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
This Application is a Continuation of U.S. Application No. 18/154,550, filed January 13, 2023, which is a Continuation of U.S. Application No. 16/700,588, filed December 2, 2019, now U.S. Patent No. 11,660,278, which Application is a Continuation of U.S. Application No. 15/968,355, filed May 1, 2018, which Application claims the benefit of United States Provisional Application No. 62/500,381, filed May 2, 2017.
Claim Status
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on June 17, 2026. Claims 1-14, and 17-21 are pending and are under examination. Claims 15 and 16 are canceled.
Action Summary
Claims 1-11, 13-14, and 17-20 rejected under 35 U.S.C. 103 as being unpatentable over Messina (US2012/0190731A1) in view of Hanson et al. ((BMC Neurosci. 2008; 9(Suppl 3): S5 Pages 1-4), Mischley et al (NPJ Parkinsons Dis. 2016; 2: 16002, Published online 2016 Feb 25, 1-6 pages), Eakin et al (PLoS One. 2014; 9(4): e90617, published online 2014 Apr 16, pages 1-7), Awasthi et al (Surg Neurol 1997;47:575-82), Alexander et al (Neural Regen Res. 2018 Dec;13(12):2102–2104), and Djupesland et al (J Cereb Blood Flow Metab. 2013 Mar 13;33(5):793–794), are maintained, but modified and revisited in light of the amendment to claim 1 and the addition to claim 21.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Messina (US2012/0190731A1) in view of Hanson et al. ((BMC Neurosci. 2008; 9(Suppl 3): S5 Pages 1-4), Mischley et al (NPJ Parkinsons Dis. 2016; 2: 16002, Published online 2016 Feb 25, 1-6 pages), Eakin et al (PLoS One. 2014; 9(4): e90617, published online 2014 Apr 16, pages 1-7), Awasthi et al (Surg Neurol 1997;47:575-82), Alexander et al (Neural Regen Res. 2018 Dec;13(12):2102–2104), and Djupesland et al (J Cereb Blood Flow Metab. 2013 Mar 13;33(5):793–794). as applied to claims 1-11, 13-14, and 17-20 in further view of Lipp et al (WO2012/030664 A1), are maintained, but modified and revisited because the rejection of claim 1 has been revisited and modified in light of the claim amendment.
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 non-obviousness.
Claims 1-11, 13-14, and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Messina (US2012/0190731A1) in view of Hanson et al. ((BMC Neurosci. 2008; 9(Suppl 3): S5 Pages 1-4), Mischley et al (NPJ Parkinsons Dis. 2016; 2: 16002, Published online 2016 Feb 25, 1-6 pages), Eakin et al (PLoS One. 2014; 9(4): e90617, published online 2014 Apr 16, pages 1-7), and Awasthi et al (Surg Neurol 1997;47:575-82). Messina, Hanson, Mischley are cited in the parent case # 18/154,550.
