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 .
Claim Amendment
Claim 1 has been amended to obviate an objection. No new matter has been added.
Election/Restrictions
Claims 11-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-10 have been considered on the merits.
Power of Attorney
Applicant has not yet submitted a Power of Attorney.
Information Disclosure Statement
The two information disclosure statements (IDSs) filed on 6/18/2026 comply with the provisions of 37 C.F.R. 1.97. Accordingly, all references cited in both IDSs have been fully considered.
Claim Objections
RE: Objection to claim
Applicant corrected the minor informality in claim 1. Thus, the claim objection has been withdrawn.
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.
RE: Rejection on claims 1-10 over Williams in view of Verhaert et al. and Levin et al.
Traversal of rejections is based on the cited references failing to teach or suggest every element of the claims: (i) Williams is asserted to be primarily concerned with treating cardiac arrythmia and does not disclose any relationship between said condition and chronic heart failure; (ii) Verhaert et al. explains that atrial fibrillation and heart failure are epidemiologically linked and share pathophysiological pathways, but allegedly does not specifically teach that William’s method of subcutaneously or intradermally injecting botulinum toxin to spinal sensory nerves would be effective for treating chronic heart failure; and (iii) Levin et al. does not remedy the deficiencies of Williams and Verhaert et al. because it treats heart failure by ablation of the greater splanchnic nerve, which is allegedly a permanent destruction of the nerve, and also does not teach that subcutaneously or intradermally injecting botulinum toxin would be effective for treating chronic heart failure. In addition, applicant argues that there is no motivation to combine the cited references, and even if all their teachings are combined, there is no reasonable expectation of success to arrive at the claimed method.
Applicant’s traversal has been fully considered and is found unpersuasive. As set forth in the last office action, Williams is directed to a method of treating cardiac arrhythmia in a patient by administering botulinum toxin by subcutaneously or intradermally injecting it to and/or around the vicinity of a nerve near a patient’s spine. Although said prior art does not explicitly teach that the disclosed method is also useful for treatment of chronic heart failure, it recognizes that not properly treating cardiac arrhythmia can cause heart failure (lines 11-14, col. col. 5). Treating cardiac arrhythmia is therefore expected to prevent the onset, or impede the development of, chronic heart failure.
In addition, Verhaert et al. shows that arrhythmia, specifically atrial fibrillation, is known in the art to share several coinciding cardiovascular risk factors with chronic heart failure and that these two ailments/diseases provoke, sustain, and aggravate each other through various mechanisms like activation of neurohumoral pathways including increased sympathetic stimulation. This teaching is supported by Levin et al., which characterizes chronic heart failure as exhibiting increased neurohumoral activation and longstanding congestion of the splanchnic vascular compartment (par. [0012], [0062]). Levin et al. teaches that the sympathetic activation of splanchnic nerves can be treated via ablation of a splanchnic nerve to relieve heart failure symptoms and reduce load of the failing heart (par. [0071]). One way to ablate a target nerve is through local drug delivery such as by injecting a neurolytic blocking agent like botulinum toxin A (par. [0036], [0080]). Given that arrhythmia and chronic heart failure often coexist and can be managed/treated together according to Verhaert et al. (Abstract, page ii40), a person with ordinary skill in the art would have performed William’s method of subcutaneously or intradermally injecting botulinum toxin to a nerve near the spine of a patient with chronic heart failure and predict that said ailment/disease would be successfully treated. There is reasonable expectation of success because injecting botulinum toxin to and/or around a splanchnic nerve is one of the means of inhibiting or decreasing the sympathetic nervous system activity based on the teachings of Levin et al..
It should also be noted that preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. MPEP § 2123 states that “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). In this case, Levin et al. teaches that there are different methods of ablating a nerve, wherein use of an endovascular catheter to apply high/ablation energy on a target nerve is only one of them. Such application of energy may be a preferred embodiment, but it does not negate other embodiments of nerve ablation including injection of a neurolytic blocking agent like botulinum toxin A (par. [0063], [0080]; claim 10).
Furthermore, nerve ablation causes injury on the applied area only. Nerves can heal and regenerate since axons and myelin can grow back. Thus, Levin et al.’s method of treating heart failure through nerve ablation does not necessarily result in permanent destruction of target nerves, contrary to applicant’s allegation.
The rejections of record have therefore been maintained.
