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 .
Status of Claims
Claims 1-28 are pending as of the response and amendments filed on 7/6/26. Claims 8-9 and 23-24 are currently withdrawn from consideration as being directed to non-elected species. Claims 1-7, 10-22, and 25-28 are currently under examination.
Claims 1-7, 10-22, and 25-28 were previously rejected under 103 as being unpatentable over Bauer, US 20200352910, in view of Ratan, and Guo. Applicants’ reasons for traversal are summarized and addressed below.
Applicants have stated as reflected in independent amended claims 1 and 15, the methods of treatment as claimed are not directed merely to the coadministration of three known therapeutic agents, as the methods reflected in the pending claims require the inhibition of three distinct pathways-NOX, 5-LOX, and COX-2 to achieve specific therapeutic endpoints, including treatment of BBB dysfunction by reducing BBB leakage and treatment of recurrent seizures by reducing seizure-mediated capillary leakage. Applicants have stated it is well-settled the mere existence of known elements of a claim alone is not sufficient to support a conclusion of obviousness, and a reason for combining those elements must exist. Applicants have argued Bauer and Ratan are directed to different physiological problems and different therapeutic endpoints, as Bauer is directed to BBB dysfunction and reducing brain capillary leakage, while Ratan is instead directed to neuroprotection in the context of hemorrhagic stroke, and preventing cell death and reducing neuronal degeneration. Applicants have maintained one of ordinary skill in the art would readily appreciate neuronal survival is not the same as BBB repair, and neuroprotection after hemorrhagic injury is not the same endpoint as restoring BBB integrity.
Applicants’ arguments are not found persuasive. While it is acknowledged the pathways identified for treatment in Bauer and Ratan differ, both teach treatment of patients having seizures, and epilepsy. Bauer teaches treating BBB dysfunction by administering a 5-LOX and COX-2 inhibitor, which is required by the instant claims. Additionally, Bauer teaches further administering an additional anti-seizure agent. As NAC is taught by Ratan for treating seizures, it would have been prima facie obvious to have administered the combination of 5-LOX inhibitor, zileuton; COX-2 inhibitor, celecoxib; and NAC, with the reasonable expectation that the combination would have been therapeutically beneficial for treating seizures.
Applicants have argued the Office Action relies on Ratan for the proposition NAC would have been expected to improve the BBB-focused treatment regimen of Bauer, however Ratan doesn’t teach NAC repairs BBB dysfunction, reduces BBB leakage, reduces brain capillary leakage, or otherwise addresses vascular barrier endpoints addressed in Bauer or in the treatments of independent claims 1 and 15.
Applicants’ arguments are not persuasive. Bauer teaches treatment of BBB dysfunction by administering the combination of COX-2 and LOX-5 inhibitors, and further teaches administering an additional anti-seizure agent. Bauer doesn’t limit the additional anti-seizure drug to be administered in the combination, and as Ratan teaches NAC to have utility for treating seizures, it is maintained it would have been prima facie obvious to have administered the combination of COX-2 inhibitor, LOX-5 inhibitor, and NAC, with the reasonable expectation that seizures would have been effectively treated. Since Bauer doesn’t limit the additional anti-seizure drug, there is no evidence that the addition of NAC to the combination regimen of COX-2 and LOX-5 inhibition would have negatively impacted treatment of BBB dysfunction.
Applicants have argued Ratan’s experimental work doesn’t provide a reasonable expectation NAC would improve vascular leakage outcomes of that disclosed in Bauer or independent claims 1 and 15, and have referred to Ex. 3 of Ratan for support. Applicants have argued Ex. 3 of Ratan shows no significant difference in hematoma size and reduction in brain swelling with NAC treatment, and that in contrast one would have expected NAC administration in Ratan would have improved the vascular or tissue-injury metrics assessed in the ICH model. Applicants have further pointed to para [0115] of Ratan where it is taught the advantages of NAC treatment “could not be attributed to suppression of collagenase activity by NAC”. Applicants have argued as collagenase breaks down collagen, this result suggests NAC administration would not be advantageous in achieving the therapeutic goals of Bauer or those reflected in independent claims 1 and 15.
Applicants’ arguments are not persuasive. Although the points made by Applicants are acknowledged, the examiner notes that Bauer doesn’t rely on collagenase suppression as the mechanism for treating BBB dysfunction and reducing capillary leakage. Therefore, the evidence of Ratan of Ex. 3 doesn’t appear to suggest the addition of NAC to the combination of COX-2 and LOX-5 inhibitors would be detrimental.
