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 Status
Claims 1-5 and 7-20 are pending. Applicant’s election without traverse of acute asymptomatic seizures and 2-(4-isobutylphenyl)propionyl methansulfonamide and salts thereof (reparixin) in the reply filed on Feb. 23, 2026 is acknowledged. Claims 1, 2, 7-8, 11-16 and 20 are active and subject to examination. Claims 3-5, 9-10 and 17-19 are withdrawn.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claim 2 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn.
The rejection of claim 6 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
The rejection of claim(s) 1-2 and 12 under 35 U.S.C. 102(a)(1) as being anticipated by Xu et al. (Brain Research Bulletin, 134 (2017), 91-98) (of record, cited in the last office action) is withdrawn.
The rejection of claims 1, 2, 6-8, 11-12 and 15 under 35 U.S.C. 102(a)(1) as being anticipated by Sousa et al. (Clinics, Vol. 68, Issue 3, 2013, p. 391-394) is withdrawn.
The rejection of claims 1, 2, 6-8, 11-12 and 15-16 under 35 U.S.C. 102(a)(1) as being anticipated by Villa et al. (Molecular Medicine, Vol. 13, 2007, p. 125-133) is withdrawn.
The rejection of claim(s) 2 under 35 U.S.C. 102(a)(1) as being anticipated by Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024) is withdrawn.
The provisional rejection of claims 1, 2, 6-8, 11-16 and 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 11, 17-21, 23 and 26 of copending Application No. 17/914,529 in view of Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024) is withdrawn.
The rejection of claims 1, 2, 6-8, 11-16 and 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,660,291 B2 in view of in view of Villa et al. (Molecular Medicine, Vol. 13, 2007, p. 125-133) and Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024) is withdrawn.
The rejection of claims 1, 2, 6-8, 11-16 and 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 12,133,843 B2 in view of in view of Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024) is withdrawn.
The rejection of claims 1, 2, 6-8, 11-16 and 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,291,641 B2 in view of in view of Villa et al. (Molecular Medicine, Vol. 13, 2007, p. 125-133) and Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024) is withdrawn.
The rejection of claims 1, 2, 6-8, 11-16 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,268,671 B2 in view of in view of Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024) is withdrawn.
The above rejections were overcome by Applicant’s amendments to the claims.
Claim Rejections – 35 USC § 112(b) – Previously Presented
The following is a quotation of 35 U.S.C. 112(b):
“(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.”
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
“The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.”
The rejection of claim 11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is maintained.
Response to Arguments
The Applicant argues that claim 11 has been amended to address the indefiniteness of claim 11 (Remarks, p. 7). These arguments were fully considered but are not persuasive. One of ordinary skill in the art cannot determine the metes and bounds of the claim because neither claim 11 or independent claim 1 provide a definition of the compounds of formulae (I) and (II).
Reiterated Rejection
Claim 11 recites the limitation "a compound of formula (I) and (II)" in the last line. One of ordinary skill in the art cannot determine the metes and bounds of the claim because it is unclear what compounds fall within the scope of formula (I) and (II). While the specification provides a general description of the compounds of formula (I) and formula (II) (e.g., Spec., p. 11-12), these descriptions provide preferences and alternatives which render the claim scope unclear (See MPEP § 2173.05(d)). An ordinary artisan would not know, based on the definitions of formula (I) and (II) in the specification, would not know what compounds are encompassed by formula (I) or formula (II) because it is not clear whether the narrower limitations present in the descriptions of these formulas are limitations. It is also unclear how a compound can be a compound of formula (I) and (II). The compound is either formula (I) or formula (II).
Claim Rejections – 35 USC § 102 – Previously Presented
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
“A person shall be entitled to a patent unless -
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.”
The rejection of claim(s) 1, 6, 13-14, and 20 under 35 U.S.C. 102(a)(1) as being anticipated by Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024) is maintained.