Maintained rejections
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Williams (Pub. No. US 10,960,060 B1) in view of Verhaert et al. (Eurospace 2021, Vol. 21, pages ii40-ii45) and Levin et al. (Pub. No. US 2018/0110561 A1).
According to Williams, cardiac arrhythmia is characterized by irregular rhythm of heartbeat which could be either too slow (<60 beats/min) or too fast (>100 beats/min) (lines 61-64, col. 4). One possible cause of arrhythmias is neuropathic hypersensitivity of the t-1 to t-3 and t-5 to t-8 sensory spinal nerves caused by the overproduction of the neuroexcitatory substances glutamate, Substance P, and CGRP. Increased levels of these substances induce hypersensitivity to the involved sensory nerves and promotes neural firing with minimal stimulation, resulting in an increased heart rate that is detected by the brain, which in turn increases firing of the vagus nerve in response and consequently slows the heart back down. The entire process results in the up and down swing in heart rate, which is characteristic of some arrhythmias (lines 64-67, col. 5; lines 1-5 and 13-17, col. 6).
Williams discloses a method for treating said disorder in a patient in need thereof comprising administering botulinum toxin to the patient (Abstract). The botulinum toxin is administered via subcutaneous or intradermal injection at locations where the overproduction of Substance P, CGRP, and glutamate causes hypersensitivity to the involved sensory nerves (lines 54-63, col. 6). The small amounts of botulinum toxin administered (ex. 2-4 units) is sufficient to produce the desired neural effect without the unneeded motor side effects (lines 17-21, col. 7; lines 25-38, col. 8).
Administration of the botulinum toxin can control the excess glutamate, Substance P, and Calcitonin Genes Related Peptide (CGRP) and consequently inhibit neural hypersensitivity (lines 47-50, col. 6) by cleaving and destroying the proteins SNAP25 and/or VAMP that normally move these molecules through the cell membrane and releases the molecules into the cerebrospinal fluid that surrounds the neurons (lines 21-33, col. 1).
The method of Williams is comparable to the instant application’s method for the following reasons:
Regarding claim 1: administering botulinum toxin to a patient in need thereof is equivalent to the step “administering a botulinum toxin to the patient in need thereof”.
Subcutaneous or intradermal injection of the botulinum toxin (lines 54-56, col. 6) is identical to the requirement that the administration is performed “by subcutaneous or intradermal injection”.
The botulinum toxin being injected to and/or around the vicinity of a trigeminal nerve, a cervical nerve, a thoracic nerve, a lumbar nerve, and/or a sacral nerve of the patient (lines 54-57, col. 7) such as in the amount of 2-4 units to and/or around the vicinity of a trigeminal nerve or 2-4 units to and/or around the vicinity of the c-2 to c-3, c-4 to c-6, and/or c-7 to c-8 of the cervical nerve, about one-inch lateral to the patient's spine (lines 25-30, col. 8) reads on “1-4 units to and/or around the vicinity of a trigeminal nerve, 1-4 units to and/or around the vicinity of a cervical nerve, lateral to the patient's spine, 1-4 units to and/or around the vicinity of a thoracic nerve, lateral to the spine, 1-4 units to and/or around the vicinity of a lumbar nerve, lateral to the spine, and/or 1-4 units to and/or around the vicinity of a sacral nerve, lateral to the spine”.
Williams differs from the claimed invention in that it does not teach that the disclosed method is useful for “treating chronic heart failure”.
It is known in the art, however, that arrhythmia and chronic heart failure can cause and sustain each other in a bidirectional cycle as substantiated by Verhaert et al. (Abstract, page ii40). Verhaert et al. teaches that persistent arrhythmias like atrial fibrillation can induce acute and chronic heart failure through loss of atrial contraction, irregularity of ventricular contractions, tachycardia, neurohumoral activation including increased sympathetic stimulation, and damage to the structural integrity of the myocardium (first to third par. in left & right columns, page ii41; Figure 1, page ii41). Conversely, the structural changes and strain from chronic heart failure often trigger arrhythmias (fourth to fifth par. in left column and first to third par. in right col., page ii42). Treatments for persistent arrhythmias can therefore help treat chronic heart failure, and vice-versa.
