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 .
Priority
Priority to US 63/733,616, filed 12/13/2024, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/15/2026 was filed after the mailing date of the non-final office action on 2/10/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-20, filed 12/12/2025, are pending. Claims 1-20 are under examination.
Claim Interpretation
The use of the term “disease” in claim 1 shall be interpreted to include conditions consistent with the usage in paragraphs [0061] and [0062] of the specification. It is possible that “disorder” was intended, but these two terms appear to have distinct meanings in this application.
Claim Rejections - 35 USC § 112
Claim 12 was previously rejected 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.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 6, para. 2, filed 6/10/2026, with respect to claim 12 have been fully considered and are persuasive. The rejection of claim 12 has been withdrawn.
Claim Rejections - 35 USC § 112
Claims 1-20 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 6, para. 4, filed 6/10/2026, with respect to claim 12 have been fully considered and are persuasive. The rejection of claim 12 has been withdrawn.
Maintained Claim Rejections - 35 USC § 112
Claims 1-14 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for N-acetyl cysteine, L-cysteine, NAC amide, and GSH for treating nervous system diseases, does not reasonably provide enablement for any NAC derivative, any NAC metabolite, any NAC congener, or any NAC dendrimer for treating nervous system diseases.
Response to Arguments
The enablement rejection of claims 1-14 were not addressed in the Applicant Reply, filed 6/10/2026.
Regardless, Examiner has reconsidered the enablement rejection. The rejection of claims 1-14 has been withdrawn.
New Claim Rejections - 35 USC § 112
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.
Claim 2 is rejected 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.
Regarding claim 2, claim 2 recites the limitations NACA, NAC derivative, NAC metabolite, D-NAC in line 2. There is insufficient antecedent basis for this limitation in the claim. Specifically, these elements were canceled in claim 1.
Maintained 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.
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.
Claims 1, 2, 7, and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)).
Regarding claim 1, amended claim 1 recites a method of treating a central nervous system disease or a central nervous system disorder in an individual in need thereof, the method comprising: intranasally administering one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof to an individual; and co-administering a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof to the individual.
Greene et al. discloses the a method of treating a brain disorder utilizing NAC that is intranasally administered in claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, to the brain from the nose, and wherein the subject is not substantially systemically exposed to the NAC, or the congener thereof, upon the intranasal administration.”
Greene does not disclose the case wherein a GLP-1 agonist is co-administered to the individual in need. However, Yang et al. discloses that GLP-1 agonists have efficacy against Parkinson’s Disease (a central nervous system disease): “The evidence presented here clearly demonstrates that growth factors such as GLP-1 and GIP that can cross the BBB have clear neuroprotective properties in the brain. First clinical trials testing GLP-1R agonists in patients with PD are a clear proof of concept that this strategy is viable and that the preclinical results translate into the clinic. Novel dual GLP-1/GIP receptor agonists that can cross the BBB at an enhanced rate show superior neuroprotective effects in animal models of PD and are likely to do the same in clinical trials.” (Yang et al., page 453, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Greene with the usage of GLP-1 agonists disclosed by Yang to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine NAC and GLP-1 agonists in order to achieve an additive or perhaps synergistic effect. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
For similar reasons, a person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 1 is obvious over Greene et al. in view of Yang et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the GLP-1 agonist and NAC are administered at the same time.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 2 is obvious over Greene et al. in view of Yang et al. and rejected.
Regarding claim 7, claim 1 is obvious as described above. Yang et al. discloses the usage of Liraglutide: “Three clinical trials testing two different GLP-1R agonists in PD patients have shown impressive neuroprotective effects, with a phase II trial demonstrating disease-modifying effects of exendin-4 [76,248], and a recent phase II trial showing good neuroprotective effects on everyday motor activities and quality of life with liraglutide.” (Yang et al., page 454, col. 1, para. 2).
Consequently, claim 7 is obvious over Greene et al. in view of Yang et al. and rejected.
Regarding claim 12, claim 1 is obvious as described above. Yang discloses: “Building on this, three clinical studies have reported impressive effects in patients with PD, testing exendin-4 (Exenatide, Bydureon) or liraglutide (Victoza, Saxenda). Glucose-dependent insulinotropic peptide (GIP) is another peptide hormone that has shown good effects in animal models of PD.” (Yang et al., page 445, Abstract). Parkinson’s Disease is a neurodegenerative disease, therefore, claim 12 is obvious over Greene et al. in view of Yang et al. and rejected.
Regarding claim 13, claim 12 is obvious as described above. Yang discloses: “Building on this, three clinical studies have reported impressive effects in patients with PD, testing exendin-4 (Exenatide, Bydureon) or liraglutide (Victoza, Saxenda). Glucose-dependent insulinotropic peptide (GIP) is another peptide hormone that has shown good effects in animal models of PD.” (Yang et al., page 445, Abstract). Parkinson’s Disease is in the list recited by claim 13, therefore, claim 13 is obvious over Greene et al. in view of Yang et al. and rejected.
Regarding claim 14, claim 12 is obvious as described above. Yang discloses: “Building on this, three clinical studies have reported impressive effects in patients with PD, testing exendin-4 (Exenatide, Bydureon) or liraglutide (Victoza, Saxenda). Glucose-dependent insulinotropic peptide (GIP) is another peptide hormone that has shown good effects in animal models of PD.” (Yang et al., page 445, Abstract). Therefore, claim 14 is obvious over Greene et al. in view of Yang et al. and rejected.
Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 2 above, and further in view of Meredith, et al. The AAPS journal 17.4: 780-787 (2015)).
Regarding claim 3, claim 2 is obvious as described above. The method of Greene and Yang does not specifically disclose intranasal administration of the GLP-1 agonist. However, Meredith et al. discloses such administration: “In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP.” (Meredith et al., page 780, Abstract).
A person of ordinary skill in the art would be motivated to combine the method of Green and Yang with the deliver method disclosed by Meredith to achieve the benefits disclosed by Meredith: “First, intranasal delivery of molecules provides a direct access to the CNS, without having to negotiate the BBB. Second, exposure of peripheral organs and tissues to the substrate is usually greatly reduced as most substances have a limited entry into the circulation, and therefore, systemic side effects are greatly reduced. Third, because substances do not have to reach the CNS through the circulation, those substances that have a rapid degradation in blood are not at a major disadvantage as they are when given by intravenous administration). Fourth, there are indications that the intranasal route may allow biologicals to be targeted to specific regions of the brain). In addition, from a clinical therapeutic standpoint, it is well recognized that intranasal administration of drugs is non-invasive.” (Meredith et al., page 780, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Meredith discloses that this has already been done with Exendin: “Intranasal administration of exendin was four times more effective in delivery to the olfactory bulb, compared to intravenous administration). The delivery was quick, with a rapid uptake of exendin 1 min after intranasal administration and was enhanced 60% by the use of cyclodextrins.” (Meredith et al., page 783, col. 1, para. 4).
Consequently, claim 3 is obvious over Greene et al. in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites the case wherein the GLP-1 agonist and NAC are mixed together. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 4 is obvious over Greene et al. in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012)).
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the GLP-1 agonist is administered via an oral or parenteral route. Greene and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
A person of ordinary skill in the art would be motivated to use the parenteral administration of Dong with the method of Greene and Yang because Kwarta et al. discloses the following advantages: “Advantages [1] Drugs that have poor absorption in the GIT and drugs like insulin which are unstable in the GIT track can easily be administered by this route. [2] It is one route that allows control over the dose to be administered. [3] It is the most reliable route in case of emergencies as the administration of the drug is faster leading to a more efficient action. [4] No side effects of gastric irritation and vomiting occur. [5] The limitation of having the medicine on an empty or a full stomach is avoided as digestive juices or food doesn’t pose any interference. [6] Interference by liver metabolism is avoided. [7] Unconscious, uncooperative and vomiting patients can be easily dealt with.” (Kwarta et al., page 416, para. 4).
A person of ordinary skill in the art would have a reasonable expectation of success because Dong discloses the parenteral delivery of Liraglutide as described above.
Consequently, claim 5 is obvious over Greene et al. in view of Yang et al. as applied to claim 1, further in view of Dong et al. and Kwarta et al. and rejected.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012)) as applied to claim 5 above, and further in view of Knudsen et al. (Knudsen, et al. Frontiers in endocrinology 10: 155 (2019)).
Regarding claim 6, claim 5 is obvious as described above. Claim 6 further recites the case wherein the GLP-1 agonist is modified to transit the blood brain barrier. Dong discloses above that Liraglutide crosses the blood brain barrier and Kundsen describes how Liraglutide is a modified molecule: “Following the selection of liraglutide as the first GLP-1-based analog suitable for OD dosing, further analysis of its structural activity was published.” (Knudsen, et al., page 4, col. 2, para. 2).
Consequently, claim 6 is obvious over Greene et al. in view of Yang et al. and Dong et al. as applied to claim 5, further in view of Knudsen et al. and rejected.
Claims 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 8, claim 1 is obvious as described above. Claim 8 further recites the usage of an additional therapeutic. Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the method of Greene and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 8 is obvious over Greene et al. in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Regarding claim 9, claim 8 is obvious as described above. Clark discloses the usage of probenecid in conjunction with NAC: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI.” (Clark, et al., page 1535, col.1, para. 1).
Consequently, claim 9 is obvious over Greene et al. in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 10, claim 1 is obvious as described above. Claim 10 further recites the administration of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients to the individual.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the method of Greene and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 10 is obvious over Greene et al. in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Adriaenssens et al. (Adriaenssens, et al. Peptides 125 :170194 (2020)).
Regarding claim 11, claim 1 is obvious as described above. The method of Greene and Yang does not specifically disclose the usage of a glucose-dependent insulinotropic polypeptide.
However, Adriaenssens et al. discloses that glucose-dependent insulinotropic polypeptides possess neuroprotective benefits: “Additionally, GIP-based therapeutics have demonstrated promising neuroprotective properties. Together these observations identify an important central component of the GIP/GIPR signaling axis, and have triggered a resurgence of research interest into the central actions of GIP.” (Adriaenssens et al., page 1, Abstract.). Adriaenssens discloses that GIP is a potentially important therapeutic molecule: “Due to innovative pharmacology, the incretin field is starting to reevaluate the GIPR signaling axis, seeing GIP now as an important therapeutic target rather than simply the sister incretin to GLP-1. In particular it has become increasingly apparent that GIPR and its downstream signaling is a critical modulator of energy balance and cognitive health, roles partially mediated by GIPR present in the CNS.” (Adriaenssens, et al., page 4, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Greene and Yang with the GIP as disclosed by Adriaenssens.
MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Therefore, a person of ordinary skill in the art would have been motivated to combine GIP as disclosed by Adrianenssens with the method of Greene and Yang to be useful for the same purpose, that being treatment of central nervous disease through neuroprotective pathways. A person of ordinary skill in the art would have a reasonable expectation of success because the GIP and the method of Greene and Yang have the same purpose.
Consequently, claim 11 is obvious over Greene et al. in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claims 15, 16, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)).
Regarding claim 15, claim 15 recites a kit comprising: an intranasal delivery system; and a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and wherein the intranasal delivery system comprises a formulation container and a nozzle; and wherein the formulation container comprises one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004).”
The combination of NAC and GLP-1 agonists is obvious as described above for claim 1.
Claim 19 of Greene et al. further discloses: “The method of claim 1, wherein the dose is administered using a nasal pump.”
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by Greene claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, to the brain from the nose, and wherein the subject is not substantially systemically exposed to the NAC, or the congener thereof, upon the intranasal administration.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by Greene and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and because Greene et al. recites such a device in claim 19.
Consequently, claim 15 is obvious over Greene et al. in view of Yang et al. and Wong et al. and rejected.
Regarding claim 16, claim 15 is obvious as described above. Claim 16 further recites the case wherein the formulation container also comprises the GLP-1 agonist.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time by having them mixed in the formulation container. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 16 is obvious over Greene et al. in view of Yang et al. and Wong et al. and rejected.
Regarding claim 20, claim 20 recites an intranasal delivery system comprising: one or more formulation containers each having a nozzle; and wherein the one or more formulation containers comprise: a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
Claim 19 of Greene et al. further discloses: “The method of claim 1, wherein the dose is administered using a nasal pump.”
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by Greene claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, to the brain from the nose, and wherein the subject is not substantially systemically exposed to the NAC, or the congener thereof, upon the intranasal administration.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by Greene and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and because Green et al. discloses such a device in claim 19.
Consequently, claim 20 is obvious over Greene et al. in view of Yang et al. and Wong et al. and rejected.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)).
