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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/17/2025 has been entered.
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.
The later-filed application (U.S. Application No. 18/154,550, U.S. Application No. 16/700,588, and U.S. Application No. 15/968,355) must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, Application No. 18/154,550, Application No. 16/700,588, and Application No. 15/968,355, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The prior-filed applications, Application No. 18/154,550, Application No. 16/700,588, and Application No. 15/968,355, fail to provide adequate support or enablement for delivering directly to an olfactory region of a nasal cavity. Therefore, the priority date given to the claims is November 15, 2023.
Claim Status
Claims 1-14, and 17-20 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), and Awasthi et al (Surg Neurol 1997;47:575-82) are withdrawn in light of the amendment.
Claims 1-14 and 17-20 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) as applied to claims 1-11, 13-14, and 17-20 in further view of Lipp et al (WO2012/030664 A1), are withdrawn 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 17-20 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), 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). 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 intranasal spray wherein the administering is to a brain of the subject through the nasal cavity of the subject although Messina teaches the composition can be formulated in the form of an aerosol spray and can be administered intranasally among other routes of administration. 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) 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.) 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.)
Alexander teaches the upper region of the nasal cavity (known as an olfactory region) remains directly connected to the brain (frontal cortex; especially olfactory bulb) via olfactory nerves. Along with this, the middle and the largest region of the nasal cavity (the respiratory region) remain supplied with the trigeminal sensory neurons and blood vessels. When the drug administered into the nasal cavity, firstly it has to pass the mucociliary clearance in the vestibular region. Further, the drug molecule reaches to the internal portion of the nasal cavity where it comes in contact with the blood vessels (respiratory epithelium) and neuronal network (olfactory and respiratory epithelium) (Crowe et al., 2018). From the blood vessels, the drug entered into the systemic circulation and distributed throughout the body as per the relative volume of distribution. This systemic bioavailability remains as the minor route of drug transport to the brain in which the drug entered the brain via BBB. (See second paragraph of the right column of page 2102.)
Djupesland teaches it is a common misconception that nose to brain transport can only occur along the olfactory nerve. As described above, evidence suggests that transport can also occur along the trigeminal nerves innervating much of the nasal respiratory mucosa in the anatomic regions beyond the nasal valve. Although direct evidence for nose to brain delivery in humans is still an emerging area of investigation, due in part to ethical and methodological challenges, several studies assessing nasal delivery with neuropeptides such as insulin and oxytocin strongly suggest the existence of an active pathway in humans. Due to inadequate delivery of formulation to deep target sites beyond the nasal valve with traditional nasal delivery devices such as nasal sprays, the full potential of direct nose to brain delivery has probably not yet been realized, and may be a simple solution that has an important and complimentary role alongside efforts to engineer molecules for carrier-mediated transport or ‘Trojan horse' delivery. (See second and third paragraphs of the right column of page 793.)
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 as the administration to a brain of a patient for treating traumatic brain injury and concussion-traumatic brain injury in addition to Parkinson’s disease to give Applicant’s claimed invention. One would have been motivated to do so because 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 and intranasal delivery could revolutionize the way we treat Alzheimer's disease and other neurodegenerative disorders, because Mischley teaches NAC is a small molecule that bypass the BBB and can deliver GSH to the CNS and intranasal administration of intranasal administration of GSH elevates GHS brain levels in PD patient along with the teaching of NAC can increase the level of GSH in the CNS, because NAC is known to treat blast-induced mTBI in a battlefield setting, to mild concussion from blunt trauma as taught by Eakin and also because TBI is characterized aby an increased in oxidative stress as taught by Awasthi, and because both Alexander and Djupesland teaches the olfactory region (upper nose) is the primary direct gateway for nose-to-brain delivery, allowing drugs to bypass the blood brain barrier via olfactory nerves to the brain. One would reasonably expect the selection of intranasal administration which contemplates the olfactory region of the nasal cavity taught by Messina, Alexander and Djupesland to successfully result in the administration to the brain of the subject through the nasal cavity for treating Parkinson’s disease, traumatic brain injury and concussion-related traumatic brain injury. One would reasonably expect the selection of intranasal administration which contemplates the olfactory region of the nasal cavity taught by Messina, Alexander and Djupesland to successfully result in the administration to the brain of a patient for treating traumatic brain injury and concussion-related traumatic brain injury in addition to Parkinson’s disease.
With respect to the comparison limitations recited in claims 17 and 18; these limitations simply express the intended result of the method step positively recited. Since the method steps claimed is obvious over the teachings of the cited references in combination. The intended results claimed would necessarily present absent evidence to the contrary.