Messina teaches a method for reducing oxidative stress in a stem or progenitor cell, the method comprising contacting a stem or progenitor cell with a composition comprising N-Acetylcysteine (NAC) or a triple therapy. (See claim 67.) Moreover, Messina teaches the cell is a hematopoietic stem or progenitor cell, a bone marrow-derived cell, a cell within or obtained from a donor subject diagnosed with a disease associated with oxidative stress or exhibiting a symptom of oxidative stress or a cell for transplantation to a recipient subject, wherein the recipient subject is diagnosed with a disease associated with oxidative stress or exhibiting a symptom of oxidative stress. (See claim 71.) Messina also teaches many human diseases and disorders are caused, at least in part, by chronic or acute oxidative stress and non-limiting examples of specific diseases include Parkinson's Disease, ALS, and Alzheimer's Disease. (See paragraphs [0118] & [0119].) The method may be useful to promote wound healing in a subject (e.g., a human) that has suffered a traumatic injury. (See paragraph [0139].) Messina teaches examples of routes of administration include but are not limited to oral, parenteral, intramuscular, intranasal, intratracheal, intrathecal, intravenous, inhalation, ocular, vaginal, and rectal. (See paragraph [0228].) Intranasal is administration through the nasal cavity. The method for reducing oxidative stress in a subject, cell, tissue, or microenvironment as provided herein further comprises diagnosing a disorder caused or associated with oxidative stress of an in vivo biochemical microenvironment, a deficiency in stem and/or progenitor cell differentiation, proliferation, survival and/or maintenance, or a state of oxidative stress or associated with oxidative stress in the Subject, cell, tissue, or microenvironment, and administering the compounds and/or agents to the Subject, cell, tissue, or microenvironment based on the result of said diagnosing or determining. (See paragraph [0033].) The composition may be may be formulated as a combination of all agents or compounds (e.g., in the form of a solid, liquid, powder, gel, or other form. (See paragraph [0207].) Messina teaches the subject is a human subject having oxidative stress. (See paragraph [0138].) Additionally, Messina teaches for administration by inhalation, the agent may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer and formulated in a powder mix and lactose, rendering the formulation a sprayable powder. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount, resulting in a metered dose pressurized aerosol spray (See paragraph [0239].) Lactose is a disaccharide. Aerosol spray reads on atomizer. Messina teaches the reducing oxidative stress agent provided under (A) which is NAC or L-arginine may be administered at a dosage of about 5 mg/kg/day or about 10 mg/kg. (See paragraphs [0185] & [0209].) Furthermore, Messina teaches the therapeutic formulations useful in the invention may be prepared for storage by mixing an agent having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers including glucose and dextran. (See paragraphs [0249] and [0245].) Lastly, Messina teaches salts such as calcium and sodium can be included in the formulation as pharmaceutically acceptable carriers. (See paragraph [0230].
Messina does not specifically teach mild traumatic brain injury and administration of NAC within 24 hours of the mild traumatic brain injury. Additionally, Messina does not teach concussion and the intranasal delivery to the brain is by delivering the NAC directly to an olfactory region of a nasal cavity.
Hanson teaches intranasal delivery provides a practical, non-invasive method of bypassing the blood-brain barrier (BBB) to deliver therapeutic agents to the brain and spinal cord. This technology allows drugs that do not cross the BBB to be delivered to the central nervous system within minutes. It also directly delivers drugs that do cross the BBB to the brain, eliminating the need for systemic administration and its potential side effects. This is possible because of the unique connections that the olfactory and trigeminal nerves provide between the brain and external environment. Intranasal delivery does not necessarily require any modification to therapeutic agents. (See Abstract.) Moreover, Hanson teaches intranasal delivery could revolutionize the way we treat Alzheimer's disease and other neurodegenerative disorders. (See page 3, left column, second paragraph.)
Mischley teaches Glu Glutathione (GSH) is depleted early in the course of Parkinson’s disease (PD), and deficiency has been shown to perpetuate oxidative stress, mitochondrial dysfunction, impaired autophagy, and cell death. GSH repletion has been proposed as a therapeutic intervention. The objective of this study was to evaluate whether intranasally administered reduced GSH, (in)GSH, is capable of augmenting central nervous system GSH concentrations, as determined by magnetic resonance spectroscopy in 15 participants with mid-stage PD. Glutathione (GSH) is depleted early in the course of Parkinson’s disease (PD), and deficiency has been shown to perpetuate oxidative stress, mitochondrial dysfunction, impaired autophagy, and cell death. GSH repletion has been proposed as a therapeutic intervention. The objective of this study was to evaluate whether intranasally administered reduced GSH, (in)GSH, is capable of augmenting central nervous system GSH concentrations, as determined by magnetic resonance spectroscopy in 15 participants with mid-stage PD. This study is the first to demonstrate that intranasal administration of GSH elevates brain GSH levels. (See Abstract.) Moreover, Mischley teaches Alternative repletion strategies have focused on oral administration of GSH precursors (e.g., cysteine and glycine supplementation), and intravenous administration of GSH, which although promising, is invasive and inconvenient, and therefore unlikely to be a practical solution. (See page 1, second paragraph of the left column.) Mischley also teaches GSH precursor N-acetyl cysteine (NAC) is capable of crossing the blood–brain barrier and providing cysteine substrate to CNS cells, thus enhancing GSH. (See page 1, last paragraph of the right column.) Additionally, Mischley teaches Intranasal administration of reduced GSH, (in)GSH, could be an effective approach for delivery of GSH to the CNS. Many studies suggest that small, polar molecules may be able to “bypass” the blood–brain barrier with nasal delivery, as the interface between the nasal cavity and brain is considered a potential point of vulnerability in the blood–brain barrier. (See page 2, third paragraph of the left column.) The fact that NAC is a small molecule that bypass the BBB and can deliver GSH to the CNS and the fact that intranasal administration of intranasal administration of GSH elevates GHS brain levels in PD patient, one of ordinary skill in the art would expect intranasal administration of NAC to effectively elevate GSH levels to the brain of a Parkinson’s patient.