Regarding claim 17, claim 15 is obvious as described above. Claim 17 further recites the case wherein the GLP-1rA or congener thereof comprises a tablet, suppository, a pill, a capsule, a powders, a liquid, a suspension, a lotion, a cream, or a gel. Greene and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a GLP-1 agonist in the form of a liquid so said agonist can be administered via intraperitoneal injections as described by Dong. A person of ordinary skill in the art would use liquid form so the GLP-1 agonist can be injected and have a reasonable expectation of success because liquids are commonly injected as drugs.
Consequently, claim 17 is obvious over Greene et al. in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Dong et al. and rejected.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 18, claim 15 is obvious as described above. Claim 18 further recites the case where the kit has of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the kit of Greene, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 18 is obvious over Greene et al. in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Chaudhari et al. and rejected.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Greene et al., US 2021/0186911, published 6/24/2021 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 19, claim 15 is obvious as described above. Claim 19 further recites an additional therapeutic agent, the additional therapeutic agent comprising a 5-lipogenase-activating protein (FLAP) inhibitor, a Cathepsin B inhibitor, poly(ADP-ribose) polymerase (PARP) inhibitor, probenecid, phenserine, or a dopaminergic agent.
Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the kit of Greene, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 19 is obvious over Greene et al. in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Clark et al. and rejected.
Response to Arguments
Applicant's arguments filed 6/10/2026 have been fully considered but they are not persuasive.
Regarding claim 1, Applicant asserts: “More importantly, Greene and Yang teach away from their claimed combination. As acknowledged in the specification, both NAC and GLP-lrA exhibit superficially similar general effects in improving both cellular oxidative stress and mitochondrial function, which would have suggested to a skilled artisan that their mechanisms of action were overlapping and therefore redundant. A person of ordinary skill in the art, reviewing the prior art at the time of filing, would have had no reason to expect that combining these two agents - each of which had individually shown only partial and inconsistent neuroprotective efficacy - would yield anything more than redundant effects. Indeed, the specification notes that neither agent alone has shown consistent evidence of complete clinical or preclinical neuroprotection, and that oral NAC therapy has failed to show clinical evidence of efficacy in PD patients. Under these circumstances, a skilled artisan would not have been motivated to combine two agents with individually incomplete efficacy profiles absent some teaching or suggestion that their combination would produce a result greater than either agent alone.” (Applicant Reply, page 7, para. 5).
Redundancy is actually motivation to combine two references, not a teaching away.
MPEP2144.06(I) states: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
In contrast, a teaching away requires actual disparagement of the combination. Even inferior performance is not considered a proper teaching away as described by MPEP 2145(X)(D)(1): “A prior art reference that "teaches away" from the claimed invention is a significant factor to be considered in determining obviousness. However, "the nature of the teaching is highly relevant and must be weighed in substance. A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (Claims were directed to an epoxy resin based printed circuit material. A prior art reference disclosed a polyester-imide resin based printed circuit material, and taught that although epoxy resin based materials have acceptable stability and some degree of flexibility, they are inferior to polyester-imide resin based materials. The court held the claims would have been obvious over the prior art because the reference taught epoxy resin based material was useful for the inventor’s purpose, applicant did not distinguish the claimed epoxy from the prior art epoxy, and applicant asserted no discovery beyond what was known to the art.).”
Therefore, this argument is not persuasive.
Applicant also asserts a theory of unexpected results: “Critically, the present application provides experimental evidence of unexpected synergy. As described in the specification and depicted in FIGS. 7A-7C, at high oxidative stress conditions (20 pM Erastin), neither 0.1 pM Exendin-4 nor 1.6 mM NAC alone provided oxidative stress protection, but together they demonstrably improved cell viability, thereby demonstrating unambiguous evidence of anti- oxidative stress synergy of NAC and a GLP-lrA in combination. This synergistic result demonstrates that the combination is non-obvious. The Examiner's assertion that a person of ordinary skill in the art would have been motivated to combine these agents to achieve "an additive or perhaps synergistic effect" is conclusory and unsupported by any evidence in the cited references. None of the cited references - Greene, Yang, or any of the secondary references - teach, suggest, or provide any data indicating that NAC and GLP-lrA would exhibit synergy when combined. The Examiner's speculation that a skilled artisan would have expected synergy is impermissible hindsight reasoning informed by the present disclosure.” (Applicant Reply, page 8, para. 2).
Examiner rebuts that nothing is unexpected about combining two materials for the same purpose and achieving a degree of efficacy greater than the two materials separately. It would be more unexpected if the efficacy became worse, because that would indicate unexpected anti-synergy.
MPEP 2145(II) states: “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) "would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art." 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991) (Appellant argued that the presence of DEHP as the plasticizer in a blood collection bag unexpectedly suppressed hemolysis and therefore rebutted any prima facie showing of obviousness. However, the closest prior art utilizing a DEHP plasticized blood collection bag inherently achieved same result, although this fact was unknown in the prior art.).”
It is not even clear if these properties would even be considered latent, when both materials are known in the prior art to be used for the same purpose. Therefore, this argument is not persuasive.
Regarding the assertion of hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Regarding the assertion of no reasonable expectation of success, anti-synergy was addressed because that is one standard for a proper teaching away. Because no such anti-synergy was taught by the prior art, MPEP2144.06(I) is again relevant: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
A person of ordinary skill in the art, absent teachings of anti-synergy or the like, would reasonably have a reasonable expectation of success employing two materials together for the same purpose for which they are used separately.
Therefore, this argument is not persuasive.
Regarding the rejections of claims 2-9, these rejections are maintained because the rejection of claim 1 is maintained above and the additional references do not need to remedy and deficiencies.
Regarding claim 10, Applicant asserts: “Chaudhari discloses pharmaceutical excipients. There is no disclosure in Chaudhari that the disclosed excipients would even be suitable for intranasal administrations and, as such, one skilled in the art would not look to combine Chaudhari with Greene and Yang. Accordingly, claim 10 should be allowable for at least its dependency to claim 1. Reconsideration is respectfully requested.”
Chaudhari discloses the importance of excipients, even describing them as indispensable: “Excipients can be considered as indispensable component of medicinal products and in most of the formulations they are present in greater proportion with regards to active pharmaceutical ingredient, as it forms the bulk of the formulation it is always necessary to select an excipient which satisfies the ideal properties for a particular excipient.” (Chaudhari et al., page 22, col. 1, para. 4).
No teaching away regarding nasal administration is disclosed and given the ubiquity of excipients as described by Chaudhari, a person of ordinary skill in the art would have a reasonable expectation of success of combining a nasal drug with a drug excipient.
Consequently, this argument is not persuasive.
The rejection of the remaining claims 11-20 is maintained because no deficiencies exist to be remedied by the cited prior art.
Maintained Rejections - 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, 2, 7, and 12-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,963,939, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)).
Regarding claim 1, amended claim 1 recites a method of treating a central nervous system disease or a central nervous system disorder in an individual in need thereof, the method comprising: intranasally administering one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof to an individual; and co-administering a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof to the individual.
The ’939 patent discloses a method of treating a Parkinson’s disease (a brain disorder) utilizing NAC that is intranasally administered in claim 1: “A method of treating a Parkinson's disease, the method comprising intranasally administering to a subject in need thereof about 100 mg to about 350 mg of N-acetyl cysteine (NAC) as an intranasal spray, wherein the administering is to a brain of the subject through a nasal cavity of the subject.”
The ’939 patent does not disclose the case wherein a GLP-1 agonist is co-administered to the individual in need. However, Yang et al. discloses that GLP-1 agonists have efficacy against Parkinson’s Disease (a central nervous system disease): “The evidence presented here clearly demonstrates that growth factors such as GLP-1 and GIP that can cross the BBB have clear neuroprotective properties in the brain. First clinical trials testing GLP-1R agonists in patients with PD are a clear proof of concept that this strategy is viable and that the preclinical results translate into the clinic. Novel dual GLP-1/GIP receptor agonists that can cross the BBB at an enhanced rate show superior neuroprotective effects in animal models of PD and are likely to do the same in clinical trials.” (Yang et al., page 453, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘939 patent with the usage of GLP-1 agonists disclosed by Yang to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine NAC and GLP-1 agonists in order to achieve an additive or perhaps synergistic effect. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
For similar reasons, a person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 1 is obvious over the ‘939 patent in view of Yang et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the GLP-1 agonist and NAC are administered at the same time.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 2 is obvious over the ‘939 patent in view of Yang et al. and rejected.
Regarding claim 7, claim 1 is obvious as described above. Yang et al. discloses the usage of Liraglutide: “Three clinical trials testing two different GLP-1R agonists in PD patients have shown impressive neuroprotective effects, with a phase II trial demonstrating disease-modifying effects of exendin-4 [76,248], and a recent phase II trial showing good neuroprotective effects on everyday motor activities and quality of life with liraglutide.” (Yang et al., page 454, col. 1, para. 2).
Consequently, claim 7 is obvious over the ‘939 patent in view of Yang et al. and rejected.
Regarding claim 12, claim 1 is obvious as described above. The ‘939 patent discloses in claim 1: “A method of treating a Parkinson's disease, the method comprising intranasally administering to a subject in need thereof about 100 mg to about 350 mg of N-acetyl cysteine (NAC) as an intranasal spray, wherein the administering is to a brain of the subject through a nasal cavity of the subject.” Parkinson’s Disease is a neurodegenerative disease, therefore, claim 12 is obvious over the ‘939 patent in view of Yang et al. and rejected.
Regarding claim 13, claim 12 is obvious as described above. The ‘939 patent discloses in claim 1: “A method of treating a Parkinson's disease, the method comprising intranasally administering to a subject in need thereof about 100 mg to about 350 mg of N-acetyl cysteine (NAC) as an intranasal spray, wherein the administering is to a brain of the subject through a nasal cavity of the subject.” Parkinson’s Disease is in the list recited by claim 13, therefore, claim 14 is obvious over the ‘939 patent in view of Yang et al. and rejected.
Regarding claim 14, claim 12 is obvious as described above. The ‘939 patent discloses in claim 1: “A method of treating a Parkinson's disease, the method comprising intranasally administering to a subject in need thereof about 100 mg to about 350 mg of N-acetyl cysteine (NAC) as an intranasal spray, wherein the administering is to a brain of the subject through a nasal cavity of the subject.” Therefore, claim 14 is obvious over the ‘939 patent in view of Yang et al. and rejected.
Claims 3 and 4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,963,939, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 2 above, and further in view of Meredith, et al. The AAPS journal 17.4: 780-787 (2015)).
Regarding claim 3, claim 2 is obvious as described above. The method of the ’939 patent and Yang does not specifically disclose intranasal administration of the GLP-1 agonist. However, Meredith et al. discloses such administration: “In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP.” (Meredith et al., page 780, Abstract).
A person of ordinary skill in the art would be motivated to combine the method of the ‘939 patent and Yang with the deliver method disclosed by Meredith to achieve the benefits disclosed by Meredith: “First, intranasal delivery of molecules provides a direct access to the CNS, without having to negotiate the BBB. Second, exposure of peripheral organs and tissues to the substrate is usually greatly reduced as most substances have a limited entry into the circulation, and therefore, systemic side effects are greatly reduced. Third, because substances do not have to reach the CNS through the circulation, those substances that have a rapid degradation in blood are not at a major disadvantage as they are when given by intravenous administration). Fourth, there are indications that the intranasal route may allow biologicals to be targeted to specific regions of the brain). In addition, from a clinical therapeutic standpoint, it is well recognized that intranasal administration of drugs is non-invasive.” (Meredith et al., page 780, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Meredith discloses that this has already been done with Exendin: “Intranasal administration of exendin was four times more effective in delivery to the olfactory bulb, compared to intravenous administration). The delivery was quick, with a rapid uptake of exendin 1 min after intranasal administration and was enhanced 60% by the use of cyclodextrins.” (Meredith et al., page 783, col. 1, para. 4).
Consequently, claim 3 is obvious over the ‘939 patent in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites the case wherein the GLP-1 agonist and NAC are mixed together. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 4 is obvious over the ‘939 patent in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,963,939, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012)).
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the GLP-1 agonist is administered via an oral or parenteral route. The ‘939 patent and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
A person of ordinary skill in the art would be motivated to use the parenteral administration of Dong with the method of the ‘939 patent and Yang because Kwarta et al. discloses the following advantages: “Advantages [1] Drugs that have poor absorption in the GIT and drugs like insulin which are unstable in the GIT track can easily be administered by this route. [2] It is one route that allows control over the dose to be administered. [3] It is the most reliable route in case of emergencies as the administration of the drug is faster leading to a more efficient action. [4] No side effects of gastric irritation and vomiting occur. [5] The limitation of having the medicine on an empty or a full stomach is avoided as digestive juices or food doesn’t pose any interference. [6] Interference by liver metabolism is avoided. [7] Unconscious, uncooperative and vomiting patients can be easily dealt with.” (Kwarta et al., page 416, para. 4).
