL bupivacaine MVL) would reasonably be expected to have substantially the same physical and chemical properties (e.g., cause a temporary reduction in the ability of the sympathetic nervous system to release norepinephrine, when administered to the SGB of patients; result in at least a 6-point decrease on HIT-6 Test or 10-point decrease on PCL-5 Checklist, 4, 6 or 8 weeks after administration, when administered to the SGB of patients). Lipov taught the PTSD checklist [abstract; see also page e261, left column, last paragraph bridging to 1st paragraph of right column].
Inherent features need not be recognized at the time of the invention. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2112 II. It should be noted that a chemical composition and its properties are inseparable. If the prior art teaches the identical chemical compounds, then the properties that the Applicant discloses and/or claims are necessarily present (see MPEP 2112).
Claim 26 is rendered prima facie obvious because Ferrillo taught 13.3 mg/mL bupivacaine [page 863, left column, 1st and 2nd full paragraphs]. The motivation to combine Ferrillo with the combined teachings of Yang and Kim was previously discussed.
Claims 28 and 33 are rendered prima facie obvious because Kim taught from about 20 mg to about 300 mg total anesthetic [0038]; bupivacaine phosphate [0041].
The instant claim 28 recites from about 10 mg to about 200 mg, 20 mg to about 100 mg or from about 25 mg to about 75 mg bupivacaine.
Kim taught from about 20 mg to about 300 mg anesthetic. A prima facie case of obviousness exists because of overlap, as previously discussed. The motivation to combine Kim with Yang was previously discussed.
Claims 29 and 34 are rendered prima facie obvious because Ferrillo taught four injections (left SBG, with liposome bupivacaine) at 2.0-2.5 mL each, timed 3-5 weeks apart (e.g., reads on total volume of 5 mL to about 10 mL for unilateral stellate ganglion block) [page 863, left column, penultimate paragraph] The patient continued to experience approximately 3 weeks (18–21 days) of pain relief with each SGB with liposome bupivacaine.
The instant claim 29 recites 5-10 mL total volume.
The instant claim 34 recites temporary reduction or interruption of sympathetic stimulation to the nervous system for up to 3 days, 7 days, 10 days, 14 days, 21 days, 21 days, or 1-6 months.
Ferrillo taught 8-10 mL administered over 3-5 weeks; pain relief for 18-21 days. A prima facie case of obviousness exists because of overlap, as previously discussed. The motivation to combine Ferrillo with the combined teachings of Yang and Kim was previously discussed.
Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over Yang et al (Int J Clin Exp Med, 2015, 8(9), 15630-15638), in view of Kim et al (US 2006/0078606 A1), further in view of Ferrillo et al (Clinical Case Reports, 2016, 4(9), 861-865), further in view of Zheng et al (Front. Neurol., 11:81, 1-14, 2020) and further in view of Lipov et al (Military Medicine, 178, 2:e260, 2013).
The 35 U.S.C. 103 rejection over Yang, Kim, Ferrillo was previously described.
Although Yang, Kim and Ferrillo taught TBI, the combined teachings of the art did not teach an association with an overactive or unbalanced sympathetic nervous system, as recited in claim 3; treating an anxiety disorder, as recited in claim 3.
Nevertheless, Zheng taught that paroxysmal sympathetic hyperactivity (PSH) has predominantly been described after TBI, which is associated with hyperthermia, hypertension, tachycardia, tachypnea, diaphoresis, dystonia (hypertonia or spasticity), and even motor features such as extensor/flexion posturing. Despite the pathophysiology of PSH not being completely understood, most researchers gradually agree that PSH is driven by the loss of the inhibition of excitation in the sympathetic nervous system without parasympathetic involvement. Recently, advances in the clinical and diagnostic features of PSH in TBI patients have reached a broad clinical consensus in many neurology departments. Clinically, a great deal of attention has been paid to the definition and diagnostic criteria, epidemiology and pathophysiology, symptomatic treatment, and prevention and control of secondary brain injury of PSH in TBI patients [abstract].
Lipov taught that the use of bupivacaine in stellate ganglion block procedures substantially improved post-traumatic stress disorder (PTSD) symptom severity and memory dysfunction, indicating SGB’s clinical utility as a treatment for PTSD [abstract; see also page e261, Methods, SGB Treatment Procedure].
Since the combined teachings of Yang, Kim and Ferrillo taught treating TBI patients, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Yang, Kim and Ferrillo, patients having an association with an overactive or unbalanced sympathetic nervous system, as taught by Zheng et al. The ordinarily skilled artisan would have been so motivated, because PSH is predominantly described after TBI injury, with agreement by most researchers and with broad clinical consensus, as taught by Zheng et al at the abstract.
Since the combined teachings of Yang, Kim, Ferrillo and Zheng taught bupivacaine administered via stellate ganglion block, it would be prima facie obvious to one of ordinary skill in the art to include, within the combined teachings of the art, the treatment of PTSD, as taught by Lipov. The ordinarily skilled artisan would be motivated to substantially improve PTSD symptom severity and memory dysfunction, indicating SGB’s clinical utility as a treatment for PTSD, as taught by Lipov [abstract; see also page e261, Methods, SGB Treatment Procedure].