Applicants have argued independent claims 1 and 15 require a NOX inhibitor that, as acknowledged by the examiner, is absent from Bauer. Applicants have argued while Guo is relied upon for the proposition NAC may function as a NOX inhibitor, neither Guo nor Ratan teach or suggest NOX inhibition should be added to Bauer’s regimen to address vascular leakage. Applicants have further argued Ratan doesn’t teach or suggest NAC should or could be used to inhibit NOX to reduce BBB leakage or seizure mediated capillary leakage, and instead teaches NAC in connection with preventing cell death or enhancing functional recovery by targeting nuclear ALOX5-derived reactive lipid species and products of COX-2 metabolism. Applicants have maintained Ratan doesn’t bridge the gap between Bauer’s BBB-focused 5-LOX and COX-2 inhibition regimen and the claimed three-way inhibition regimen.
Applicants’ arguments are not persuasive. As discussed previously, Bauer teaches administering the combination of a COX-2 inhibitor and a LOX-5 inhibitor for treating BBB dysfunction and reducing capillary leakage. Bauer further teaches the addition of another anti-seizure drug to the regimen, while Ratan teaches NAC has therapeutic utility for treating seizures. While Ratan doesn’t teach NAC to inhibit NOX, Guo was cited for this limitation. Since Bauer doesn’t limit the type of additional anti-seizure agent, it would have been prima facie obvious to have administered the combination of NAC, COX-2 inhibitor, and LOX-5 inhibitor for the treatment of seizures, and have had a reasonable expectation of success.
Applicants have stated the examiner relies on the zileuton and celecoxib treatment regimen disclosed in Bauer together with the NAC administration as disclosed in Ratan to arrive at the claimed subject matter, however, Ratan teaches administration of NAC with PGE2 provides synergy against hemin-induced toxicity in primary cortical neurons and permitted a 10-fold reduction in NAC concentration needed for cortical neuron protection. Applicants have argued Ratan teaches NAC is synergistic with PGE2, not with a 5-LOX and COX-2 inhibitor as required by the claims. Applicants have further argued the single instance in Ratan where celecoxib was administered was found to produce no therapeutic effect (para [0121-0123]), therefore Ratan doesn’t supply a motivation or a reasonable expectation of success for combining NAC with a treatment regimen involving COX-2 inhibition.
Applicants’ arguments are not found persuasive. As noted by Applicants earlier, the claimed regimen involves administration of the combination of NOX, COX-2, and LOX-5 inhibitors, not just NAC with celecoxib. Bauer clearly teaches administration of the combination of COX-2 and LOX-5 inhibitors, with celecoxib and zileuton exemplified, respectively, for treating BBB dysfunction and reducing capillary leakage in conditions such as epilepsy and seizures. While Ratan teaches synergy of NAC with PGE2, the teachings of Ratan don’t require this combination, as Ratan teaches NAC can be administered without PGE2. Moreover, Ratan teaches conditions to be treated with NAC include seizures, and Bauer teaches the addition of broadly any anti-seizure drug. Therefore, one of ordinary skill in the art would have arrived at the claimed method of treatment in view of the combined teachings of Bauer, Ratan, and Guo. Lastly, it is noted that with the exception of claims 5-7 and 20-22, the claims don’t require celecoxib as the COX-2 inhibitor in the treatment regimen. For these reasons, the 103 rejection of record is reiterated, with slight modification to address any amendments.
Claims 1-6, 10-11, 13-21, 25-26, and 28 were previously rejected for nonstatutory double patenting over claims 1-5, 10-19, and 24 of US 11433052 in view of Ratan and Guo. Applicants have argued as acknowledged by the examiner, the claims of US 11433052 don’t recite further administering a NOX inhibitor. Applicants have argued the previous discussion addressing the 103 rejections in the Office Action establishes the subject matter of the instant claims is patentably distinct from the claims of US 11433052.
Applicants’ arguments are not persuasive, for the reasons discussed above in response to the arguments presented over the 103 rejection. The nonstatutory double patenting rejection is thus maintained and reiterated below.
Claims 1-7, 10-22, and 25-28 were examined and are rejected.
Claim Rejections-35 USC § 103
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) 1-7, 10-22, and 25-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bauer et. al., US 20200352910 A1, publ. 11/12/2020 in view of Ratan et. al., WO 2018204393 A1, publ. 11/8/2018, and Guo et. al., Am. J. Physiol. Heart Circ. Physiol., vol. 292, pp. H1728-H1736, publ. 2007.