A person of ordinary skill in the art would have a reasonable expectation of success because Dong discloses the parenteral delivery of Liraglutide as described above.
Consequently, claim 5 is obvious over the ‘939 patent in view of Yang et al. as applied to claim 1, further in view of Dong et al. and Kwarta et al. and rejected.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,963,939, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012) as applied to claim 5 above, and further in view of Knudsen et al. (Knudsen, et al. Frontiers in endocrinology 10: 155 (2019)).
Regarding claim 6, claim 5 is obvious as described above. Claim 6 further recites the case wherein the GLP-1 agonist is modified to transit the blood brain barrier. Dong discloses above that Liraglutide crosses the blood brain barrier and Kundsen describes how Liraglutide is a modified molecule: “Following the selection of liraglutide as the first GLP-1-based analog suitable for OD dosing, further analysis of its structural activity was published.” (Knudsen, et al., page 4, col. 2, para. 2).
Consequently, claim 6 is obvious over the ‘939 patent in view of Yang et al. and Dong et al. and Kwarta et al. as applied to claim 5, further in view of Knudsen et al. and rejected.
Claims 8 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,963,939, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 8, claim 1 is obvious as described above. Claim 8 further recites the usage of an additional therapeutic. Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the method of the ‘939 patent and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 8 is obvious over the ‘939 patent in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Regarding claim 9, claim 8 is obvious as described above. Clark discloses the usage of probenecid in conjunction with NAC: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI.” (Clark, et al., page 1535, col.1, para. 1).
Consequently, claim 9 is obvious over the ‘939 patent in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. U.S. Patent No. 11,963,939, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 10, claim 1 is obvious as described above. Claim 10 further recites the administration of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients to the individual.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the method of the ‘939 patent and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 10 is obvious over the ‘939 patent in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,963,939, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Adriaenssens et al. (Adriaenssens, et al. Peptides 125 :170194 (2020)).
Regarding claim 11, claim 1 is obvious as described above. The method of the ‘939 patent and Yang does not specifically disclose the usage of a glucose-dependent insulinotropic polypeptide.
However, Adriaenssens et al. discloses that glucose-dependent insulinotropic polypeptides possess neuroprotective benefits: “Additionally, GIP-based therapeutics have demonstrated promising neuroprotective properties. Together these observations identify an important central component of the GIP/GIPR signaling axis, and have triggered a resurgence of research interest into the central actions of GIP.” (Adriaenssens et al., page 1, Abstract.). Adriaenssens discloses that GIP is a potentially important therapeutic molecule: “Due to innovative pharmacology, the incretin field is starting to reevaluate the GIPR signaling axis, seeing GIP now as an important therapeutic target rather than simply the sister incretin to GLP-1. In particular it has become increasingly apparent that GIPR and its downstream signaling is a critical modulator of energy balance and cognitive health, roles partially mediated by GIPR present in the CNS.” (Adriaenssens, et al., page 4, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘939 patent and Yang with the GIP as disclosed by Adriaenssens.
MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Therefore, a person of ordinary skill in the art would have been motivated to combine GIP as disclosed by Adrianenssens with the method of the ‘939 patent and Yang to be useful for the same purpose, that being treatment of central nervous disease through neuroprotective pathways. A person of ordinary skill in the art would have a reasonable expectation of success because the GIP and the method of the ‘939 patent and Yang have the same purpose.
Consequently, claim 11 is obvious over the ‘939 patent in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claims 15, 16, 17, 18 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,963,939, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)).
Regarding claim 15, claim 15 recites a kit comprising: an intranasal delivery system; and a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and wherein the intranasal delivery system comprises a formulation container and a nozzle; and wherein the formulation container comprises one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004).”
The combination of NAC and GLP-1 agonists is obvious as described above for claim 1.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘939 claim 1: “A method of treating a Parkinson's disease, the method comprising intranasally administering to a subject in need thereof about 100 mg to about 350 mg of N-acetyl cysteine (NAC) as an intranasal spray, wherein the administering is to a brain of the subject through a nasal cavity of the subject.”
Furthermore, claims 19 and 20 of the ‘939 patent disclose: “19. A method of treating a Parkinson's disease condition, the method comprising intranasally administering to a subject in need thereof about 100 mg to about 350 mg of N-acetyl cysteine (NAC) using a nasal sprayer, wherein the administering is to a brain of the subject through a nasal cavity of the subject.
20. The method of claim 19, wherein the nasal sprayer is any of a multi-dose metered-dose spray pump, single-dose spray pump, a duo-dose spray pump, and a bidirectional multi-dose spray pump.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘939 patent and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘939 patent discloses using such nasal devices.
Consequently, claim 15 is obvious over the ‘939 patent in view of Yang et al. and Wong et al. and rejected.
Regarding claim 16, claim 15 is obvious as described above. Claim 16 further recites the case wherein the formulation container also comprises the GLP-1 agonist.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time by having them mixed in the formulation container. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 16 is obvious over the ‘939 patent in view of Yang et al. and Wong et al. and rejected.
Regarding claim 17, claim 15 is obvious as described above. Claim 17 further recites the case wherein the GLP-1rA or congener thereof comprises a tablet, suppository, a pill, a capsule, a powders, a liquid, a suspension, a lotion, a cream, or a gel. Greene and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
Claim 3 of the ‘939 patent discloses: “3. The method of claim 1, wherein the NAC is administered as a powder formulation.”
Consequently, claim 17 is obvious over the ‘939 patent in view of Yang et al. and Wong et al. and rejected.
Regarding claim 18, claim 15 is obvious as described above. Claim 18 further recites the case where the kit has of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients.
Claim 4 of the ‘939 patent discloses: “4. The method of claim 3, wherein the powder formulation further comprises a pharmaceutically acceptable excipient.”
Consequently, claim 18 is obvious over the ‘939 patent in view of Yang et al. and Wong et al. and rejected.
Regarding claim 20, claim 20 recites an intranasal delivery system comprising: one or more formulation containers each having a nozzle; and wherein the one or more formulation containers comprise: a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and one or more of N-acetylcysteine (NAC) a NAC congener, or a pharmaceutically acceptable salt thereof.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘939 claim 1: “A method of treating a Parkinson's disease, the method comprising intranasally administering to a subject in need thereof about 100 mg to about 350 mg of N-acetyl cysteine (NAC) as an intranasal spray, wherein the administering is to a brain of the subject through a nasal cavity of the subject.”
Furthermore, claims 19 and 20 of the ‘939 patent disclose: “19. A method of treating a Parkinson's disease condition, the method comprising intranasally administering to a subject in need thereof about 100 mg to about 350 mg of N-acetyl cysteine (NAC) using a nasal sprayer, wherein the administering is to a brain of the subject through a nasal cavity of the subject.
20. The method of claim 19, wherein the nasal sprayer is any of a multi-dose metered-dose spray pump, single-dose spray pump, a duo-dose spray pump, and a bidirectional multi-dose spray pump.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘939 patent and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘939 patent discloses the delivery of NAC via such a device.
Consequently, claim 20 is obvious over the ‘939 patent in view of Yang et al. and Wong et al. and rejected.
Claim 19 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,963,939, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 19, claim 15 is obvious as described above. Claim 19 further recites an additional therapeutic agent, the additional therapeutic agent comprising a 5-lipogenase-activating protein (FLAP) inhibitor, a Cathepsin B inhibitor, poly(ADP-ribose) polymerase (PARP) inhibitor, probenecid, phenserine, or a dopaminergic agent.
Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the kit of the ‘939 patent, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 19 is obvious over the ‘939 patent in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Clark et al. and rejected.
Claims 1, 2, 7, and 12-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)).
Regarding claim 1, amended claim 1 recites a method of treating a central nervous system disease or a central nervous system disorder in an individual in need thereof, the method comprising: intranasally administering one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof to an individual; and co-administering a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof to the individual.
The ’130 patent discloses a method of treating a brain disorder utilizing NAC that is intranasally administered in claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, from the nose of the subject to one or more selective regions of the brain involved in the brain disorder, and wherein to reach the one or more selective regions of the brain upon the intranasal administration, a first portion of the dose is transported through an olfactory pathway of the subject and a second portion of the does is transported through a trigeminal pathway of the subject.”
The ’130 patent does not disclose the case wherein a GLP-1 agonist is co-administered to the individual in need. However, Yang et al. discloses that GLP-1 agonists have efficacy against Parkinson’s Disease (a central nervous system disease): “The evidence presented here clearly demonstrates that growth factors such as GLP-1 and GIP that can cross the BBB have clear neuroprotective properties in the brain. First clinical trials testing GLP-1R agonists in patients with PD are a clear proof of concept that this strategy is viable and that the preclinical results translate into the clinic. Novel dual GLP-1/GIP receptor agonists that can cross the BBB at an enhanced rate show superior neuroprotective effects in animal models of PD and are likely to do the same in clinical trials.” (Yang et al., page 453, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘130 patent with the usage of GLP-1 agonists disclosed by Yang to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine NAC and GLP-1 agonists in order to achieve an additive or perhaps synergistic effect. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
For similar reasons, a person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 1 is obvious over the ‘130 patent in view of Yang et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the GLP-1 agonist and NAC are administered at the same time.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 2 is obvious over the ‘130 patent in view of Yang et al. and rejected.
Regarding claim 7, claim 1 is obvious as described above. Yang et al. discloses the usage of Liraglutide: “Three clinical trials testing two different GLP-1R agonists in PD patients have shown impressive neuroprotective effects, with a phase II trial demonstrating disease-modifying effects of exendin-4 [76,248], and a recent phase II trial showing good neuroprotective effects on everyday motor activities and quality of life with liraglutide.” (Yang et al., page 454, col. 1, para. 2).
Consequently, claim 7 is obvious over the ‘130 patent in view of Yang et al. and rejected.
Regarding claim 12, claim 1 is obvious as described above. The ‘130 patent discloses in claim 7: “The method of claim 1, wherein the brain disorder is a neurodegenerative disease.” Therefore, claim 12 is obvious over the ‘130 patent in view of Yang et al. and rejected.
Regarding claim 13, claim 12 is obvious as described above. The ‘130 patent discloses in claim 10: “The method of claim 1, wherein the brain disorder is Parkinson's disease.” Therefore, claim 13 is obvious over the ‘130 patent in view of Yang et al. and rejected.
Regarding claim 14, claim 12 is obvious as described above. The ‘130 patent discloses in claim 10: “The method of claim 1, wherein the brain disorder is Parkinson's disease.” Therefore, claim 14 is obvious over the ‘130 patent in view of Yang et al. and rejected.
Claims 3 and 4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 2 above, and further in view of Meredith, et al. The AAPS journal 17.4: 780-787 (2015)).
Regarding claim 3, claim 2 is obvious as described above. The method of the ’130 patent and Yang does not specifically disclose intranasal administration of the GLP-1 agonist. However, Meredith et al. discloses such administration: “In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP.” (Meredith et al., page 780, Abstract).
A person of ordinary skill in the art would be motivated to combine the method of the ‘130 patent and Yang with the deliver method disclosed by Meredith to achieve the benefits disclosed by Meredith: “First, intranasal delivery of molecules provides a direct access to the CNS, without having to negotiate the BBB. Second, exposure of peripheral organs and tissues to the substrate is usually greatly reduced as most substances have a limited entry into the circulation, and therefore, systemic side effects are greatly reduced. Third, because substances do not have to reach the CNS through the circulation, those substances that have a rapid degradation in blood are not at a major disadvantage as they are when given by intravenous administration). Fourth, there are indications that the intranasal route may allow biologicals to be targeted to specific regions of the brain). In addition, from a clinical therapeutic standpoint, it is well recognized that intranasal administration of drugs is non-invasive.” (Meredith et al., page 780, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Meredith discloses that this has already been done with Exendin: “Intranasal administration of exendin was four times more effective in delivery to the olfactory bulb, compared to intravenous administration). The delivery was quick, with a rapid uptake of exendin 1 min after intranasal administration and was enhanced 60% by the use of cyclodextrins.” (Meredith et al., page 783, col. 1, para. 4).
Consequently, claim 3 is obvious over the ‘130 patent in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites the case wherein the GLP-1 agonist and NAC are mixed together. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 4 is obvious over the ‘130 patent in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,090,130, published 9/17/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012)).
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the GLP-1 agonist is administered via an oral or parenteral route. The ‘130 patent and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
A person of ordinary skill in the art would be motivated to use the parenteral administration of Dong with the method of the ‘130 patent and Yang because Kwarta et al. discloses the following advantages: “Advantages [1] Drugs that have poor absorption in the GIT and drugs like insulin which are unstable in the GIT track can easily be administered by this route. [2] It is one route that allows control over the dose to be administered. [3] It is the most reliable route in case of emergencies as the administration of the drug is faster leading to a more efficient action. [4] No side effects of gastric irritation and vomiting occur. [5] The limitation of having the medicine on an empty or a full stomach is avoided as digestive juices or food doesn’t pose any interference. [6] Interference by liver metabolism is avoided. [7] Unconscious, uncooperative and vomiting patients can be easily dealt with.” (Kwarta et al., page 416, para. 4).