Response to Arguments
The Applicant argues that “the anti-seizure effects of dapsone are merely conjectured to be through the inhibition of IL-8 release and a ‘blinding effect’ on IL-8 receptors” and therefore “Kast does not teach the specific mechanistic limitation of CXCL8 inhibition by a CXCR1 or dual CXCR1/CXCR2 inhibitor as specified by the claims” (Remarks, p. 8). These arguments were fully considered but are not persuasive. Lopez-Gomez administers dapsone to adults with drug-resistant partial-onset seizures at 100 mg/day and 16 of 22 patients had a greater than 50% seizure reduction. This is the same compound, same population, and for the same purpose as the instantly claimed method. The receptor-level activity possessed by dapsone is necessarily possessed by the compound, not just conjecturally possessed. Kast relies on primary literature to show that dapsone inhibits IL-8 driven neutrophil chemotaxis and signal transduction, establishing that dapsone is an CXCL8 inhibitor which inhibits binding of CXCL8 to its receptors (Kast, p. 814, col. 2) The mechanism is an inherent property of the compound, not a step the applicant added. Inherent anticipation requires no recognition or appreciation in the prior art, so it is irrelevant whether Kast (or Lopez-Gomez) understood or merely hypothesized the mechanism involved in seizures (see MPEP § 2112.II). Applicant is invited to show that dapsone is not a CXCR1 or dual CXCR2 inhibitor as a reference appearing to be substantially identical is the basis of the rejection and evidence was presented to show inherency (see MPEP 2112.V).
Reiterated Rejection
Claim(s) 1, 6, 13-14, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024).
Kast is cited to show an inherent disclosure by Lopez-Gomez (MPEP § 2131.01).
Claim 1 is directed towards a method for the prevention or treatment of seizures or the prevention of the onset of epilepsy or the progression of an established epilepsy in an individual, the method comprising administering a CXCL8 inhibitor, a pharmaceutically acceptable salt thereof or a prodrug thereof to the individual.
Lopez-Gomez teaches a method for the treatment of drug-resistant partial onset seizures comprising administering to a patient in need thereof 100 mg of dapsone per day:
Dapsone has shown anti-convulsive properties in animal models of epilepsy. In the present study, we tested the safety and tolerability of dapsone as adjunctive therapy in adult patients with drug-resistant partial-onset seizures. Twenty-two adult patients with drug-resistant partial-onset seizures were included. After a 3-month baseline period, patients received dapsone 100 mg per day, for a 3-month evaluation period. Plasma concentrations of anti-epileptic drugs (AEDs) did not significantly change during the study. No alteration of mean clinical laboratory values was observed. The reported adverse events were: mild methemoglobinemia (50%), headache (31.8%), pale ness (27.3%) and somnolence (4.5%). Sixteen of 22 patients reduced their seizure frequency in more than 50% as a result of dapsone treatment. Three subjects remained sei zure-free during the entire dapsone treatment period. This open-label study of adjunctive dapsone therapy at 100 mg/ day suggests that dapsone is safe, and well-tolerated in adults with drug-resistant partial-onset seizures.
Lopez-Gomez, Abstract.
While Lopez-Gomez does not teach that dapsone is a CXCL8 (interleukin-8) inhibitor, this is a known inherent property of dapsone that is responsible for its anti-seizure effects. For example, Kast teaches that “dapsone is operating to inhibit interleukin-8 (IL-8) function in its antiseizure role.” (Kast, p. 813, col. 1-2).
Therefore, claim 1 is anticipated.
Claim 2 does not further limit the method of claim 1 because claim 1 and does not require that the drug is administered to a patient in need thereof and therefore is also anticipated for the reasons given in the rejection of claim 1.
Claim 6 is directed towards the method of claim 1, wherein said CXCL8 inhibitor is a CXCR1 receptor inhibitor or a dual CXCR1 and CXCR2 receptor inhibitor.
Kast teaches that IL-8 receptors are CXCR1 and CXCR2 (Kast, p. 813, col. 2) and that dapsone is has a blinding effect on IL-8 receptors (i.e. is a dual CXCR1/2 receptor inhibitor) (Kast, p. 814, col. 2).
Therefore, claim 6 is anticipated.
Claim 13 is directed towards the method of claim 1, wherein the CXCL8 inhibitor is administered in combination with at least another drug, wherein said at least another drug is administered simultaneously, sequentially or separately.
Lopez-Gomez teaches that the dapsone is administered concomitantly with at least two anti-epileptic drugs (AEDs) (Lopez-Gomez, p. 1064, col. 2).
Therefore, claim 13 is anticipated.
Claim 14 is directed towards the method of claim 13, wherein the at least another drug is selected from benzodiazepines and AEDs. As shown in the rejection of claim 13, Lopez-Gomez teaches that the at least another drug(s) are AEDs. Therefore, claim 14 is anticipated.
Claim 20 is directed towards the method of claim 14, wherein the at least another drug is selected from diazepam, lorazepam, phenytoin and valproic acid (VPA).