Claims 1-14, and 17-20 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), 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).
The teachings of Messina, Hanson et al, Mischley et al, Eakin et al, Awasthi et al, Alexander et al, and Djupesland have been discussed in the first above rejection.
Messina, Hanson et al, Mischley et al, Eakin et al, Awasthi et al, Alexander et al, and Djupesland 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 method taught by Messina, Hanson et al, Mischley et al, Eakin et al, Awasthi et al, Alexander et al, and Djupesland to include calcium carbonate or sodium chloride as the pharmaceutically acceptable excipients to give Applicants claimed invention. One would have been motivated to do so because not only Messina provide guidance for using calcium carbonate or sodium chloride salts as pharmaceutically acceptable excipients or salts, but also because Lipp teaches calcium carbonate and sodium carbonate as salts that can provide survivor efficacy of dry powder. One would reasonably expect the inclusion of calcium carbonate and sodium chloride to provide superior efficacy of the inhaler formulation of Messina with success.
The vast majority of arguments presented in this response filed on 11/17/2025 have been previously addressed. It is emphasized that the instant rejection has been maintained in (1) the Final Rejection mailed on 05/12/2025. A response to these arguments can be found in this Office Actions. Newly presented arguments are addressed below.
Applicant’s argument
Applicant argues that the Examiner's combination of references is based on impermissible hindsight. The prior art, when viewed properly without the benefit of Applicant's specification as a guide, does not teach or suggest the specific method now recited in the claims
Examiner’s answer
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).
Applicant’s argument
Applicant argues that the distinction between general "intranasal administration" and "delivering directly to an olfactory region" is crucial. The latter is a specialized technique, a specific subset of intranasal delivery that requires particular methodologies or devices, such as the atomizers, nebulizers, or insufflators disclosed in Applicant's specification (see paragraphs [0090], [0092], and [0093]), to ensure the therapeutic reaches the upper portion of the nasal cavity where the olfactory nerves are located. The prior art combination contains no suggestion to undertake such a specific, targeted delivery.
Examiner’s answer
In response, Applicant’s argument is not persuasive. It may well be true that the prior art combination does specifically teach or suggest delivering NAC directly to an olfactory region of a nasal cavity. However, 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.) Alexander teaches the upper region of the nasal cavity (known as an olfactory region) remains directly connected to the brain (frontal cortex; especially olfactory bulb) via olfactory nerves. Along with this, the middle and the largest region of the nasal cavity (the respiratory region) remain supplied with the trigeminal sensory neurons and blood vessels. When the drug administered into the nasal cavity, firstly it has to pass the mucociliary clearance in the vestibular region. Further, the drug molecule reaches to the internal portion of the nasal cavity where it comes in contact with the blood vessels (respiratory epithelium) and neuronal network (olfactory and respiratory epithelium) (Crowe et al., 2018). From the blood vessels, the drug entered into the systemic circulation and distributed throughout the body as per the relative volume of distribution. This systemic bioavailability remains as the minor route of drug transport to the brain in which the drug entered the brain via BBB. (See second paragraph of the right column of page 2102.)
Djupesland teaches it is a common misconception that nose to brain transport can only occur along the olfactory nerve. As described above, evidence suggests that transport can also occur along the trigeminal nerves innervating much of the nasal respiratory mucosa in the anatomic regions beyond the nasal valve. Although direct evidence for nose to brain delivery in humans is still an emerging area of investigation, due in part to ethical and methodological challenges, several studies assessing nasal delivery with neuropeptides such as insulin and oxytocin strongly suggest the existence of an active pathway in humans. Due to inadequate delivery of formulation to deep target sites beyond the nasal valve with traditional nasal delivery devices such as nasal sprays, the full potential of direct nose to brain delivery has probably not yet been realized, and may be a simple solution that has an important and complimentary role alongside efforts to engineer molecules for carrier-mediated transport or ‘Trojan horse' delivery. (See second and third paragraphs of the right column of page 793.) Thus, one would reasonably expect the selection of intranasal administration which contemplates the olfactory region of the nasal cavity taught by Messina, Alexander and Djupesland to successfully result in the administration to the brain of a patient for treating traumatic brain injury and concussion-related traumatic brain injury in addition to Parkinson’s disease.
Conclusion
Claims 1-14 and 17-20 are not allowed-
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/JEAN P CORNET/Primary Examiner, Art Unit 1628