A person of ordinary skill in the art would have a reasonable expectation of success because Dong discloses the parenteral delivery of Liraglutide as described above.
Consequently, claim 5 is obvious over the ‘130 patent in view of Yang et al. as applied to claim 1, further in view of Dong et al. and Kwarta et al. and rejected.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012) as applied to claim 5 above, and further in view of Knudsen et al. (Knudsen, et al. Frontiers in endocrinology 10: 155 (2019)).
Regarding claim 6, claim 5 is obvious as described above. Claim 6 further recites the case wherein the GLP-1 agonist is modified to transit the blood brain barrier. Dong discloses above that Liraglutide crosses the blood brain barrier and Kundsen describes how Liraglutide is a modified molecule: “Following the selection of liraglutide as the first GLP-1-based analog suitable for OD dosing, further analysis of its structural activity was published.” (Knudsen, et al., page 4, col. 2, para. 2).
Consequently, claim 6 is obvious over the ‘130 patent in view of Yang et al. and Dong et al. and Kwarta et al. as applied to claim 5, further in view of Knudsen et al. and rejected.
Claims 8 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 8, claim 1 is obvious as described above. Claim 8 further recites the usage of an additional therapeutic. Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the method of the ‘130 patent and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 8 is obvious over the ‘130 patent in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Regarding claim 9, claim 8 is obvious as described above. Clark discloses the usage of probenecid in conjunction with NAC: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI.” (Clark, et al., page 1535, col.1, para. 1).
Consequently, claim 9 is obvious over the ‘130 patent in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 10, claim 1 is obvious as described above. Claim 10 further recites the administration of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients to the individual.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the method of the ‘130 patent and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 10 is obvious over the ‘130 patent in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Adriaenssens et al. (Adriaenssens, et al. Peptides 125 :170194 (2020)).
Regarding claim 11, claim 1 is obvious as described above. The method of the ‘130 patent and Yang does not specifically disclose the usage of a glucose-dependent insulinotropic polypeptide.
However, Adriaenssens et al. discloses that glucose-dependent insulinotropic polypeptides possess neuroprotective benefits: “Additionally, GIP-based therapeutics have demonstrated promising neuroprotective properties. Together these observations identify an important central component of the GIP/GIPR signaling axis, and have triggered a resurgence of research interest into the central actions of GIP.” (Adriaenssens et al., page 1, Abstract.). Adriaenssens discloses that GIP is a potentially important therapeutic molecule: “Due to innovative pharmacology, the incretin field is starting to reevaluate the GIPR signaling axis, seeing GIP now as an important therapeutic target rather than simply the sister incretin to GLP-1. In particular it has become increasingly apparent that GIPR and its downstream signaling is a critical modulator of energy balance and cognitive health, roles partially mediated by GIPR present in the CNS.” (Adriaenssens, et al., page 4, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘130 patent and Yang with the GIP as disclosed by Adriaenssens.
MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Therefore, a person of ordinary skill in the art would have been motivated to combine GIP as disclosed by Adrianenssens with the method of the ‘130 patent and Yang to be useful for the same purpose, that being treatment of central nervous disease through neuroprotective pathways. A person of ordinary skill in the art would have a reasonable expectation of success because the GIP and the method of the ‘130 patent and Yang have the same purpose.
Consequently, claim 11 is obvious over the ‘130 patent in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claims 15, 16, 17, 18 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)).
Regarding claim 15, claim 15 recites a kit comprising: an intranasal delivery system; and a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and wherein the intranasal delivery system comprises a formulation container and a nozzle; and wherein the formulation container comprises one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004).”
The combination of NAC and GLP-1 agonists is obvious as described above for claim 1.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘130 claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, from the nose of the subject to one or more selective regions of the brain involved in the brain disorder, and wherein to reach the one or more selective regions of the brain upon the intranasal administration, a first portion of the dose is transported through an olfactory pathway of the subject and a second portion of the does is transported through a trigeminal pathway of the subject.”
Furthermore, claim 19 of the ‘130 patent discloses: “The method of claim 1, wherein the dose is administered using a nasal pump.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘130 patent and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘130 patent discloses using such nasal devices.
Consequently, claim 15 is obvious over the ‘130 patent in view of Yang et al. and Wong et al. and rejected.
Regarding claim 16, claim 15 is obvious as described above. Claim 16 further recites the case wherein the formulation container also comprises the GLP-1 agonist.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time by having them mixed in the formulation container. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 16 is obvious over the ‘130 patent in view of Yang et al. and Wong et al. and rejected.
Regarding claim 20, claim 20 recites an intranasal delivery system comprising: one or more formulation containers each having a nozzle; and wherein the one or more formulation containers comprise: a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘130 claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, from the nose of the subject to one or more selective regions of the brain involved in the brain disorder, and wherein to reach the one or more selective regions of the brain upon the intranasal administration, a first portion of the dose is transported through an olfactory pathway of the subject and a second portion of the does is transported through a trigeminal pathway of the subject.”
Furthermore, claim 19 of the ‘130 patent discloses: “The method of claim 1, wherein the dose is administered using a nasal pump.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘130 patent and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘130 patent discloses the delivery of NAC via such a device.
Consequently, claim 20 is obvious over the ‘130 patent in view of Yang et al. and Wong et al. and rejected.
Claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)).
Regarding claim 17, claim 15 is obvious as described above. Claim 17 further recites the case wherein the GLP-1rA or congener thereof comprises a tablet, suppository, a pill, a capsule, a powders, a liquid, a suspension, a lotion, a cream, or a gel. Greene and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a GLP-1 agonist in the form of a liquid so said agonist can be administered via intraperitoneal injections as described by Dong. A person of ordinary skill in the art would use liquid form so the GLP-1 agonist can be injected and have a reasonable expectation of success because liquids are commonly injected as drugs.
Consequently, claim 17 is obvious over the ‘130 patent in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Dong et al. and rejected.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024 in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 18, claim 15 is obvious as described above. Claim 18 further recites the case where the kit has of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the kit of the ‘130 patent, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 18 is obvious over the ‘130 patent in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Chaudhari et al. and rejected.
Claim 19 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,090,130, published 9/17/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 19, claim 15 is obvious as described above. Claim 19 further recites an additional therapeutic agent, the additional therapeutic agent comprising a 5-lipogenase-activating protein (FLAP) inhibitor, a Cathepsin B inhibitor, poly(ADP-ribose) polymerase (PARP) inhibitor, probenecid, phenserine, or a dopaminergic agent.
Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the kit of the ‘130 patent, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 19 is obvious over the ‘130 patent in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Clark et al. and rejected.
Claims 1, 2, 7, and 12-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018)).
Regarding claim 1, claim 1 recites a method of treating a central nervous system disease in an individual in need thereof, the method comprising: intranasally administering one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof to an individual; and co-administering a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof to the individual.
The ’929 patent discloses a method of treating a brain disorder utilizing NAC that is intranasally administered in claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising intranasally administering to a nose of the subject a dose of a composition comprising glutathione (GSH), wherein the intranasal administration provides a therapeutically-effective amount of the GSH to one or more selective regions of the brain involved in the brain disorder, wherein a first portion of the dose is transported through an olfactory pathway of the subject and a second portion of the dose is transported through a trigeminal pathway of the subject; and wherein the brain disorder is any of a concussion, post-concussion syndrome, a mild traumatic brain injury, a traumatic brain injury, dementia, age-related, Parkinson's disease, and a stroke.”
Miller et al. discloses that GSH is a derivative and/or congener of NAC: “Following its uptake, NAC is deacetylated to yield L-cysteine, which stimulates intracellular glutathione (GSH) production.” (Miller et al., page 2, para. 5). Therefore, GSH reads on this element of Applicant claim 1.
The ’929 patent does not disclose the case wherein a GLP-1 agonist is co-administered to the individual in need. However, Yang et al. discloses that GLP-1 agonists have efficacy against Parkinson’s Disease (a central nervous system disease): “The evidence presented here clearly demonstrates that growth factors such as GLP-1 and GIP that can cross the BBB have clear neuroprotective properties in the brain. First clinical trials testing GLP-1R agonists in patients with PD are a clear proof of concept that this strategy is viable and that the preclinical results translate into the clinic. Novel dual GLP-1/GIP receptor agonists that can cross the BBB at an enhanced rate show superior neuroprotective effects in animal models of PD and are likely to do the same in clinical trials.” (Yang et al., page 453, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘929 patent with the usage of GLP-1 agonists disclosed by Yang to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine NAC and GLP-1 agonists in order to achieve an additive or perhaps synergistic effect. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
For similar reasons, a person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 1 is obvious over the ‘929 patent in view of Yang et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the GLP-1 agonist and NAC are administered at the same time.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 2 is obvious over the ‘929 patent in view of Yang et al. and rejected.
Regarding claim 7, claim 1 is obvious as described above. Yang et al. discloses the usage of Liraglutide: “Three clinical trials testing two different GLP-1R agonists in PD patients have shown impressive neuroprotective effects, with a phase II trial demonstrating disease-modifying effects of exendin-4 [76,248], and a recent phase II trial showing good neuroprotective effects on everyday motor activities and quality of life with liraglutide.” (Yang et al., page 454, col. 1, para. 2).
Consequently, claim 7 is obvious over the ‘929 patent in view of Yang et al. and rejected.
Regarding claim 12, claim 1 is obvious as described above. The ‘929 patent discloses in claim 8: “The method of claim 1, wherein the brain disorder is Parkinson's disease.” Parkinson’s is a neurodegenerative disease. Therefore, claim 12 is obvious over the ‘929 patent in view of Yang et al. and rejected.
Regarding claim 13, claim 12 is obvious as described above. The ‘929 patent discloses in claim 8: “The method of claim 1, wherein the brain disorder is Parkinson's disease.” Therefore, claim 13 is obvious over the ‘929 patent in view of Yang et al. and rejected.
Regarding claim 14, claim 12 is obvious as described above. The ‘929 patent discloses in claim 8: “The method of claim 1, wherein the brain disorder is Parkinson's disease.” Therefore, claim 14 is obvious over the ‘929 patent in view of Yang et al. and rejected.
Claims 3 and 4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018)) as applied to claim 2 above, and further in view of Meredith, et al. The AAPS journal 17.4: 780-787 (2015)).
Regarding claim 3, claim 2 is obvious as described above. The method of the ’929 patent and Yang does not specifically disclose intranasal administration of the GLP-1 agonist. However, Meredith et al. discloses such administration: “In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP.” (Meredith et al., page 780, Abstract).
A person of ordinary skill in the art would be motivated to combine the method of the ‘929 patent and Yang with the deliver method disclosed by Meredith to achieve the benefits disclosed by Meredith: “First, intranasal delivery of molecules provides a direct access to the CNS, without having to negotiate the BBB. Second, exposure of peripheral organs and tissues to the substrate is usually greatly reduced as most substances have a limited entry into the circulation, and therefore, systemic side effects are greatly reduced. Third, because substances do not have to reach the CNS through the circulation, those substances that have a rapid degradation in blood are not at a major disadvantage as they are when given by intravenous administration). Fourth, there are indications that the intranasal route may allow biologicals to be targeted to specific regions of the brain). In addition, from a clinical therapeutic standpoint, it is well recognized that intranasal administration of drugs is non-invasive.” (Meredith et al., page 780, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Meredith discloses that this has already been done with Exendin: “Intranasal administration of exendin was four times more effective in delivery to the olfactory bulb, compared to intravenous administration). The delivery was quick, with a rapid uptake of exendin 1 min after intranasal administration and was enhanced 60% by the use of cyclodextrins.” (Meredith et al., page 783, col. 1, para. 4).
Consequently, claim 3 is obvious over the ‘929 patent in view of Yang et al. and Miller et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites the case wherein the GLP-1 agonist and NAC are mixed together. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 4 is obvious over the ‘929 patent in view of Yang et al. and Miller et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018)), as applied to claim 1 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012)).
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the GLP-1 agonist is administered via an oral or parenteral route. The ‘929 patent and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
A person of ordinary skill in the art would be motivated to use the parenteral administration of Dong with the method of the ‘929 patent and Yang because Kwarta et al. discloses the following advantages: “Advantages [1] Drugs that have poor absorption in the GIT and drugs like insulin which are unstable in the GIT track can easily be administered by this route. [2] It is one route that allows control over the dose to be administered. [3] It is the most reliable route in case of emergencies as the administration of the drug is faster leading to a more efficient action. [4] No side effects of gastric irritation and vomiting occur. [5] The limitation of having the medicine on an empty or a full stomach is avoided as digestive juices or food doesn’t pose any interference. [6] Interference by liver metabolism is avoided. [7] Unconscious, uncooperative and vomiting patients can be easily dealt with.” (Kwarta et al., page 416, para. 4).