Lopez-Gomez teaches that the AEDs include phenytoin and VPA:
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Potential interactions of dapsone with other AEDs were assessed by comparison of serum AED levels before and after dapsone administration. From all AEDs only topiramate and lamotrigine were not measured. Modifications in the dosing of any concomitant AED were not needed. There was no evidence that dapsone at 100 mg/day, interacted with concomitantly administered AED’s.
Lopez-Gomez, p. 1065, col. 1.
Therefore, claim 20 is anticipated.
Claim Rejections – 35 USC § 103 – New Grounds of Rejection Necessitated by Amendment
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 7, 8, 11-15 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Brain Research Bulletin, 134 (2017), 91-98) (of record) in view of Vezzani et al. (Nature Reviews Neurology, Vol. 15, July 2019, 459-472) and Marsh et al. (Spinal Cord, Vol. 49, 2011, 337-344), and Villa et al. (Molecular Medicine, Vol. 13, 2007, 125-133) (of record).
Claim 1 is directed to a method for the prevention or treatment of seizures or the prevention of the onset of epilepsy or the progression of an established epilepsy in an individual in need thereof, the method comprising administering a CXCL8 inhibitor, a pharmaceutically acceptable salt thereof, or a prodrug thereof to the individual, wherein the CXCL8 inhibitor is a CXCR1 inhibitor or a dual CXCR1 and CXCR2 inhibitor.
Xu teaches a method for treating epilepsy comprising administering SB225002, an antagonist for CXCR2, the receptor for CXCL8 (interleukin 8) (i.e. SB225002 is a CXCL8 inhibitor):
C-X-C motif chemokine receptor 2 (CXCR2) is one of the most well characterized chemokine receptors and is a potential target for treating brain pathologies involving inflammatory processes, including epilepsy. However, the role of CXCR2 in epilepsy has not been investigated, and whether CXCR2 modulates seizure activity in temporal lobe epilepsy (TLE) remains unknown. In this study, we aimed to determine the potential role of CXCR2 in intractable TLE patients and in pilocarpine-induced epileptic mice. Here, through Western blotting and semi-quantitative immunohistochemistry, we detected that CXCR2 protein expression was up-regulated (by nearly 50%) in the temporal neocortex of TLE patients and in the hippocampus and adjacent temporal cortex of pilocarpine mice model. Double-label immunofluorescence and immunohistochemical analysis indicated that CXCR2 was expressed in neurons. To investigate the effect of the CXCR2 selective antagonist SB225002 on seizure activity, SB225002 was i.p. administered during the latency window of spontaneous recurrent seizures (SRSs). This treatment increased (by nearly 40%) the latency of SRSs and reduced (by nearly 50%) the frequency of SRSs during the chronic period of epilepsy. This study suggests that CXCR2 plays a critical role in modifying epileptic seizure activity and that CXCR2 blockade could be a potential molecular therapeutic target for epilepsy.
Xu, Abstract;
Clinical and experimental evidences indicate that inflammatory cytokines, including IL6 and IL8, are associated with the development of epilepsy (Youn et al., 2012, Pernhorst et al., 2013). IL6 and IL8 are secreted by brain cells and peripheral immune cells, and abnormal expression of these proteins has been detected in the cerebrospinal fluid and blood of epilepsy patients (Youn et al., 2012, Pernhorst et al., 2013, Ishikawa et al., 2015). Abnormal expression of IL6 and IL8 is indicative of active brain immuno-inflammatory responses in patients with epilepsy. IL6 and IL8 are the main ligands of CXCR2 (Manjavachi et al., 2010a, Manjavachi et al., 2010b, Semple et al., 2010), and the functions of IL6 and IL8 are mediated and regulated by CXCR2 signaling (Manjavachi et al., 2010a, Manjavachi et al., 2010b, Semple et al., 2010). Therefore, we assumed that CXCR2 might be related to TLE. The results of this study further support the association of CXCR2 with epilepsy.
Xu, col. 1, p. 97.
In the above passages, Xu teaches that CXCR2 protein expression is upregulated by nearly 50% in the temporal neocortex of TLE patients and in the hippocampus and adjacent temporal cortex of pilocarpine mice, that CXCR2 is expressed in neurons, and that i.p. administration of SB225002 during the latency window increased the latency of spontaneous recurrent seizures by nearly 40% and reduced their frequency by nearly 50% (Xu, Abstract). Xu further teaches that IL6 and IL8 are the primary ligands of CXCR2 and that their functions are mediated and regulated by CXCR2 signaling (Xu, col. 1, p. 97). Xu therefore teaches the claimed method but for the express requirement that the CXCL8 inhibitor block CXCR1, alone or together with CXCR2.