Eakin teaches early post-injury treatment with N-Acetyl Cysteine (NAC) beginning 30-60 minutes after injury, reversed the behavioral deficits associated with the TBI. These data suggest generalization of a protocol similar to our recent clinical trial with NAC in blast- induced mTBI in a battlefield setting, to mild concussion from blunt trauma. (See Abstract.) Eakin teaches administering NAC approximately 30 minutes following injury, which necessarily falls within the claimed period of 24 hours. Moreover, Eakin supports the potential role of GSH in the effects of NAC, it has been shown that, despite its poor penetration into the CNS, NAC can significantly elevate GSH levels in brain after oxidative stress and GSH deficiency. Moreover, it has recently been shown that, in a unique animal model of mTBI using thinning of the skull and compression, that glutathione from the periphery can enter the brain and exert neuroprotective activity. (See page 6, first paragraph of right column.)
Awasthi teaches that 60 minutes following TBI there was a significantly increased level of oxidative stress in the brain. This may reflect formation of free radical species with subsequent interaction with ascorbate (antioxidant) during the 60-minute period. (See Abstract.) Awasthi also teaches an important mechanism for secondary neuronal and cerebrovascular damage following traumatic brain injury (TBI) may be an increase in oxidative reactions initiated by free radicals generated by the injury. (See page first page of right column.) Awasthi further teaches that oxidative stress develops rapidly after traumatic brain injury, providing additional motivation for early administration.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to select the intranasal administration through the nasal cavity for administering NAC to treat mild traumatic brain injury (mTBI), including concussion within 24 hours of injury as claimed. One would have been motivated to do so, because Messina teaches pharmaceutical compositions comprising NAC suitable for intranasal administration; Hanson teaches intranasal delivery provides a practical, non-invasive means of delivering therapeutic agents to the brain by bypassing the blood-brain barrier; Mischley further demonstrates intranasal NAC is an effective route for increasing central nervous system glutathione levels and teaches that NAC servers as a glutathione precursor capable increasing CNS glutathione levels; Eakin teaches that NAC is effective for treating mild traumatic brain injury, including blast-induced mTBI and mild concussion resulting from blunt trauma, and administers NAC beginning 30 minutes after injury; and Awasthi taches that oxidative stress develops rapidly following traumatic brain injury, thereby providing further motivation to initiate NAC treatment promptly after injury. Accordingly, one of ordinary skill in the art would have reasonably expected that administration of NAC intranasally through the nasal cavity within 24 hours of mTBI would have been a suitable and effective modification of the combined teachings of the cited references.
With respect to the comparison limitations recited in claims 17 and 18; the recited comparisons to intravenously or orally administered NAC merely describe the expected pharmacokinetic and therapeutic properties resulting from the positively recited method of intranasal administration. The claims do not require any additional affirmative step for determining or measuring the comparison. Once the claimed method of intranasally administering NAC is render obvious by the combined teachings of the cited references, the recited properties are considered inherent or naturally resulting characteristics of that method absent persuasive evidence demonstrating otherwise.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Messina (US2012/0190731A1) in view of Hanson et al. ((BMC Neurosci. 2008; 9(Suppl 3): S5 Pages 1-4), Mischley et al (NPJ Parkinsons Dis. 2016; 2: 16002, Published online 2016 Feb 25, 1-6 pages), Eakin et al (PLoS One. 2014; 9(4): e90617, published online 2014 Apr 16, pages 1-7), and Awasthi et al (Surg Neurol 1997;47:575-82) as applied to claims 1-11, 13-14, and 17-21 in further view of Lipp et al (WO2012/030664 A1).