A person of ordinary skill in the art would have a reasonable expectation of success because Dong discloses the parenteral delivery of Liraglutide as described above.
Consequently, claim 5 is obvious over the ‘929 patent in view of Yang et al. and Miller et al. as applied to claim 1, further in view of Dong et al. and Kwarta et al. and rejected.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022), Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018)) and Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012) as applied to claim 5 above, and further in view of Knudsen et al. (Knudsen, et al. Frontiers in endocrinology 10: 155 (2019)).
Regarding claim 6, claim 5 is obvious as described above. Claim 6 further recites the case wherein the GLP-1 agonist is modified to transit the blood brain barrier. Dong discloses above that Liraglutide crosses the blood brain barrier and Kundsen describes how Liraglutide is a modified molecule: “Following the selection of liraglutide as the first GLP-1-based analog suitable for OD dosing, further analysis of its structural activity was published.” (Knudsen, et al., page 4, col. 2, para. 2).
Consequently, claim 6 is obvious over the ‘929 patent in view of Yang et al., Miller et al. and Dong et al. and Kwarta et al. as applied to claim 5, further in view of Knudsen et al. and rejected.
Claims 8 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018)) as applied to claim 1 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 8, claim 1 is obvious as described above. Claim 8 further recites the usage of an additional therapeutic. Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the method of the ‘929 patent and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 8 is obvious over the ‘929 patent in view of Yang et al. and Miller et al. as applied to claim 1, further in view of Clark et al. and rejected.
Regarding claim 9, claim 8 is obvious as described above. Clark discloses the usage of probenecid in conjunction with NAC: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI.” (Clark, et al., page 1535, col.1, para. 1).
Consequently, claim 9 is obvious over the ‘929 patent in view of Yang et al. and Miller et al. as applied to claim 1, further in view of Clark et al. and rejected.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018)) as applied to claim 1 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 10, claim 1 is obvious as described above. Claim 10 further recites the administration of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients to the individual.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the method of the ‘929 patent and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 10 is obvious over the ‘929 patent in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018)) as applied to claim 1 above, and further in view of Adriaenssens et al. (Adriaenssens, et al. Peptides 125 :170194 (2020)).
Regarding claim 11, claim 1 is obvious as described above. The method of the ‘929 patent and Yang does not specifically disclose the usage of a glucose-dependent insulinotropic polypeptide.
However, Adriaenssens et al. discloses that glucose-dependent insulinotropic polypeptides possess neuroprotective benefits: “Additionally, GIP-based therapeutics have demonstrated promising neuroprotective properties. Together these observations identify an important central component of the GIP/GIPR signaling axis, and have triggered a resurgence of research interest into the central actions of GIP.” (Adriaenssens et al., page 1, Abstract.). Adriaenssens discloses that GIP is a potentially important therapeutic molecule: “Due to innovative pharmacology, the incretin field is starting to reevaluate the GIPR signaling axis, seeing GIP now as an important therapeutic target rather than simply the sister incretin to GLP-1. In particular it has become increasingly apparent that GIPR and its downstream signaling is a critical modulator of energy balance and cognitive health, roles partially mediated by GIPR present in the CNS.” (Adriaenssens, et al., page 4, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘929 patent and Yang with the GIP as disclosed by Adriaenssens.
MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Therefore, a person of ordinary skill in the art would have been motivated to combine GIP as disclosed by Adrianenssens with the method of the ‘929 patent and Yang to be useful for the same purpose, that being treatment of central nervous disease through neuroprotective pathways. A person of ordinary skill in the art would have a reasonable expectation of success because the GIP and the method of the ‘130 patent and Yang have the same purpose.
Consequently, claim 11 is obvious over the ‘130 patent in view of Yang et al. and Miller et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claims 15, 16, 17, 18 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018), and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)).
Regarding claim 15, claim 15 recites a kit comprising: an intranasal delivery system; and a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and wherein the intranasal delivery system comprises a formulation container and a nozzle; and wherein the formulation container comprises one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004).”
The combination of NAC and GLP-1 agonists is obvious as described above for claim 1.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘929 claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising intranasally administering to a nose of the subject a dose of a composition comprising glutathione (GSH), wherein the intranasal administration provides a therapeutically-effective amount of the GSH to one or more selective regions of the brain involved in the brain disorder, wherein a first portion of the dose is transported through an olfactory pathway of the subject and a second portion of the dose is transported through a trigeminal pathway of the subject; and wherein the brain disorder is any of a concussion, post-concussion syndrome, a mild traumatic brain injury, a traumatic brain injury, dementia, age-related, Parkinson's disease, and a stroke.”
Furthermore, claim 18 of the ‘929 patent discloses: “The method of claim 1, wherein the dose is administered using any of a nasal pump, an atomizer, and a nebulizer.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘929 patent and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘929 patent discloses using such nasal devices.
Consequently, claim 15 is obvious over the ‘929 patent in view of Yang et al., Miller et al., and Wong et al. and rejected.
Regarding claim 16, claim 15 is obvious as described above. Claim 16 further recites the case wherein the formulation container also comprises the GLP-1 agonist.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time by having them mixed in the formulation container. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 16 is obvious over the ‘929 patent in view of Yang et al., Miller et al. and Wong et al. and rejected.
Regarding claim 20, claim 20 recites an intranasal delivery system comprising: one or more formulation containers each having a nozzle; and wherein the one or more formulation containers comprise: a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘929 claim 1: “. A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising intranasally administering to a nose of the subject a dose of a composition comprising glutathione (GSH), wherein the intranasal administration provides a therapeutically-effective amount of the GSH to one or more selective regions of the brain involved in the brain disorder, wherein a first portion of the dose is transported through an olfactory pathway of the subject and a second portion of the dose is transported through a trigeminal pathway of the subject; and wherein the brain disorder is any of a concussion, post-concussion syndrome, a mild traumatic brain injury, a traumatic brain injury, dementia, age-related, Parkinson's disease, and a stroke.”
Furthermore, claim 18 of the ‘929 patent discloses: “The method of claim 1, wherein the dose is administered using any of a nasal pump, an atomizer, and a nebulizer.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘929 patent and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘929 patent discloses the delivery of NAC via such a device.
Consequently, claim 20 is obvious over the ‘929 patent in view of Yang et al., Miller et al., and Wong et al. and rejected.
Claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022), Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)).
Regarding claim 17, claim 15 is obvious as described above. Claim 17 further recites the case wherein the GLP-1rA or congener thereof comprises a tablet, suppository, a pill, a capsule, a powders, a liquid, a suspension, a lotion, a cream, or a gel. Greene and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a GLP-1 agonist in the form of a liquid so said agonist can be administered via intraperitoneal injections as described by Dong. A person of ordinary skill in the art would use liquid form so the GLP-1 agonist can be injected and have a reasonable expectation of success because liquids are commonly injected as drugs.
Consequently, claim 17 is obvious over the ‘929 patent in view of Yang et al., Miller et al. and Wong et al. as applied to claim 15, further in view of Dong et al. and rejected.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022), Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 18, claim 15 is obvious as described above. Claim 18 further recites the case where the kit has of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the kit of the ‘929 patent, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 18 is obvious over the ‘929 patent in view of Yang et al., Miller et al., and Wong et al. as applied to claim 15, further in view of Chaudhari et al. and rejected.
Claim 19 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,414,929, published 9/16/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022), Miller et al. (Miller, et al. Journal of clinical nutrition and food science 1.1: 035 (2018) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 19, claim 15 is obvious as described above. Claim 19 further recites an additional therapeutic agent, the additional therapeutic agent comprising a 5-lipogenase-activating protein (FLAP) inhibitor, a Cathepsin B inhibitor, poly(ADP-ribose) polymerase (PARP) inhibitor, probenecid, phenserine, or a dopaminergic agent.
Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the kit of the ‘929 patent, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 19 is obvious over the ‘929 patent in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Clark et al. and rejected.
Claims 1, 2, 7, and 12-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)).
Regarding claim 1, claim 1 recites a method of treating a central nervous system disease in an individual in need thereof, the method comprising: intranasally administering one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof to an individual; and co-administering a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof to the individual.
The ‘254 patent discloses a method of treating a brain disorder with NAC in claim 22: “A method of treating a brain disorder in a subject in need thereof, the method comprising intranasally administering to a nose of the subject: a) a dose of a compound, wherein the compound is N-acetylcysteine (NAC) or a pharmaceutically-acceptable salt thereof or glutathione (GSH); and b) a therapeutically-effective amount of a therapeutic agent, wherein the brain disorder is any of a traumatic brain injury, a mild traumatic brain injury, a concussion, post-concussion syndrome, a stroke, a neurodegenerative disease, dementia, Parkinson's disease, or an age-related disorder.”
The ‘254 patent does not disclose the case wherein a GLP-1 agonist is co-administered to the individual in need. However, Yang et al. discloses that GLP-1 agonists have efficacy against Parkinson’s Disease (a central nervous system disease): “The evidence presented here clearly demonstrates that growth factors such as GLP-1 and GIP that can cross the BBB have clear neuroprotective properties in the brain. First clinical trials testing GLP-1R agonists in patients with PD are a clear proof of concept that this strategy is viable and that the preclinical results translate into the clinic. Novel dual GLP-1/GIP receptor agonists that can cross the BBB at an enhanced rate show superior neuroprotective effects in animal models of PD and are likely to do the same in clinical trials.” (Yang et al., page 453, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘254 patent with the usage of GLP-1 agonists disclosed by Yang to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine NAC and GLP-1 agonists in order to achieve an additive or perhaps synergistic effect. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
For similar reasons, a person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 1 is obvious over the ‘254 patent in view of Yang et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the GLP-1 agonist and NAC are administered at the same time.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 2 is obvious over the ‘254 patent in view of Yang et al. and rejected.
Regarding claim 7, claim 1 is obvious as described above. Yang et al. discloses the usage of Liraglutide: “Three clinical trials testing two different GLP-1R agonists in PD patients have shown impressive neuroprotective effects, with a phase II trial demonstrating disease-modifying effects of exendin-4 [76,248], and a recent phase II trial showing good neuroprotective effects on everyday motor activities and quality of life with liraglutide.” (Yang et al., page 454, col. 1, para. 2).
Consequently, claim 7 is obvious over the ‘254 patent in view of Yang et al. and rejected.
Regarding claim 12, claim 1 is obvious as described above. The ‘254 patent discloses in claim 22 that the disease may be a neurodegenerative disease.
Therefore, claim 12 is obvious over the ‘254 patent in view of Yang et al. and rejected.
Regarding claim 13, claim 12 is obvious as described above. The ‘254 patent discloses in claim 22 that the disease may be Parkinson’s disease.
Therefore, claim 13 is obvious over the ‘254 patent in view of Yang et al. and rejected.
Regarding claim 14, claim 12 is obvious as described above. The ‘254 patent discloses in claim 22 that the disease may be Parkinson’s disease.
Therefore, claim 13 is obvious over the ‘254 patent in view of Yang et al. and rejected.
Claims 3 and 4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 2 above, and further in view of Meredith, et al. The AAPS journal 17.4: 780-787 (2015)).
Regarding claim 3, claim 2 is obvious as described above. The method of the ‘254 patent and Yang does not specifically disclose intranasal administration of the GLP-1 agonist. However, Meredith et al. discloses such administration: “In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP.” (Meredith et al., page 780, Abstract).
A person of ordinary skill in the art would be motivated to combine the method of the ‘254 patent and Yang with the deliver method disclosed by Meredith to achieve the benefits disclosed by Meredith: “First, intranasal delivery of molecules provides a direct access to the CNS, without having to negotiate the BBB. Second, exposure of peripheral organs and tissues to the substrate is usually greatly reduced as most substances have a limited entry into the circulation, and therefore, systemic side effects are greatly reduced. Third, because substances do not have to reach the CNS through the circulation, those substances that have a rapid degradation in blood are not at a major disadvantage as they are when given by intravenous administration). Fourth, there are indications that the intranasal route may allow biologicals to be targeted to specific regions of the brain). In addition, from a clinical therapeutic standpoint, it is well recognized that intranasal administration of drugs is non-invasive.” (Meredith et al., page 780, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Meredith discloses that this has already been done with Exendin: “Intranasal administration of exendin was four times more effective in delivery to the olfactory bulb, compared to intravenous administration). The delivery was quick, with a rapid uptake of exendin 1 min after intranasal administration and was enhanced 60% by the use of cyclodextrins.” (Meredith et al., page 783, col. 1, para. 4).