While Xu does not teach that the CXCL8 inhibitor is a CXCR1 inhibitor or dual CXCR1/CXCR2 inhibitor, one of ordinary skill in the art would have a reasonable expectation of success to substitute a dual CXCR1/CXCR2 inhibitor for a CXCR2 inhibitor because Vezzani supplies the express suggestion to use reparixin for this purpose, a well-known CXCR1/CXCR2 inhibitor with CNS efficacy and established neuroprotective effects.
Vezzani teaches that neuroinflammation is active during epileptogenesis, acute symptomatic seizures and chronic epilepsy:
Advances in our understanding of the mechanisms that govern neuroinflammation in epilepsy have raised some considerations for its importance in the clinical management of seizures. First, we know that this intrinsic brain response is active during epileptogenesis, acute symptomatic seizures and chronic epilepsy5,11. Evidence suggests that neuroinflammation during disease development can mediate the transition to pathology and that this process depends on inefficiency of anti- inflammatory mechanisms (Box 1).
Vezzani, col. 2, p. 460.
Vezzani further teaches that IL-8 is elevated in the blood of patients with drug-resistant focal epilepsy, that IL-8 mediator expression correlates with seizure frequency in epileptic brain tissue, and that blood IL-8 is increased in children with febrile status epilepticus (id., p. 467-68). On that basis, Vezzani teaches that the “observed changes in blood levels of specific cytokines associated with development of seizures also raise the possibility of using drugs to normalize levels of these molecules and their signalling to prevent epilepsy” and identifies three drugs which are candidates for this purpose: “anakinra (the human recombinant IL-1Ra), tocilizumab (a monoclonal anti body against the IL-6 receptor) and reparixin (an IL-8 receptor inhibitor)” (Id., col. 2, p. 468 (emphasis added)).
Marsh establishes that reparixin is a dual CXCR1 and CXCR2 inhibitor and teaches its administration, dosing, and CNS efficacy. Marsh teaches that “Reparixin (R(-)-2-(4-isobuthylphenyl)propionyl methanesulfonamide) is a novel small molecule antagonist that functions as an allosteric noncompetitive inhibitor of CXCR1 and CXCR2” involved in inflammation (Marsh, p. 337, col. 2). Marsh teaches administration of reparixin at 7.5 mg/kg and 15 mg/kg by tail vein injection, subcutaneous injection, and osmotic pump (id., p. 338). Marsh teaches that reparixin treatment decreased CINC-1 (rat IL8) in CNS tissue, reduced macrophage content and lesion area, increased neuron number in grey matter, and improved neurological outcomes (Id., Results, Discussion).
Marsh further teaches that autonomic dysreflexia is characterized by episodic hypertension and that the rapid increase in arterial pressure can lead to “arrhythmias, seizures and hemorrhagic strokes” (id., p. 338, col. 1). Marsh concludes that that acute treatment with 15 mg/kg Reparixin produces “a significant reduction in the severity of autonomic dysreflexia.” (Id., abstract, conclusion). This demonstrates that one of ordinary skill in the art would have reason to administer reparixin to patients in need thereof for the prevention of seizures, independent of the IL-8 rationale of Xu and Vezzani, because Marsh recognizes hypertensive episodes of autonomic dysreflexia cause seizures and demonstrates that reparixin treatment substantially reduces the severity of these episodes.
Moreover, as shown above, Xu demonstrates, in vivo, in both human epileptic tissue and in an animal model of epilepsy, that blockade of the IL-8 receptor, CXCR2, reduces seizure frequency and delays seizure onset. Vezzani teaches that reparixin, a dual CXCR1/ CXCR2 inhibitor, should have utility in the treatment and prevention of seizures because inflammatory pathways common to epilepsies of different etiology are appropriate targets for therapeutic intervention. Marsh demonstrates that systemically administered reparixin reaches CNS tissue, and thereby reduces rat IL-8, spares gray matter, preserves neurons and improves neurological outcomes. Because IL-8 signals through both CXCR1 and CXCR2, the additional blockade of CXCR1 by reparixin would have been expected to be at least effective as the CXCR2-selective blockade of Xu. Absolute predictability is not required, only a reasonable expectation of success (See MPEP § 2143.02).