Bauer teaches methods of reducing blood brain barrier dysfunction by inhibiting 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2), which further results in reducing both brain capillary leakage and vascular inflammation (title & abstract; para [0003]). Bauer teaches blood brain barrier (BBB) dysfunction to induce vessel deformation, vascular leakage, vascular inflammation, altered clearance, changes to tight junction proteins, changes to metabolic enzymes, changes to signaling molecules, and changes in leukocyte recruitment (para [0004]). Bauer further teaches BBB dysfunction is associated with various CNS conditions such as epilepsy, seizures, Alzheimer’s, Parkinson’s, stroke, brain trauma, as well as peripheral and CNS inflammation (para [0005]). In particular, BBB dysfunction is recognized as both a cause and consequence of seizures in epilepsy (para [0006]). Bauer teaches administering a composition comprising an effective amount of a 5-LOX inhibitor and a COX-2 inhibitor to reduce BBB dysfunction, reduce brain capillary leakage, and treat any of the conditions recited above (para [0010-0012], [0030-0032]). Bauer teaches zileuton as a 5-LOX inhibitor (para [0033]), and celecoxib as a COX-2 inhibitor (para [0034]). The combination of zileuton as the 5-LOX inhibitor and celecoxib as the COX-2 inhibitor is exemplified (para [0069]; p. 5, claims 1, 3, and 4), wherein the dose of zileuton administered is 5 mg/kg and the dose of celecoxib is 10 mg/kg (para [0069]). Further administration of an anti-seizure drug with the combination of COX-2 inhibitor and 5-LOX inhibitor is taught (para [0014]). Administration of zileuton and celecoxib for a period of 10 days, every 12 hours is exemplified (para [0072]). Identification of a subject having or at risk of having BBB dysfunction, epileptogenesis, or controlling seizures is also taught (para [0012-0014], [0039], [0042]). Treatment of a subject having epileptogenesis following brain trauma or a CNS condition is further taught, with CNS conditions associated with such epileptogenesis taught to include stroke, MS, Alzheimer’s, and Parkinson’s (para [0042]).
Bauer doesn’t explicitly teach or suggest further administration of a NOX inhibitor, such as N-acetylcysteine.
Ratan teaches the use of N-acetylcysteine, taught as a 5-lipoxygenase activating protein (FLAP) inhibitor, for treating CNS disorders, optionally in combination with an additional therapeutic (title & abstract; para [048]). Ratan teaches administration of N-acetylcysteine (“NAC”) for preventing cell death and enhancement of functional recovery, and exertion of neuroprotection (para [054]). Ratan acknowledges NAC inhibits more than one target, e.g., inhibition of ALOX-5 and products of COX-2 metabolism (para [055]). Ratan teaches administration of NAC to treat a neurological disorder characterized by brain dysfunction, e.g., loss of memory as well as seizure disorders and epilepsy, in addition to stroke (para [050-053]). Single as well as multi-doses are taught (para [073]). Ratan teaches a therapeutically effective dose to range from about 1 mg/kg up to about 500 mg/kg (para [0001]).
NAC is an inhibitor of NADPH oxidase (NOX), as taught by Guo (title & abstract; p. H1730, right col., 2nd para; p. 1731, right col., 3rd para).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have treated BBB dysfunction in a subject by administering the combination of the NOX inhibitor, NAC; the 5-LOX inhibitor, zileuton; and the COX-2 inhibitor, celecoxib, in consideration of the combined teachings of Bauer, Ratan, and Guo. Bauer teaches the combination of the 5-LOX inhibitor, zileuton; and the COX-2 inhibitor, celecoxib for treating BBB dysfunction. Additionally, Bauer teaches this combination for treating CNS conditions and seizures, as well as epileptogenesis due to CNS conditions such as Alzheimer’s or stroke, at the doses for zileuton and celecoxib recited by instant claim 7. Although Bauer doesn’t explicitly teach or suggest further administering a NOX inhibitor such as NAC, Ratan teaches administration of NAC to treat CNS disorder such as epilepsy and stroke, and that NAC enhances functional recovery in these disorders. Ratan further teaches NAC can be combined with other therapeutic agents for treatment, while Guo acknowledges NAC to have activity as a NOX inhibitor. As such, one of ordinary skill in the art would have been motivated to have further administered NAC in combination with zileuton and celecoxib to treat BBB dysfunction, and treat recurrent seizures, as Ratan teaches NAC to have therapeutic effects in treating disorders taught to be associated with BBB dysfunction, such as stroke and epilepsy. One of ordinary skill in the art would have had a reasonable expectation that the addition of NAC to the combination of zileuton and celecoxib would have further enhanced functional treatment of disorders associated with BBB dysfunction, such as epilepsy and stroke, as well as epilepsy due to Alzheimer’s and recurrent seizures. Regarding instant claim 15, “to reduce seizure-mediated capillary leakage”, Bauer teaches administration of the combination of COX-2 inhibitor, LOX-5 inhibitor, and additional anti-seizure drug to treat BBB dysfunction and reduce capillary leakage, as well as treat epilepsy and seizures. Therefore, it would have been prima facie obvious to have administered the combination of the COX-2 inhibitor, celecoxib; the LOX-5 inhibitor, zileuton; and the NOX inhibitor, NAC, to reduce capillary leakage mediated by a seizure.