Consequently, claim 3 is obvious over the ‘254 patent in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites the case wherein the GLP-1 agonist and NAC are mixed together. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 4 is obvious over the ‘254 patent in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012)).
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the GLP-1 agonist is administered via an oral or parenteral route. The ‘254 patent and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
A person of ordinary skill in the art would be motivated to use the parenteral administration of Dong with the method of the ‘254 patent and Yang because Kwarta et al. discloses the following advantages: “Advantages [1] Drugs that have poor absorption in the GIT and drugs like insulin which are unstable in the GIT track can easily be administered by this route. [2] It is one route that allows control over the dose to be administered. [3] It is the most reliable route in case of emergencies as the administration of the drug is faster leading to a more efficient action. [4] No side effects of gastric irritation and vomiting occur. [5] The limitation of having the medicine on an empty or a full stomach is avoided as digestive juices or food doesn’t pose any interference. [6] Interference by liver metabolism is avoided. [7] Unconscious, uncooperative and vomiting patients can be easily dealt with.” (Kwarta et al., page 416, para. 4).
A person of ordinary skill in the art would have a reasonable expectation of success because Dong discloses the parenteral delivery of Liraglutide as described above.
Consequently, claim 5 is obvious over the ‘254 patent in view of Yang et al. as applied to claim 1, further in view of Dong et al. and Kwarta et al. and rejected.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012) as applied to claim 5 above, and further in view of Knudsen et al. (Knudsen, et al. Frontiers in endocrinology 10: 155 (2019)).
Regarding claim 6, claim 5 is obvious as described above. Claim 6 further recites the case wherein the GLP-1 agonist is modified to transit the blood brain barrier. Dong discloses above that Liraglutide crosses the blood brain barrier and Kundsen describes how Liraglutide is a modified molecule: “Following the selection of liraglutide as the first GLP-1-based analog suitable for OD dosing, further analysis of its structural activity was published.” (Knudsen, et al., page 4, col. 2, para. 2).
Consequently, claim 6 is obvious over the ‘254 patent in view of Yang et al. and Dong et al. and Kwarta et al. as applied to claim 5, further in view of Knudsen et al. and rejected.
Claims 8 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, published 4/23/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 8, claim 1 is obvious as described above. Claim 8 further recites the usage of an additional therapeutic. Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the method of the ‘254 patent and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 8 is obvious over the ‘254 patent in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Regarding claim 9, claim 8 is obvious as described above. Clark discloses the usage of probenecid in conjunction with NAC: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI.” (Clark, et al., page 1535, col.1, para. 1).
Consequently, claim 9 is obvious over the ‘254 patent in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
Regarding claim 10, claim 1 is obvious as described above. Claim 10 further recites the administration of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients to the individual.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the method of the ‘254 patent and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 10 is obvious over the ‘254 patent in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Adriaenssens et al. (Adriaenssens, et al. Peptides 125 :170194 (2020)).
Regarding claim 11, claim 1 is obvious as described above. The method of the ‘254 patent and Yang does not specifically disclose the usage of a glucose-dependent insulinotropic polypeptide.
However, Adriaenssens et al. discloses that glucose-dependent insulinotropic polypeptides possess neuroprotective benefits: “Additionally, GIP-based therapeutics have demonstrated promising neuroprotective properties. Together these observations identify an important central component of the GIP/GIPR signaling axis, and have triggered a resurgence of research interest into the central actions of GIP.” (Adriaenssens et al., page 1, Abstract.). Adriaenssens discloses that GIP is a potentially important therapeutic molecule: “Due to innovative pharmacology, the incretin field is starting to reevaluate the GIPR signaling axis, seeing GIP now as an important therapeutic target rather than simply the sister incretin to GLP-1. In particular it has become increasingly apparent that GIPR and its downstream signaling is a critical modulator of energy balance and cognitive health, roles partially mediated by GIPR present in the CNS.” (Adriaenssens, et al., page 4, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘254 patent and Yang with the GIP as disclosed by Adriaenssens.
MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Therefore, a person of ordinary skill in the art would have been motivated to combine GIP as disclosed by Adrianenssens with the method of the ‘‘254 patent and Yang to be useful for the same purpose, that being treatment of central nervous disease through neuroprotective pathways. A person of ordinary skill in the art would have a reasonable expectation of success because the GIP and the method of the ‘130 patent and Yang have the same purpose.
Consequently, claim 11 is obvious over the ‘‘254 patent in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claims 15, 16, 17, 18 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)).
Regarding claim 15, claim 15 recites a kit comprising: an intranasal delivery system; and a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and wherein the intranasal delivery system comprises a formulation container and a nozzle; and wherein the formulation container comprises one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004).”
The combination of NAC and GLP-1 agonists is obvious as described above for claim 1.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘254 patent claim 23: “A method of treating a brain disorder in a subject in need thereof, the method comprising intranasally administering to a nose of the subject: a) a dose of a compound, wherein the compound is N-acetylcysteine (NAC) or a pharmaceutically-acceptable salt thereof or glutathione (GSH); and b) a therapeutically-effective amount of a therapeutic agent, wherein the brain disorder is any of a traumatic brain injury, a mild traumatic brain injury, a concussion, post-concussion syndrome, a stroke, a neurodegenerative disease, dementia, Parkinson's disease, or an age-related disorder.”
Furthermore, claim 35 of the ‘254 patent discloses: “The method of claim 22, wherein the dose of the compound is administered using a nasal pump.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘254 patent and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘254 patent discloses using such nasal devices.
Consequently, claim 15 is obvious over the ‘254 patent in view of Yang et al. and Wong et al. and rejected.
Regarding claim 16, claim 15 is obvious as described above. Claim 16 further recites the case wherein the formulation container also comprises the GLP-1 agonist.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time by having them mixed in the formulation container. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 16 is obvious over the ‘254 patent in view of Yang et al. and Wong et al. and rejected.
Regarding claim 20, claim 20 recites an intranasal delivery system comprising: one or more formulation containers each having a nozzle; and wherein the one or more formulation containers comprise: a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘254 patent claim 22: “A method of treating a brain disorder in a subject in need thereof, the method comprising intranasally administering to a nose of the subject:
a) a dose of a compound, wherein the compound is N-acetylcysteine (NAC) or a pharmaceutically-acceptable salt thereof or glutathione (GSH); and
b) a therapeutically-effective amount of a therapeutic agent, wherein the brain disorder is any of a traumatic brain injury, a mild traumatic brain injury, a concussion, post-concussion syndrome, a stroke, a neurodegenerative disease, dementia, Parkinson's disease, or an age-related disorder.”
Furthermore, claim 35 of the ‘254 patent discloses: “The method of claim 22, wherein the dose of the compound is administered using a nasal pump.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘254 patent and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘254 patent discloses the delivery of NAC via such a device.
Consequently, claim 20 is obvious over the ‘254 patent in view of Yang et al. and Wong et al. and rejected.
Claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)).
Regarding claim 17, claim 15 is obvious as described above. Claim 17 further recites the case wherein the GLP-1rA or congener thereof comprises a tablet, suppository, a pill, a capsule, a powders, a liquid, a suspension, a lotion, a cream, or a gel. Greene and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a GLP-1 agonist in the form of a liquid so said agonist can be administered via intraperitoneal injections as described by Dong. A person of ordinary skill in the art would use liquid form so the GLP-1 agonist can be injected and have a reasonable expectation of success because liquids are commonly injected as drugs.
Consequently, claim 17 is obvious over the ‘254 patent in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Dong et al. and rejected.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 18, claim 15 is obvious as described above. Claim 18 further recites the case where the kit has of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the kit of the ‘254 patent, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 18 is obvious over the ‘254 patent in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Chaudhari et al. and rejected.
Claim 19 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent 12,594,254, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
Regarding claim 19, claim 15 is obvious as described above. Claim 19 further recites an additional therapeutic agent, the additional therapeutic agent comprising a 5-lipogenase-activating protein (FLAP) inhibitor, a Cathepsin B inhibitor, poly(ADP-ribose) polymerase (PARP) inhibitor, probenecid, phenserine, or a dopaminergic agent.
Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the kit of the ‘254 patent, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 19 is obvious over the ‘254 patent in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Clark et al. and rejected.
Claims 1, 2, 7, and 12-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, claim 1 recites a method of treating a central nervous system disease in an individual in need thereof, the method comprising: intranasally administering one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof to an individual; and co-administering a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof to the individual.
The ’413 application discloses a method of treating a brain disorder with NAC in claim 23: “A method of treating a brain disorder in a brain of a subject in need thereof, comprising intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, to the brain from the nose, wherein a first portion of the dose crosses an olfactory epithelium of the subject after the intranasal administration and then enters an olfactory nerve of the subject and then enters the brain, wherein a second portion of the dose crosses a respiratory epithelium of the subject after the intranasal administration and then crosses a trigeminal nerve of the subject and then enters the brain, and wherein the subject is not substantially systemically exposed to the NAC, or the congener thereof, upon the intranasal administration.”
The ’413 application does not disclose the case wherein a GLP-1 agonist is co-administered to the individual in need. However, Yang et al. discloses that GLP-1 agonists have efficacy against Parkinson’s Disease (a central nervous system disease): “The evidence presented here clearly demonstrates that growth factors such as GLP-1 and GIP that can cross the BBB have clear neuroprotective properties in the brain. First clinical trials testing GLP-1R agonists in patients with PD are a clear proof of concept that this strategy is viable and that the preclinical results translate into the clinic. Novel dual GLP-1/GIP receptor agonists that can cross the BBB at an enhanced rate show superior neuroprotective effects in animal models of PD and are likely to do the same in clinical trials.” (Yang et al., page 453, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘413 application with the usage of GLP-1 agonists disclosed by Yang to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine NAC and GLP-1 agonists in order to achieve an additive or perhaps synergistic effect. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
For similar reasons, a person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 1 is obvious over the ‘413 application in view of Yang et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the GLP-1 agonist and NAC are administered at the same time.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 2 is obvious over the ‘413 application in view of Yang et al. and rejected.
Regarding claim 7, claim 1 is obvious as described above. Yang et al. discloses the usage of Liraglutide: “Three clinical trials testing two different GLP-1R agonists in PD patients have shown impressive neuroprotective effects, with a phase II trial demonstrating disease-modifying effects of exendin-4 [76,248], and a recent phase II trial showing good neuroprotective effects on everyday motor activities and quality of life with liraglutide.” (Yang et al., page 454, col. 1, para. 2).
Consequently, claim 7 is obvious over the ‘413 application in view of Yang et al. and rejected.
Regarding claim 12, claim 1 is obvious as described above. The ‘413 application discloses in claim 4: “The method of claim 1, wherein the brain disorder is a neurodegenerative disease.” Therefore, claim 12 is obvious over the ‘413 application in view of Yang et al. and rejected.
Regarding claim 13, claim 12 is obvious as described above. The ‘413 application discloses in claim 5: “The method of claim 4, wherein the neurodegenerative disease is Parkinson's disease.” Therefore, claim 13 is obvious over the ‘413 application in view of Yang et al. and rejected.
Regarding claim 14, claim 12 is obvious as described above. The ‘413 application discloses in claim 5: “The method of claim 4, wherein the neurodegenerative disease is Parkinson's disease.” Therefore, claim 13 is obvious over the ‘413 application in view of Yang et al. and rejected.
Claims 3 and 4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 2 above, and further in view of Meredith, et al. The AAPS journal 17.4: 780-787 (2015)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 3, claim 2 is obvious as described above. The method of the ’413 application and Yang does not specifically disclose intranasal administration of the GLP-1 agonist. However, Meredith et al. discloses such administration: “In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP.” (Meredith et al., page 780, Abstract).
A person of ordinary skill in the art would be motivated to combine the method of the ‘254 patent and Yang with the deliver method disclosed by Meredith to achieve the benefits disclosed by Meredith: “First, intranasal delivery of molecules provides a direct access to the CNS, without having to negotiate the BBB. Second, exposure of peripheral organs and tissues to the substrate is usually greatly reduced as most substances have a limited entry into the circulation, and therefore, systemic side effects are greatly reduced. Third, because substances do not have to reach the CNS through the circulation, those substances that have a rapid degradation in blood are not at a major disadvantage as they are when given by intravenous administration). Fourth, there are indications that the intranasal route may allow biologicals to be targeted to specific regions of the brain). In addition, from a clinical therapeutic standpoint, it is well recognized that intranasal administration of drugs is non-invasive.” (Meredith et al., page 780, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Meredith discloses that this has already been done with Exendin: “Intranasal administration of exendin was four times more effective in delivery to the olfactory bulb, compared to intravenous administration). The delivery was quick, with a rapid uptake of exendin 1 min after intranasal administration and was enhanced 60% by the use of cyclodextrins.” (Meredith et al., page 783, col. 1, para. 4).