The teachings of Messina, Hanson et al., Mischley et al., Eakin et al., and Awasthi et al. have been discussed in the first above rejection.
Messina, Hanson et al., Mischley et al., Eakin et al., and Awasthi et al. collectively do not teach the sodium and calcium salts as pharmaceutically acceptable excipients are calcium carbonate and sodium chloride. (See claim 12).
Lipp teaches a respirable dry powder comprises respirable dry particles comprising a divalent metal cation salt, a monovalent metal cation salt, one or more additional therapeutic agents, and optionally an excipient, wherein the ratio of divalent metal cation to monovalent metal cation is from about 8: 1 (mole:mole) to about 2: 1 (mole:mole), about 4: 1 (mole:mole) to about 2: 1 (mole:mole), or 3.9: 1 (mole:mole) to about 2: 1 (mole:mole). The respirable dry particles that contain calcium ions such as calcium carbonate and sodium ions sodium chloride with these ranges provide superior efficacy. (See paragraph [0012].)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the pharmaceutical composition taught by Messina in view of Hanson et al., Mischley et al., Eakin et al., and Awasthi et al. to include calcium carbonate or sodium chloride as the pharmaceutically acceptable excipients recited in claim 12. One of ordinary skill in the art would have been motivated to do so, because not only Messina teaches dry powder pharmaceutical formulations comprising pharmaceutically acceptable excipients, while Lipp specifically teaches calcium carbonate and sodium carbonate as suitable excipients for dry powder pharmaceutical compositions. Since these excipients were known in the art to be compatible with dry powder formulations and to provide desirable formulation characteristics, one of ordinary skill in the art would have reasonably expected their incorporation into Messina’s dry powder formulation to have predictable modification with a reasonable expectation of success.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on June 17, 2026.
Response to Applicant’s Argument regarding Impermissible Hindsight
Applicant’s argument
Applicant argues that the Examiner’s obviousness rejection is based on impermissible highlight because the cited references allegedly fail to teach or suggest the specific combination of N-acetylcysteine (NAC), intranasal administration, treatment of mild traumatic brain injury (mTBI), and the claimed dosage and timing limitations. Applicant further argues that the Examiner improperly selects NAC from Messina, intranasal administration from Hanson, and Mischley, and mTBI from Eakin without a sufficient reason to combine.
Examiner’s response
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper 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). In the present case, Applicant’s arguments improperly evaluate each reference individually rather than considering the combined teachings of the references as a whole. Obviousness under 35 U.S.C. 103 does not require that every claimed limitation be disclosed within a single reference. Rather, the issue is whether the collective teachings of the prior art would have suggested the claimed invention to one of ordinary skill in the art with a reasonable expectation of success. Applicant’s characterization of the rejection merely identifies the respective teachings relied upon from each reference. Such an argument does not demonstrate reversible error. The rejection expressly explains why a person of ordinary skill in the art would have combined the references. Specifically, Messina teaches pharmaceutical composition comprising NAC that are suitable for intranasal administration, including powder formulations, pharmaceutically acceptable excipients, and dosage ranges encompassing the presently claimed range. Hanson teaches that intranasal administration provides practical, non-invasive route for delivering therapeutic agents for the central nervous system by bypassing the blood-brain barrier. Mischley further demonstrates that intranasal administration is an effective route for increasing glutathione levels within the central nervous system and teaches that NAC serves as a glutathione precursor capable of increasing glutathione concentrations within the CNS. Eakin teaches that NAC is effective for treating mild traumatic brain injury, including blast-induced mTBI and mild concussion resulting from blunt trauma, and further teaches administration shortly after injury. Awasthi teaches that oxidative stress develops rapidly following traumatic brain injury, thereby providing additional motivation to initiate antioxidant therapy promptly following injury. These teachings are complementary rather than contradictory. The Examiner has not reconstructed Applicant’s invention using hindsight but has instead relied upon the ordinary creativity of one of ordinary skill in the art to combine familiar elements according to their functions to obtain predictable results.