It appears that the methods and compositions of the instant claims (administering bupivacaine MVL to SGB to treat anxiety disorder) and those of the combined teachings of the prior art (administering bupivacaine MVL to SGB) would reasonably be expected to have substantially the same physical and chemical properties (treatment of PTSD).
Inherent features need not be recognized at the time of the invention. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2112 II. It should be noted that a chemical composition (bupivacaine MVL administered by SGB) and its properties (treatment of PTSD) are inseparable. If the prior art teaches the identical chemical compounds, then the properties that the Applicant discloses and/or claims are necessarily present.
Claim(s) 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al (Int J Clin Exp Med, 2015, 8(9), 15630-15638), in view of Kim et al (US 2006/0078606 A1), further in view of Ferrillo et al (Clinical Case Reports, 2016, 4(9), 861-865) further in view of Lipov et al (Military Medicine, 178, 2:e260, 2013) and further in view of Haugland et al (US 2021/0322669 A1).
The 35 U.S.C. 103 rejection over Yang, Kim, Ferrillo and Lipov was previously discussed.
The combined teachings of Yang, Kim, Ferrillo and Lipov did not teach intravenous ketamine injection, or amounts thereof, as recited in claims 20-21.
Haugland taught a method for treating a patient with a traumatic brain injury, including performing ketamine infusion therapy on the patient [abstract], wherein treating the patient with ketamine infusion therapy included intravenously injecting one or more doses of ketamine hydrochloride, at a dosage of 0.5-1.1 mg/kg [0009, 0031 and Table 1]. As per Haugland, TBI patients often suffer comorbid depression, and ketamine provides relief from depression or symptoms [0028-0029].
Since Yang taught treating TBI patients, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Yang, ketamine injections, as taught by Haugland. The ordinarily skilled artisan would have been motivated to treat comorbid depression and symptoms thereof, as taught by Haugland [0028-0029].
The skilled artisan would have included ketamine injections at a dosage of 0.5-1.1 mg/kg, because at the said dosage, the drug treats comorbid depression and symptoms thereof, in TBI patients, as taught by Haugland et al [0009, 0031 and Table 1].
The instant claim 21 recites ketamine at from about 0.5 to about 1 mg/kg.
Haugland taught ketamine at 0.5-1.1 mg/kg. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art", a prima facie case of obviousness exists. MPEP 2144.05 A.
Claim(s) 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al (Int J Clin Exp Med, 2015, 8(9), 15630-15638), in view of Kim et al (US 2006/0078606 A1), further in view of Ferrillo et al (Clinical Case Reports, 2016, 4(9), 861-865), further in view of Lipov et al (Military Medicine, 178, 2:e260, 2013) and further in view of Bright et al (US 2019/0038646A1).
The 35 U.S.C. 103 rejection over Yang, Kim, Ferrillo and Lipov was previously described.
Although the combined teachings of the prior art taught bupivacaine as a SGB block in the management of pain, the combined teachings of the art were not specific nerves of the paravertebral chain, as recited in claims 47-48.
Bright taught neuromodulation of the autonomic nervous system, by injection with drug formulations, at or near [abstract, ¶ 0005] the stellate ganglion and adjacent cervical and thoracic ganglia of the sympathetic chain [0007], in order to treat different diseases [abstract]. For example, the treatment of pain, by nerve block (e.g., stellate ganglion block, autonomic neural block, local nerve block) with bupivacaine, was taught [0115, 0143, 0147, 0172]. Bright taught that the cervical ganglia are paravertebral ganglia of the sympathetic nervous system (SNS), and include the middle cervical ganglion (adjacent to C6), and the inferior cervical ganglion (adjacent to C7) [0022].
Since the combined teachings of Yang, Kim and Ferrillo taught bupivacaine as a nerve block in the management of pain, it would have been prima facie obvious to one of ordinary skill in the art to include, within the teachings of Yang, Kim and Ferrillo, nerves of the paravertebral chain (e.g., C6 and C7), as taught by Bright. The ordinarily skilled artisan would have been motivated to modulate the autonomic nervous system through local chemical neuro-manipulation, for the treatment of pain, as taught by Bright [abstract, ¶ 0005].
Nonstatutory Double Patenting
A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 7, 9, 11-12, 16-18, 20-22, 24-26, 28-29, 33-34, 45 and 47-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 7, 16-23, 25, 28-29, 32-35 and 38 of copending Application No. 18/949,639, in view of Lipov et al (Military Medicine, 178, 2:e260, 2013).
Claims 1, 3, 7, 9, 11-12, 16-18, 20-22, 24-26, 28-29, 33-34, 45 and 47-48 are on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-11, 13, 15-18, 20, 23-28, 30 and 33-34 of copending Application No. 18/171,831, which has issued as a U.S. Patent, in view of Lipov et al (Military Medicine, 178, 2:e260, 2013).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims require the treatment of an anxiety disorder, which is not recited by the copending claims.
Lipov taught the administration of bupivacaine as stellate ganglion block (SGB) treatment of post-traumatic stress disorder patients (PTSB).
It would have been prima facie obvious to one of ordinary skill in the art to include PTSB patients within the copending and issued claims. The ordinarily skilled artisan would have been motivated to treat a patient population that responded to SGB therapy with bupivacaine, as taught by Lipov et al.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/CELESTE A RONEY/Primary Examiner, Art Unit 1612
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