Consequently, claim 3 is obvious over the ‘413 application in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites the case wherein the GLP-1 agonist and NAC are mixed together. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 4 is obvious over the ‘413 application in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the GLP-1 agonist is administered via an oral or parenteral route. The ‘413 application and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
A person of ordinary skill in the art would be motivated to use the parenteral administration of Dong with the method of the ‘413 application and Yang because Kwarta et al. discloses the following advantages: “Advantages [1] Drugs that have poor absorption in the GIT and drugs like insulin which are unstable in the GIT track can easily be administered by this route. [2] It is one route that allows control over the dose to be administered. [3] It is the most reliable route in case of emergencies as the administration of the drug is faster leading to a more efficient action. [4] No side effects of gastric irritation and vomiting occur. [5] The limitation of having the medicine on an empty or a full stomach is avoided as digestive juices or food doesn’t pose any interference. [6] Interference by liver metabolism is avoided. [7] Unconscious, uncooperative and vomiting patients can be easily dealt with.” (Kwarta et al., page 416, para. 4).
A person of ordinary skill in the art would have a reasonable expectation of success because Dong discloses the parenteral delivery of Liraglutide as described above.
Consequently, claim 5 is obvious over the ‘413 application in view of Yang et al. as applied to claim 1, further in view of Dong et al. and Kwarta et al. and rejected.
Claim 6 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012) as applied to claim 5 above, and further in view of Knudsen et al. (Knudsen, et al. Frontiers in endocrinology 10: 155 (2019)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 6, claim 5 is obvious as described above. Claim 6 further recites the case wherein the GLP-1 agonist is modified to transit the blood brain barrier. Dong discloses above that Liraglutide crosses the blood brain barrier and Kundsen describes how Liraglutide is a modified molecule: “Following the selection of liraglutide as the first GLP-1-based analog suitable for OD dosing, further analysis of its structural activity was published.” (Knudsen, et al., page 4, col. 2, para. 2).
Consequently, claim 6 is obvious over the ‘413 application in view of Yang et al. and Dong et al. and Kwarta et al. as applied to claim 5, further in view of Knudsen et al. and rejected.
Claims 8 and 9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 8, claim 1 is obvious as described above. Claim 8 further recites the usage of an additional therapeutic. Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the method of the ‘413 application and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 8 is obvious over the ‘413 application in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Regarding claim 9, claim 8 is obvious as described above. Clark discloses the usage of probenecid in conjunction with NAC: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI.” (Clark, et al., page 1535, col.1, para. 1).
Consequently, claim 9 is obvious over the ‘413 application in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Claim 10 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 10, claim 1 is obvious as described above. Claim 10 further recites the administration of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients to the individual.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the method of the ‘413 application and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 10 is obvious over the ‘413 application in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Adriaenssens et al. (Adriaenssens, et al. Peptides 125 :170194 (2020)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 11, claim 1 is obvious as described above. The method of the ‘413 application and Yang does not specifically disclose the usage of a glucose-dependent insulinotropic polypeptide.
However, Adriaenssens et al. discloses that glucose-dependent insulinotropic polypeptides possess neuroprotective benefits: “Additionally, GIP-based therapeutics have demonstrated promising neuroprotective properties. Together these observations identify an important central component of the GIP/GIPR signaling axis, and have triggered a resurgence of research interest into the central actions of GIP.” (Adriaenssens et al., page 1, Abstract.). Adriaenssens discloses that GIP is a potentially important therapeutic molecule: “Due to innovative pharmacology, the incretin field is starting to reevaluate the GIPR signaling axis, seeing GIP now as an important therapeutic target rather than simply the sister incretin to GLP-1. In particular it has become increasingly apparent that GIPR and its downstream signaling is a critical modulator of energy balance and cognitive health, roles partially mediated by GIPR present in the CNS.” (Adriaenssens, et al., page 4, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘254 patent and Yang with the GIP as disclosed by Adriaenssens.
MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Therefore, a person of ordinary skill in the art would have been motivated to combine GIP as disclosed by Adrianenssens with the method of the ’413 application and Yang to be useful for the same purpose, that being treatment of central nervous disease through neuroprotective pathways. A person of ordinary skill in the art would have a reasonable expectation of success because the GIP and the method of the ‘130 patent and Yang have the same purpose.
Consequently, claim 11 is obvious over the ‘413 application in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claims 15, 16, 17, 18 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 15, claim 15 recites a kit comprising: an intranasal delivery system; and a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and wherein the intranasal delivery system comprises a formulation container and a nozzle; and wherein the formulation container comprises one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004).”
The combination of NAC and GLP-1 agonists is obvious as described above for claim 1.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘413 application claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, comprising intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, to the brain from the nose, wherein a first portion of the dose crosses an olfactory epithelium of the subject after the intranasal administration and then enters an olfactory nerve of the subject and then enters the brain, wherein a second portion of the dose crosses a respiratory epithelium of the subject after the intranasal administration and then crosses a trigeminal nerve of the subject and then enters the brain, and wherein the subject is not substantially systemically exposed to the NAC, or the congener thereof, upon the intranasal administration.”
Furthermore, claim 10 of the ‘413 application discloses: “The method of claim 9, wherein the dose is administered using a nasal pump.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘413 application and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘413 application discloses using such nasal devices.
Consequently, claim 15 is obvious over the ‘413 application in view of Yang et al. and Wong et al. and rejected.
Regarding claim 16, claim 15 is obvious as described above. Claim 16 further recites the case wherein the formulation container also comprises the GLP-1 agonist.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time by having them mixed in the formulation container. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 16 is obvious over the ‘413 application in view of Yang et al. and Wong et al. and rejected.
Regarding claim 20, claim 20 recites an intranasal delivery system comprising: one or more formulation containers each having a nozzle; and wherein the one or more formulation containers comprise: a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘413 application claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, comprising intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, to the brain from the nose, wherein a first portion of the dose crosses an olfactory epithelium of the subject after the intranasal administration and then enters an olfactory nerve of the subject and then enters the brain, wherein a second portion of the dose crosses a respiratory epithelium of the subject after the intranasal administration and then crosses a trigeminal nerve of the subject and then enters the brain, and wherein the subject is not substantially systemically exposed to the NAC, or the congener thereof, upon the intranasal administration.”
Furthermore, claim 10 of the ‘413 application discloses: “The method of claim 9, wherein the dose is administered using a nasal pump.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘413 application and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘413 application discloses the delivery of NAC via such a device.
Consequently, claim 20 is obvious over the ‘413 application in view of Yang et al. and Wong et al. and rejected.
Claim 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 17, claim 15 is obvious as described above. Claim 17 further recites the case wherein the GLP-1rA or congener thereof comprises a tablet, suppository, a pill, a capsule, a powders, a liquid, a suspension, a lotion, a cream, or a gel. Greene and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a GLP-1 agonist in the form of a liquid so said agonist can be administered via intraperitoneal injections as described by Dong. A person of ordinary skill in the art would use liquid form so the GLP-1 agonist can be injected and have a reasonable expectation of success because liquids are commonly injected as drugs.
Consequently, claim 17 is obvious over the ‘413 application in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Dong et al. and rejected.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 18, claim 15 is obvious as described above. Claim 18 further recites the case where the kit has of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the kit of the ‘130 patent, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 18 is obvious over the ‘413 application in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Chaudhari et al. and rejected.
Claim 19 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/328,413, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 19, claim 15 is obvious as described above. Claim 19 further recites an additional therapeutic agent, the additional therapeutic agent comprising a 5-lipogenase-activating protein (FLAP) inhibitor, a Cathepsin B inhibitor, poly(ADP-ribose) polymerase (PARP) inhibitor, probenecid, phenserine, or a dopaminergic agent.
Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the kit of the ‘413 application, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 19 is obvious over the ‘413 application in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Clark et al. and rejected.
Response to Arguments
Applicant's arguments filed 6/10/2026 have been fully considered but they are not persuasive. Applicant’s argument is centered around the arguments rendered for claim 1 under U.S.C. 103. As described above, that rejection is maintained as proper and therefore, all the non-statutory double patenting rejections are maintained as proper as well.
New Rejections Double Patenting
Claims 1, 2, 7, and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, claim 1 recites a method of treating a central nervous system disease in an individual in need thereof, the method comprising: intranasally administering one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof to an individual; and co-administering a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof to the individual.
The ‘260 application discloses a method of treating a brain disorder with NAC in claim 1: “. A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising:intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, to the brain from the nose, wherein the NAC, or the congener thereof, crosses an olfactory epithelium of the subject after the intranasal administration, and then after crossing the olfactory epithelium, the NAC, or the congener thereof, enters an olfactory nerve of the subject, and then after crossing the olfactory nerve, the NAC, or the congener thereof, enters the brain; and intranasally administering to the nose of the subject a therapeutic agent, wherein the brain disorder is selected from the group consisting of traumatic brain injury, mild traumatic brain injury, concussion, post-concussion syndrome, stroke, and a neurodegenerative disease, wherein the intranasal administration increases a GSH/creatine ratio in a region of the brain, and wherein the subject is not substantially systemically exposed to the NAC, or the congener thereof, upon the intranasal administration..”
The ‘260 application does not disclose the case wherein a GLP-1 agonist is co-administered to the individual in need. However, Yang et al. discloses that GLP-1 agonists have efficacy against Parkinson’s Disease (a central nervous system disease): “The evidence presented here clearly demonstrates that growth factors such as GLP-1 and GIP that can cross the BBB have clear neuroprotective properties in the brain. First clinical trials testing GLP-1R agonists in patients with PD are a clear proof of concept that this strategy is viable and that the preclinical results translate into the clinic. Novel dual GLP-1/GIP receptor agonists that can cross the BBB at an enhanced rate show superior neuroprotective effects in animal models of PD and are likely to do the same in clinical trials.” (Yang et al., page 453, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘260 application with the usage of GLP-1 agonists disclosed by Yang to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine NAC and GLP-1 agonists in order to achieve an additive or perhaps synergistic effect. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
For similar reasons, a person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 1 is obvious over the ‘260 application in view of Yang et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the GLP-1 agonist and NAC are administered at the same time.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 2 is obvious over the ‘260 application in view of Yang et al. and rejected.
Regarding claim 7, claim 1 is obvious as described above. Yang et al. discloses the usage of Liraglutide: “Three clinical trials testing two different GLP-1R agonists in PD patients have shown impressive neuroprotective effects, with a phase II trial demonstrating disease-modifying effects of exendin-4 [76,248], and a recent phase II trial showing good neuroprotective effects on everyday motor activities and quality of life with liraglutide.” (Yang et al., page 454, col. 1, para. 2).
Consequently, claim 7 is obvious over the ‘260 application in view of Yang et al. and rejected.
Regarding claim 12, claim 1 is obvious as described above. The ‘260 application discloses in claim 1 that the disease may be a neurodegenerative disease.” Therefore, claim 12 is obvious over the ‘260 application in view of Yang et al. and rejected.
Claims 3 and 4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 2 above, and further in view of Meredith, et al. The AAPS journal 17.4: 780-787 (2015)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 3, claim 2 is obvious as described above. The method of the ‘260 application and Yang does not specifically disclose intranasal administration of the GLP-1 agonist. However, Meredith et al. discloses such administration: “In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP.” (Meredith et al., page 780, Abstract).
A person of ordinary skill in the art would be motivated to combine the method of the ‘254 patent and Yang with the deliver method disclosed by Meredith to achieve the benefits disclosed by Meredith: “First, intranasal delivery of molecules provides a direct access to the CNS, without having to negotiate the BBB. Second, exposure of peripheral organs and tissues to the substrate is usually greatly reduced as most substances have a limited entry into the circulation, and therefore, systemic side effects are greatly reduced. Third, because substances do not have to reach the CNS through the circulation, those substances that have a rapid degradation in blood are not at a major disadvantage as they are when given by intravenous administration). Fourth, there are indications that the intranasal route may allow biologicals to be targeted to specific regions of the brain). In addition, from a clinical therapeutic standpoint, it is well recognized that intranasal administration of drugs is non-invasive.” (Meredith et al., page 780, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Meredith discloses that this has already been done with Exendin: “Intranasal administration of exendin was four times more effective in delivery to the olfactory bulb, compared to intravenous administration). The delivery was quick, with a rapid uptake of exendin 1 min after intranasal administration and was enhanced 60% by the use of cyclodextrins.” (Meredith et al., page 783, col. 1, para. 4).