Response to Applicant’s argument Regarding Eakin
Applicant’s argument
Applicant argues that Eakin administers NAC intraperitoneally rather than intranasally and therefore fails to teach or suggest the presently claimed method.
Examiner’s response
This argument is not persuasive because the rejection does not rely upon Eakin for the route of administration. Rather, Eakin is relied upon for its teaching that NAC is useful for treating mild traumatic brain injury and that treatment is initiated shortly after injury. The route of administration is supplied by Messina and Hanson, which teach intranasal administration and explain the advantages of that route for delivering therapeutic agents to the central nervous system. A determination of obviousness does not require that every feature relied upon be disclosed in the same reference. Accordingly, Applicant’s criticism of Eakin individually does not identify reversible error in the rejection because it does not address the teaching supplied by the remaining references.
Response to Applicant’s Argument that the Remaining References Do Not Cure the Alleged Deficiency
Applicant’s argument
Applicant argues that Messina list intranasal administration among many possible routes of administration, Hanson is directed to Alzheimer’s diseases, Mischley is directed to glutathione rather than NAC, and Awasthi merely discloses oxidative stress.
Examiner’s response
These arguments are likewise unpersuasive because they improperly attack the references individually. Specifically, Messina is relied upon because it teaches pharmaceutic al compositions comprising NAC that are suitable for intranasal administration. Hanson is relied upon because it teaches the advantages and expected success associated with intranasal delivery to the central nervous system. Mischley is relied upon because it teaches that intranasal administration of capable of increasing CNS glutathione levels and further recognizes NAC as a precursor capable of increasing glutathione levels or concentrations within the CNS. Eakin supplies the disease indication, namely mild traumatic brain injury, while Awasthi supplies additional motivation for early antioxidant intervention following traumatic brain injury due to rapidly developing oxidative stress. Nothing in Applicant’s arguments identifies any teaching within the cited references that would discourage or teach away from combining these references.
Response to Applicant’s argument Regarding Reasonable Expectation of Success
Applicant’s argument
Applicant argues that a person of ordinary skill in the art would not have reasonably expected success because Eakin relied upon systemic administration at higher doses.
Examiner’s response
This argument is not persuasive. A reasonable expectation of success does not require absolute predictability or certainty that the modified method will achieve every desired clinical outcome. Rather, the relevant inquiry is whether one of ordinary skill in the art would reasonably the proposed modification to function for its intended purpose. Specifically, Hanson expressly teaches that intranasal administration provides an effective route for delivering therapeutic agents to the CNS while bypassing the blood-brain barrier. Mischley further demonstrates successful intranasal CNS delivery context of glutathione-related therapy. In view of these teachings, one of ordinary skill in the art would have reasonably expected intranasal administration to represent a suitable alternative route for delivering NAC to the CNS while treating mTBI as taught by Eakin. Applicant has not directed the Examiner to persuasive evidence establishing that the proposed combination would have been expected to fail or that the cited references teach away from the proposed modification.
Response to Applicant’s argument Regarding claim 21
Applicant’s argument
Applicant argues that none of the references teaches intranasal administration within 24 hours of mTBI.
Examiner’s response
This argument is not persuasive. Eakin expressly teaches administration NAC approximately thirty minutes following traumatic brain injury. Thirty minutes necessarily falls within the claimed twenty-four hours. Although Eakin employs a different route of administration, the rejection relies upon Messina and Hanson for the intranasal route. Furthermore, Awasthi teaches that oxidative stress develops rapidly following traumatic brain injury, thereby providing additional motivation for prompt administration of antioxidant therapy. Consequently, the collective teachings of the cited references would have suggested administer NAC intranasally within the claimed 24-hour period.
Conclusion
Claims 1-14 and 17-21 are not allowed-
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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