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 .
Priority
This application, filed 09/20/2023 Claims Priority from Provisional Application 63408739, filed 09/21/2022.
Status of Claims
Claims 1-28 are pending as of the response filed on 1/9/26.
Applicant’s election of the following species without traverse in the reply filed on 1/9/26 is acknowledged: N-acetylcysteine as the NOX inhibitor; zileuton as the 5-LOX inhibitor; and celecoxib as the COX-2 inhibitor. The elected species are encompassed by claims 1-7, 10-22, and 25-28.
Claims 8-9, and 23-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/9/26.
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.
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.
Information Disclosure Statement
The IDS filed on 9/22/23 has been considered.
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