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 2 recites: “The method of claim 1, wherein said seizures are acute symptomatic seizures.” As shown in the rejection of claim 1, while Xu does not teach acute asymptomatic seizures, one of ordinary skill in the art would have a reasonable expectation of success to treat or prevent acute asymptomatic seizures because Vezzani teaches that neuroinflammation is active during acute symptomatic seizures and may be prevented by administering an anti-inflammatory compound such as reparixin. Additionally, Marsh recognizes seizures arising acutely from the hypertensive episodes of autonomic dysreflexia following spinal cord injury, and that autonomic dysreflexia can be treated by administering reparixin. Therefore, claim 2 was prima facie obvious at the time of filing.
Claims 7-8, 11 and 15 are directed towards the method of claim 1, wherein the CXCL8 inhibitor is reparixin. The rejection of claim 1 is incorporated herein by reference. As such claims 7-8, 11 and 15 were prima facie obvious at the time of filing.
Claim 12 is directed towards the method of claim 1, wherein the CXCL8 inhibitor is comprised within a pharmaceutical formulation. Xu teaches dissolving the CXCL8 inhibitor in 1% DMSO, an inert pharmaceutically acceptable excipient for injection (Xu, p. 92, col. 2). Therefore, claim 12 was prima facie obvious at the time of filing.
Claims 13-14 and 20 are directed towards the method of claim 1, wherein the CXCL8 inhibitor is administered in combination with at least another drug, administered simultaneously, sequentially or separately, wherein said drug is a benzodiazepine or an antiepileptic drug (AED), and specifically diazepam. While Xu does not teach combination administration, one of ordinary skill in the art would have a reasonable expectation of success in administering the CXCL8 inhibitor in combination with a benzodiazepine or AED, specifically diazepam, because it is commonly known in the art to administer anti-inflammatory agents as add-on therapy to existing anti-epileptic treatment.
For example, see the teachings of Vezzani, who teaches that “[c]ontrolled clinical trials of drugs that target neuroinflammation as an add- on to existing therapy are warranted to test their preventive and disease- modifying effects in eligible patient populations” (Vezzani, p. 469-70) and specifically that “anakinra increased the efficacy of diazepam in reducing the duration of status epilepticus” (id., p. 467).
Therefore, claims 13-14 and 20 were prima facie obvious at the time of filing.
Claim(s) 1, 2, 7, 8, 11-16 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Brain Research Bulletin, 134 (2017), 91-98) (of record) in view of Vezzani et al. (Nature Reviews Neurology, Vol. 15, July 2019, 459-472) and Marsh et al. (Spinal Cord, Vol. 49, 2011, 337-344), and Villa et al. (Molecular Medicine, Vol. 13, 2007, 125-133) (of record), as applied to claims 1, 2, 7, 8, 11-15 and 20 above, and further in view of Villa et al. (Molecular Medicine, Vol. 13, 2007, p. 125-133).
The rejection of claims 1, 2, 7, 8, 11-15 and 20 above is incorporated herein by reference.
Claim 16 is directed towards the method of claim 15, wherein said CXCL8 inhibitor is the lysine salt of R-(-)-2- (4-isobutylphenyl)propionyl methansulfonamide.
While Xu does not teach that the CXCL8 inhibitor is the lysine salt of R-(-)-2- (4-isobutylphenyl)propionyl methansulfonamide, one of ordinary skill in the art would have a reasonable expectation of success to apply the lysine salt of R-(-)-2- (4-isobutylphenyl)propionyl methansulfonamide because this salt is commonly known in the art for the treatment of CNS disorders and neuroprotection. For example, Villa teaches a method of improving neurological function and inhibiting long term inflammation following transient cerebral ischemia in an individual comprising administering to the individual the lysine salt of reparixin:
Leukocyte infiltration is viewed as a pharmacological target in cerebral ischemia. We previously reported that reparixin, a CXCL8 receptor blocker that inhibits neutrophil infiltration, and related molecules can reduce infarct size in a rat model of transient middle cerebral artery occlusion (MCAO). The study aims were to compare the effects of reparixin in transient and permanent MCAO using varied treatment schedules and therapeutic windows to evaluate effects on long-term neurological deficits and late inflammatory response. Reparixin, administered for 1 to 3 days, 3.5 to 6 h after MCAO, ameliorates neurological function recovery and inhibits long-term inflammation. The infarct size reduction at 24 h, evaluated by TTC staining, is more pronounced in transient MCAO. MRI analysis identified a decrease in the progression of infarct size by reparixin that was more evident at 48 h in permanent MCAO, and was associated with a significantly improved recovery from long-term neurological deficits.