Ratan teaches the dose of NAC to range from about 1 mg/kg up to about 500 mg/kg, thereby one of ordinary skill in the art would have arrived at the claimed dose of about 100 mg/kg of NAC recited by instant claims 7 and 22.
Bauer teaches administration of zileuton and celecoxib every 12 hours, e.g., twice daily for more than two days, i.e., 10 days. As NAC is similarly taught to be beneficial for treating CNS disorders, it would have been prima facie obvious to have further administered the combination of three agents, NAC, zileuton, and celecoxib in the same regimen, e.g., every 12 hours for 10 days.
Ratan teaches NAC can be administered as a single dosage in a composition or via multiple dosages. Since Ratan also teaches NAC in a combination therapy, it would have been prima facie obvious to have administered the combination of NAC, zileuton, and celecoxib in a single dosage form as recited by instant claims 10 and 25, or as a multi-dosage form as recited by instant claims 11 and 26.
Claim Rejections-Nonstatutory 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.
Claims 1-6, 10-11, 13-21, 25-26, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10-19, and 24 of U.S. Patent No. 11433052 B2 in view of Ratan et. al., WO 2018204393 A1, publ. 11/8/2018, and Guo et. al., Am. J. Physiol. Heart Circ. Physiol., vol. 292, pp. H1728-H1736, publ. 2007. The instant and patented claims are similar in that they are drawn to reducing brain capillary leakage in a subject having seizure, epilepsy, Alzheimer’s disease, or stroke by administering an effective amount of a combination of a 5-LOX inhibitor and a COX-2 inhibitor. Additionally, both sets of claims further recite zileuton as the 5-LOX inhibitor and celecoxib as the COX-2 inhibitor (see instant claims 4-5 & patented claim 5); and further administering an anti-seizure drug (instant claim 15 & patented claim 24). The difference between the claims is that the patented claims don’t recite further administering a NOX inhibitor such as NAC. However, such a modification to the patented claims would have been prima facie obvious in view of Ratan and Guo. Ratan teaches the use of N-acetylcysteine, taught as a 5-lipoxygenase activating protein (FLAP) inhibitor, for treating CNS disorders, optionally in combination with an additional therapeutic (title & abstract; para [048]). Ratan teaches administration of N-acetylcysteine (“NAC”) for preventing cell death and enhancement of functional recovery, and exertion of neuroprotection (para [054]). Ratan acknowledges NAC inhibits more than one target, e.g., inhibition of ALOX-5 and products of COX-2 metabolism (para [055]). Ratan teaches administration of NAC to treat a neurological disorder characterized by brain dysfunction, e.g., loss of memory as well as seizure disorders and epilepsy, in addition to stroke (para [050-053]). Single as well as multi-doses are taught (para [073]). Ratan teaches a therapeutically effective dose to range from about 1 mg/kg up to about 500 mg/kg (para [0001]). NAC is an inhibitor of NADPH oxidase (NOX), as taught by Guo (title & abstract; p. H1730, right col., 2nd para; p. 1731, right col., 3rd para). As such, it would have been prima facie obvious to have added administration of the NOX inhibitor, NAC, to the method of the patented claims, since Ratan teaches NAC to treat disorders such as stroke, seizure, and epilepsy, which are treated by the patented claims, and as Ratan teaches NAC can be combined with other therapeutic agents. The instant and patented claims are therefore obvious variants of each other and are not patentably distinct.
Regarding instant claim 15, “to reduce seizure-mediated capillary leakage”, Bauer teaches administration of the combination of COX-2 inhibitor, LOX-5 inhibitor, and additional anti-seizure drug to treat BBB dysfunction and reduce capillary leakage, as well as treat epilepsy and seizures. Therefore, it would have been prima facie obvious to have administered the combination of the COX-2 inhibitor, celecoxib; the LOX-5 inhibitor, zileuton; and the NOX inhibitor, NAC, to reduce capillary leakage mediated by a seizure.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH PIHONAK whose telephone number is (571)270-7710. The examiner can normally be reached Monday-Friday 9:00-5:30 EST.
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SARAH . PIHONAK
Primary Examiner
Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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