In addition, Levin et al. teaches that chronic heart failure is characterized by increased neurohumoral activation and longstanding venous congestion, wherein the splanchnic vascular bed has been identified as a major contributor to blood pooling and cardiac physiology. Thus, blocking and regulation of the sympathetic nervous system has become a novel target for treatment of chronic heart failure (par. [0012]). One way of decreasing the activity of sympathetic nervous system is to subject a splanchic nerve to ablation (par. [0076]) such as by injecting a neurolytic blocking agent, specifically a sympatholytic agent like botulinum toxin A (par. [0080]).
Based on the teachings of Verhaert et al. and Levin et al., a person with ordinary skill in the art before the effective filing date of the claimed invention would have recognized that Williams’ method is also suitable for treating chronic heart failure. It would have thus been obvious to perform the disclosed method to a patient with chronic heart failure and expect that administering botulinum toxin to said patient would cleave SNAP25 and/or VAMP, thereby inhibiting the patient’s sympathetic nervous system. Such modification to the method of Williams would advantageously facilitate treatment of chronic heart failure. The obviousness of the instant claim is based on some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP § 2143.01 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007).
Hence, claim 1 is obvious over Williams in view of Verhaert et al. and Levin et al..
Regarding claim 2: the modified method involves injecting botulinum toxin injected to and/or around the vicinity of a trigeminal nerve including the ophthalmic, maxillary, mandibular nerve, supraorbital nerve, supratrochlear nerve, infraorbital nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser greater occipital nerve, or a combination thereof (lines 10-20, col. 3; lines 60-67, col. 7), which is the same as “wherein the trigeminal nerve is selected from the group consisting of an ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratrochlear nerve, infraorbital nerve, lacrimal nerve, nasociliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, an auriculotemporal nerve, a lesser occipital nerve, a greater occipital nerve, or a combination thereof”.
Regarding claim 3: injecting botulinum toxin to and/or around the vicinity of the cervical nerve like the c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, or a combination thereof (lines 9-13, col. 8) corresponds to “wherein the cervical nerve is selected from the group consisting of a c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, or a combination thereof”.
Regarding claim 4: injecting botulinum toxin to and/or around the vicinity of the thoracic nerve such as the t-2 to t-3 nerve, t-5 to t-6 nerve, t-7 to t-9 nerve, and/or t-10 to t-12 nerve, or a combination thereof (lines 13-17, col. 8) meets the limitation “wherein the thoracic nerve is selected from the group consisting of a t-2 nerve, t-3 nerve, t-5 nerve, t-6 nerve, t-7 nerve, t-8 nerve, t-9 nerve, t-10 nerve, t- 11 nerve, t-12 nerve and a combination thereof”.
Regarding claim 5: injecting botulinum toxin to and/or around the vicinity of the lumbar nerve including the l-1 to l-2 nerve, l-2 to l-3 nerve, and/or l-4 to 1-5 nerve, or a combination thereof (lines 17-21, col. 8) is identical to “wherein the lumbar nerve is selected from the group consisting of a 1-1 nerve, 1-2 nerve, 1-3 nerve, 1-4 nerve, 1-5 nerve and a combination thereof”.
Regarding claim 6: injecting botulinum toxin to and/or around the vicinity of the sacral nerve like the s-1 to s-2, s-3 to s-4, and/or s-4 to s-5, or a combination thereof (lines 21-24, col. 8) is equivalent to “wherein the sacral nerve is selected from the group consisting of a s-1 nerve, s-2 nerve, s-3 nerve, s-4 nerve, s-5 nerve and a combination thereof”.
Regarding claim 7: the botulinum toxin used in the treatment can comprise botulinum toxin type A, botulinum toxin type B, botulinum toxin type C, botulinum toxin type D, botulinum toxin type E, botulinum toxin type F, botulinum toxin type G, a fragment thereof, a hybrid thereof, and/or a chimera thereof (lines 65-67, col. 3; lines 1-2, col. 4; lines 36-44, col. 10), thus satisfying “wherein the botulinum toxin is selected from the group consisting of botulinum toxin type A, botulinum toxin type B, botulinum toxin type C, botulinum toxin type D, botulinum toxin type E, botulinum toxin type F, and botulinum toxin type G, a fragment thereof, a hybrid thereof, a chimera thereof, or a combination thereof”.