Villa, Abstract;
Reparixin (as L-lysine salt) was from Dompé pha.r.ma. s.p.a., L’Aquila, Italy. The drug was dissolved in saline and ad ministered as described in the text.
Villa, p. 126, col. 2.
Therefore, claim 16 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Nonstatutory Double Patenting – Previously Presented
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.
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The provisional rejection of claims 1, 2, 6-8, 11-16 and 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application no. 18/996,270 in view of Villa et al. (Molecular Medicine, Vol. 13, 2007, p. 125-133) and Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024) is maintained.
The provisional rejection of claims 1, 2, 6-8, 11-16 and 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application no. 18/996,171 in view of Villa et al. (Molecular Medicine, Vol. 13, 2007, p. 125-133) and Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024) is maintained.
Response to Arguments
The Applicant argues that the above rejections are cured by reciting “an individual in need thereof” (Remarks, p. 8). These arguments were fully considered but are not persuasive. The copending claims in the rejection above still read on the treatment or prevention of seizures, as explained in the prior office action.
Reiterated Rejection
Claim 1, 2, 6-8, 11-16 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application no. 18/996,270 in view of Villa et al. (Molecular Medicine, Vol. 13, 2007, p. 125-133) and Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024).
Although the claims at issue are not identical, they are not patentably distinct because the present claims read on administering a CXCL8 antagonist to an individual, as do the claims of copending Application No. 18/996,270, which are particularly towards a powder pharmaceutical composition comprising reparixin and related methods of use. Claim 17 of 18/996,270 is directed towards a method for the treatment or prevention of seizures in an individual, the method comprising administering a pharmaceutical composition comprising reparixin to the subject, similar to the instant claims. While 18/996,270 does not claim a lysine salt of reparixin, one of ordinary skill in the art would have a reasonable expectation of success to administer the lysine salt of reparixin because it is commonly known in the art for the treatment of neurological conditions. For example, see the teachings of Villa above in the 102 rejection of the claims, incorporated herein by reference.
While copending Application No. 18/996,270 does not claim a method wherein the CXCL8 inhibitor is administered in combination with an AED such as VPA (dependent claims 14 and 20), one of ordinary skill in the art would have a reasonable expectation of success to administer the CXCL8 inhibitor in combination with an AED such as VPA because it is commonly known in the art to administer CXCL8 inhibitors in combination with AEDs, particularly phenytoin and VPA. For example, see the teachings of Lopez-Gomez above, presented in the 102 rejection of the claims over Lopez-Gomez, incorporated herein by reference.
Claim 1, 2, 6-8, 11-16 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application no. 18/996,171 in view of Villa et al. (Molecular Medicine, Vol. 13, 2007, p. 125-133) and Lopez-Gomez et al. (Neurological Sciences, Vol. 32, p. 1063-1067, May 2011) as evidenced by Kast et al. (British Journal of Neurology, Vol. 26, Issue 6, p. 813-817, May 2012) (of record, IDS dated Jan. 2, 2024).
Although the claims at issue are not identical, they are not patentably distinct because the present claims read on administering a CXCL8 antagonist to an individual, as do the claims of copending Application No. 18/996,171, which are particularly towards a liquid suspension pharmaceutical composition comprising reparixin and related methods of use. Claim 17 of 18/996,171 is directed towards a method for the treatment or prevention of seizures in an individual, the method comprising administering a pharmaceutical composition comprising reparixin to the subject, similar to the instant claims. While 18/996,171 does not claim a lysine salt of reparixin, one of ordinary skill in the art would have a reasonable expectation of success to administer the lysine salt of reparixin because it is commonly known in the art for the treatment of neurological conditions. For example, see the teachings of Villa above in the 102 rejection of the claims, incorporated herein by reference.
While copending Application No. 18/996,171 does not claim a method wherein the CXCL8 inhibitor is administered in combination with an AED such as VPA (dependent claims 14 and 20), one of ordinary skill in the art would have a reasonable expectation of success to administer the CXCL8 inhibitor in combination with an AED such as VPA because it is commonly known in the art to administer CXCL8 inhibitors in combination with AEDs, particularly phenytoin and VPA. For example, see the teachings of Lopez-Gomez above, presented in the 102 rejection of the claims over Lopez-Gomez, incorporated herein by reference.
Conclusion
No claim is found to be allowable.
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 extension fee 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 date of this final action.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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