Consequently, claim 3 is obvious over the ‘260 application in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Regarding claim 4, claim 3 is obvious as described above. Claim 4 further recites the case wherein the GLP-1 agonist and NAC are mixed together. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 4 is obvious over the ‘260 application in view of Yang et al. as applied to claim 2, further in view of Meredith et al. and rejected.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the GLP-1 agonist is administered via an oral or parenteral route. The ‘260 application and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
A person of ordinary skill in the art would be motivated to use the parenteral administration of Dong with the method of the ‘260 application and Yang because Kwarta et al. discloses the following advantages: “Advantages [1] Drugs that have poor absorption in the GIT and drugs like insulin which are unstable in the GIT track can easily be administered by this route. [2] It is one route that allows control over the dose to be administered. [3] It is the most reliable route in case of emergencies as the administration of the drug is faster leading to a more efficient action. [4] No side effects of gastric irritation and vomiting occur. [5] The limitation of having the medicine on an empty or a full stomach is avoided as digestive juices or food doesn’t pose any interference. [6] Interference by liver metabolism is avoided. [7] Unconscious, uncooperative and vomiting patients can be easily dealt with.” (Kwarta et al., page 416, para. 4).
A person of ordinary skill in the art would have a reasonable expectation of success because Dong discloses the parenteral delivery of Liraglutide as described above.
Consequently, claim 5 is obvious over the ‘260 application in view of Yang et al. as applied to claim 1, further in view of Dong et al. and Kwarta et al. and rejected.
Claim 6 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, filed 10/9/2024, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)) and Kwarta et al. (Kwarta, et al. Indo Global Journal of Pharmaceutical Sciences 2.4: 409-426 (2012) as applied to claim 5 above, and further in view of Knudsen et al. (Knudsen, et al. Frontiers in endocrinology 10: 155 (2019)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 6, claim 5 is obvious as described above. Claim 6 further recites the case wherein the GLP-1 agonist is modified to transit the blood brain barrier. Dong discloses above that Liraglutide crosses the blood brain barrier and Kundsen describes how Liraglutide is a modified molecule: “Following the selection of liraglutide as the first GLP-1-based analog suitable for OD dosing, further analysis of its structural activity was published.” (Knudsen, et al., page 4, col. 2, para. 2).
Consequently, claim 6 is obvious over the ‘260 application in view of Yang et al. and Dong et al. and Kwarta et al. as applied to claim 5, further in view of Knudsen et al. and rejected.
Claims 8 and 9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 8, claim 1 is obvious as described above. Claim 8 further recites the usage of an additional therapeutic. Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the method of the ‘260 application and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 8 is obvious over the ‘260 application in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Regarding claim 9, claim 8 is obvious as described above. Clark discloses the usage of probenecid in conjunction with NAC: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI.” (Clark, et al., page 1535, col.1, para. 1).
Consequently, claim 9 is obvious over the ‘260 application in view of Yang et al. as applied to claim 1, further in view of Clark et al. and rejected.
Claim 10 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 10, claim 1 is obvious as described above. Claim 10 further recites the administration of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients to the individual.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the method of the ‘260 application and Yang. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 10 is obvious over the ‘260 application in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) as applied to claim 1 above, and further in view of Adriaenssens et al. (Adriaenssens, et al. Peptides 125 :170194 (2020)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 11, claim 1 is obvious as described above. The method of the ‘260 application and Yang does not specifically disclose the usage of a glucose-dependent insulinotropic polypeptide.
However, Adriaenssens et al. discloses that glucose-dependent insulinotropic polypeptides possess neuroprotective benefits: “Additionally, GIP-based therapeutics have demonstrated promising neuroprotective properties. Together these observations identify an important central component of the GIP/GIPR signaling axis, and have triggered a resurgence of research interest into the central actions of GIP.” (Adriaenssens et al., page 1, Abstract.). Adriaenssens discloses that GIP is a potentially important therapeutic molecule: “Due to innovative pharmacology, the incretin field is starting to reevaluate the GIPR signaling axis, seeing GIP now as an important therapeutic target rather than simply the sister incretin to GLP-1. In particular it has become increasingly apparent that GIPR and its downstream signaling is a critical modulator of energy balance and cognitive health, roles partially mediated by GIPR present in the CNS.” (Adriaenssens, et al., page 4, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of the ‘254 patent and Yang with the GIP as disclosed by Adriaenssens.
MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Therefore, a person of ordinary skill in the art would have been motivated to combine GIP as disclosed by Adrianenssens with the method of the ‘260 application and Yang to be useful for the same purpose, that being treatment of central nervous disease through neuroprotective pathways. A person of ordinary skill in the art would have a reasonable expectation of success because the GIP and the method of the ‘130 patent and Yang have the same purpose.
Consequently, claim 11 is obvious over the ‘260 application in view of Yang et al. as applied to claim 1, further in view of Chaudhari et al. and rejected.
Claims 15, 16, 17, 18 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 15, claim 15 recites a kit comprising: an intranasal delivery system; and a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and wherein the intranasal delivery system comprises a formulation container and a nozzle; and wherein the formulation container comprises one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004).”
The combination of NAC and GLP-1 agonists is obvious as described above for claim 1.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘260 application claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising: intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, to the brain from the nose, wherein the NAC, or the congener thereof, crosses an olfactory epithelium of the subject after the intranasal administration, and then after crossing the olfactory epithelium, the NAC, or the congener thereof, enters an olfactory nerve of the subject, and then after crossing the olfactory nerve, the NAC, or the congener thereof, enters the brain; and intranasally administering to the nose of the subject a therapeutic agent, wherein the brain disorder is selected from the group consisting of traumatic brain injury, mild traumatic brain injury, concussion, post-concussion syndrome, stroke, and a neurodegenerative disease, wherein the intranasal administration increases a GSH/creatine ratio in a region of the brain, and wherein the subject is not substantially systemically exposed to the NAC, or the congener thereof, upon the intranasal administration.”
Furthermore, claim 6 of the ‘260 application discloses: “The method of claim 1, wherein the dose is administered using an atomizer.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘260 application and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘260 application discloses using such nasal devices.
Consequently, claim 15 is obvious over the ‘260 application in view of Yang et al. and Wong et al. and rejected.
Regarding claim 16, claim 15 is obvious as described above. Claim 16 further recites the case wherein the formulation container also comprises the GLP-1 agonist.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer these two elements at the same time by having them mixed in the formulation container. A finite number of ways exists to administer two therapeutics. Therapeutic A first, therapeutic B second, Therapeutic B first, therapeutic A second, or both at the same time. A person of ordinary skill in the art would be motivated to administer both therapeutics at the same time as a matter of routine optimization and as a matter of there being a finite number of choices and therefore simultaneous administration is obvious to try.
A person of ordinary skill in the art would have a reasonable expectation of success because each substance is useful individually and there is no art teaching that such a combination possesses negative synergy. MPEP2144.06(I) is again relevant: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).”
Consequently, claim 16 is obvious over the ‘260 application in view of Yang et al. and Wong et al. and rejected.
Regarding claim 20, claim 20 recites an intranasal delivery system comprising: one or more formulation containers each having a nozzle; and wherein the one or more formulation containers comprise: a glucagon-like peptide 1 receptor agonists (GLP-1rA) or congener thereof; and one or more of N-acetylcysteine (NAC), a NAC congener, or a pharmaceutically acceptable salt thereof.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an intranasal delivery system to deliver NAC nasally as disclosed by the ‘260 application claim 1: “A method of treating a brain disorder in a brain of a subject in need thereof, the method comprising: intranasally administering to a nose of the subject a dose of N-acetylcysteine (NAC), or a congener thereof, wherein the intranasal administration provides a therapeutically-effective amount of the NAC, or the congener thereof, to the brain from the nose, wherein the NAC, or the congener thereof, crosses an olfactory epithelium of the subject after the intranasal administration, and then after crossing the olfactory epithelium, the NAC, or the congener thereof, enters an olfactory nerve of the subject, and then after crossing the olfactory nerve, the NAC, or the congener thereof, enters the brain; and intranasally administering to the nose of the subject a therapeutic agent, wherein the brain disorder is selected from the group consisting of traumatic brain injury, mild traumatic brain injury, concussion, post-concussion syndrome, stroke, and a neurodegenerative disease, wherein the intranasal administration increases a GSH/creatine ratio in a region of the brain, and wherein the subject is not substantially systemically exposed to the NAC, or the congener thereof, upon the intranasal administration.”
Furthermore, claim 6 of the ‘260 application discloses: “The method of claim 1, wherein the dose is administered using an atomizer.”
A person of ordinary skill in the art would be motivated to add an intranasal delivery system to facilitate the nasal administration of NAC as disclosed by the ‘260 application and would have a reasonable expectation of success because intranasal delivery systems because Wong discloses that: “Accruing evidence suggests nasal route drug administration may be a potentially attractive strategy for N-acetylcysteine on top of the highly vascularized nasal cavity and large surface area for drug absorption.” (Wong et al., page 3008, col. 2, para. 1) and the ‘413 application discloses the delivery of NAC via such a device.
Consequently, claim 20 is obvious over the ‘260 application in view of Yang et al. and Wong et al. and rejected.
Claim 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Dong et al. (Dong, et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy : 2583-2597 (2022)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 17, claim 15 is obvious as described above. Claim 17 further recites the case wherein the GLP-1rA or congener thereof comprises a tablet, suppository, a pill, a capsule, a powders, a liquid, a suspension, a lotion, a cream, or a gel. Greene and Yang do not specifically disclose these administration routes for the GLP-1 agonist.
However, Dong et al. discloses that Liraglutide is administered parenterally: “Liraglutide is a GLP-1 agonist with neuroprotective properties in Alzheimer’s disease. It has demonstrated the ability to cross the BBB. The pharmacological concentration of GLP-1RA in the brain was proportional to the intraperitoneal injections, with 2.5, 25, or 250 nmol per kg of body weight protecting against impairment of recognition memory synaptic loss and degradation in the hippocampus of patients.” (Dong et al., page 2587, para. 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a GLP-1 agonist in the form of a liquid so said agonist can be administered via intraperitoneal injections as described by Dong. A person of ordinary skill in the art would use liquid form so the GLP-1 agonist can be injected and have a reasonable expectation of success because liquids are commonly injected as drugs.
Consequently, claim 17 is obvious over the ‘260 application in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Dong et al. and rejected.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Chaudhari et al. (Chaudhari, et al. Int J Adv Pharm Biol Chem 1.1: 21-34 (2012)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 18, claim 15 is obvious as described above. Claim 18 further recites the case where the kit has of one or more carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, or excipients.
Chaudhari discloses the usage of excipients: “Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to Protect, support or enhance stability of the formulation:- Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its
stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time
thus improving the shelf life of dosage formulation.” (Chaudhari et al., page 21, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the pharmaceutical excipients of Chaudhari with the kit of the ‘130 patent, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the benefits disclosed by Chaudhari (Chaudhari et al., page 28, Table 1) and have a reasonable expectation of success because Chaudhari discloses that these excipients are already in use and what they contribute (Chaudhari et al., page 28, Table 1).
Consequently, claim 18 is obvious over the ‘260 application in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Chaudhari et al. and rejected.
Claim 19 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Application No. 19/638,260, filed 4/3/2026, filed 9/15/2025, in view of Yang, et al. (Yang, et al. Expert opinion on therapeutic targets 26.5: 445-460 (2022)) and Wong et al. (Wong, et al., Journal of inflammation research : 2993-3013.(2021)) as applied to claim 15 above, and further in view of Clark et al. (Clark, Robert SB, et al. "N-acetylcysteine and probenecid adjuvant therapy for traumatic brain injury." Neurotherapeutics 20.6: 1529-1537 (2023)).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 19, claim 15 is obvious as described above. Claim 19 further recites an additional therapeutic agent, the additional therapeutic agent comprising a 5-lipogenase-activating protein (FLAP) inhibitor, a Cathepsin B inhibitor, poly(ADP-ribose) polymerase (PARP) inhibitor, probenecid, phenserine, or a dopaminergic agent.
Clark discloses the usage of NAC and probenecid in combination: “Both preclinical and clinical studies directly support the use of NAC as a neurotherapeutic for TBI, with a few preclinical studies also suggesting that probenecid may have efficacy. Combination therapy with probenecid and NAC has a strong biological basis, and target engagement has been demonstrated using a pharmacometabolomic approach in children with severe TBI. Given potential neurotherapeutic effects of NAC alone, potential synergism of combination therapy with probenecid, favorable safety profiles and FDA approval of both drugs, and the fact that no targeted neurotherapeutics currently exist for treatment of TBI in humans, further investigation using the combination of probenecid and NAC appears warranted.” (Clark, et al., page 1535, col.1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the combination of NAC and probenecid as disclosed by Clark with the kit of the ‘260 application, Yang, and Wong. A person of ordinary skill in the art would be motivated to make this combination to gain the potential synergism described by Clark and would have a reasonable expectation of success because Clark discloses that this combination has a strong biological basis.
Consequently, claim 19 is obvious over the ‘260 application in view of Yang et al. and Wong et al. as applied to claim 15, further in view of Clark et al. and rejected.
Conclusion
No claim is allowed.
Claims 1-20 are rejected.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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