Regarding claim 8: Williams teaches that the therapeutically effective amount of botulinum toxin can be 1-150 units depending on the patient’s body weight such as about 1-30 units for toddlers (lines 32-37, col. 9), which reads on the limitation “wherein the therapeutically effective amount of the botulinum toxin administered is between about 1 unit and about 60 units”.
Regarding claim 9: the preferred embodiment of administering a total dosage of 10-150 units for adults weighing about 150 lbs (lines 45-48, col. 9), wherein the total dosage can be adjusted to the adult’s body weight (lines 34-35, col. 9), fulfills “wherein a total dosage of the botulinum toxin to an adult who weighs about 150 lbs. is less than or equal to about 50 units, and the total dosage of the botulinum toxin in an adult is adjusted for weight”.
MPEP § 2144.05 states that a prima facie case of obviousness exists when the claimed ranges "overlap or lie inside ranges disclosed by the prior art". 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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.). Since the disclosed amount of 10-150 units overlaps with the claimed amount, the limitation of the instant claim is considered obvious.
Regarding claim 10: injecting the botulinum toxin bilaterally (lines 25-52, col. 8) fulfills “wherein each of the subcutaneous or intradermal injections is bilateral”.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. 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.
RE: Rejection on claims 1-10 over Williams in view of Verhaert et al. and Levin et al.
Applicant traverses the rejections because the U.S. patent is directed to a method for treating cardiac arrhythmia, and neither one of the secondary references provides the necessary bridge between treating arrhythmia and chronic heart failure.
The traversal has been considered but is found unpersuasive for the same reasons discussed above. It is respectfully submitted that Verhaert et al. and Levin et al. do provide the reason or motivation to modify the method of U.S. 10,960,060 (see “Claim Rejections - 35 USC § 103” for detailed explanation).
Hence, the double patenting rejections have been maintained.
Maintained rejections
Claims 1-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,960,060 in view of Verhaert et al. (Eurospace 2021, Vol. 21, pages ii40-ii45) and Levin et al. (Pub. No. US 2018/0110561 A1).
U.S. patent 10,960,060 is directed to a method for treating arrythmia in a patient in need thereof by administering botulinum toxin to the patient. The botulinum toxin is administered by injecting 2-4 units subcutaneously or intradermally to and/or around the vicinity of a trigerminal nerve, cervical nerve lateral to the patient’s spine, thoracic nerve lateral to the patient’s spine, lumbar nerve lateral to the patient’s spine, and/or sacral nerve lateral to the patient’s spine. In an embodiment, the subcutaneous or intradermal injection is bilateral. The botulinum toxin can be type A, B, C, D, E, F, G, a fragment thereof, a hybrid thereof, a chimera thereof, or a combination thereof. Moreover, the total dosage of the botulinum toxin for an adult weighing about 150 lbs is about 2-150 units.
Although the U.S. patent is not drawn to a method of treating chronic heart failure as claimed by the instant application, treatments for persistent arrhythmias can alleviate or impede chronic heart failure. Verhaert et al. teaches that persistent arrhythmias like atrial fibrillation can cause acute and chronic heart failure through various factors including increased sympathetic stimulation and damage to the structural integrity of the myocardium (first to third par. in left & right columns, page ii41; Figure 1, page ii41). The structural changes and strain from chronic heart failure, in turn, can provoke arrhythmias (fourth to fifth par. in left column and first to third par. in right col., page ii42). Levin et al. also teaches treating chronic heart failure via blocking and regulation of the sympathetic nervous system (par. [0012]) such as by injecting a sympatholytic agent like botulinum toxin A (par. [0080]).
One with ordinary skill in the art before the effective filing date of the claimed invention would have thus performed the U.S. patent’s method in a person having chronic heart failure with reasonable expectation that administering botulinum toxin to said patient would degrade SNAP25 and/or VAMP. Consequently, it can be predicted that reducing the activity of the sympathetic nervous system would aid in the treatment of chronic heart failure. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Accordingly, the claims of the instant application are obvious over U.S. patent 10,960,060 in view of Verhaert et al. and Levin et al..
Conclusion
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHELLE F PAGUIO FRISING whose telephone number is (571)272-6224. The examiner can normally be reached Monday-Friday, 8:00 a.m. - 4:00 p.m..
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie L. Gordon can be reached at (571) 272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Michelle F. Paguio Frising/Primary Examiner, Art Unit 1651
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