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 .1
Status of Claims and Prosecution
Claims 1-21 are pending and directed to the elected species of a patient suffering from Parkinson’s disease, mild traumatic brain injury and brain cancer remain under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 17 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 7-14, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over MISCHLEY ET AL. Nature Partner Journals, 2016, 2, 16002, pages 1-6.
Claim 1 is directed to a method of optimizing an intranasal therapeutic regimen for a condition in a subject, the method comprising:
a) administering to a subject in need thereof a therapeutically effective amount of a therapeutic agent, wherein the administering is intranasal;
b) after the administering, quantifying a concentration of glutathione in a brain region of the subject by magnetic resonance spectroscopy; and
c) selecting a delivery parameter for a subsequent intranasal administration based on the quantified concentration of glutathione, wherein the delivery parameter is selected from the group consisting of a dose, a formulation, and a delivery device.
The specification defines N-acetylcysteine (NAC) and derivatives thereof as therapeutic agents, known to increase the concentration and bioavailability of the antioxidant glutathione (GSH). See paragraphs 18-19. In an embodiment, NAC derivative is GSH., i.e. a therapeutic agent. See paragraph 29.
Regarding instant claim 1 step a) of administration of therapeutic agent to a subject in need and step b) quantifying glutathione concentration by MRI in the subject’s brain region, as well as claim 3, Mischley discloses it evaluated whether intranasally administered reduced GSH, (in)GSH (i.e., a therapeutic agent), is capable of augmenting central nervous system GSH concentrations, as determined by magnetic resonance spectroscopy in 15 participants with mid-stage Parkinson’s. See abstract.
As required by claims 1, 4, 7 and 8, in particular the preamble citing a condition of claim 1, as per dependent claims 4, 7 and 8, a brain/CNS condition, such as elected species Parkinson’s disease (PD), Mischley discloses treatment of PD, as defined by a lack of GSH. See abstract. Mischley teaches administration of therapeutically effective amounts of an agent are administered intranasally to a patient in need. See abstract.
While Mischley expressly teaches the limitations of the preamble, steps a) and b) of claim 1, it does not expressly disclose step c) of claim 1, the selection of a delivery parameter (dose, formulation and delivery device) for subsequent intranasal administration based on glutathione (GSH) concentration (quantified).
However, based on the teachings of Mischley noting its study was the first to demonstrate an increase an increase in CNS GSH levels with a noninvasive GSH augmentation, See page 3, column 1, Discussion, a person having ordinary skill in the art (PHOSITA) would have routinely optimized the selection of a dose and/or formulation for any subsequent intranasal administration based on glutathione concentrations in said subject. MPEP 2144.05(II)
Mischley teaches that previous obstacles of inability to assess human CNS GSH concentrations in vivo and poor oral absorption of GSH were overcome by its H-MRS editing method to measure CNS GSH levels and a noninvasive (intranasal) GSH administration strategy as a therapeutic approach for only on PD but also other CNS GSH deficiency disorders. Page 3, column 1. Thus Mischley teaches in particular, the selection of dose delivery formulation parameter for subsequent intranasal formulation for administration throughout its disclosure. See especially page 3, column 1. For example, Table 2 demonstrates changes in brain GSH levels (GSH/cr peak ratios) relative to baseline after 200 mg nasally administered GSH. See page 3, top of page. Based off the teachings of Mischley, for example Table 2, where a 200 mg intranasal dose of GSH resulted in various GSH/Cr peak ratios over time, a PHOSITA would routinely optimize the delivery parameter of dose with potential subsequent intranasal administration to optimize GSH levels based on resulting GSH levels measured. Optimization of dosing, whether higher or lower than the 200 mg intranasal taught be Mischley would be readily apparent to a PHOSITA, as a clinician of ordinary skill in the art would no doubt lower or increase doses of GSH, based on teachings of Mischley (Table 2) to achieve desired clinical profiles to treat the subject in need via intranasal administration.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference in Mischley teachings steps a) and b) of claim 1 (administration of therapeutic agent (GSH) to a subject to treat a condition such as PD,) to modify with the secondary teachings of Mischley (selection of dose delivery formulation parameter) so as to routinely optimize treatment based on quantified GSH concentrations in the subject.
The PHOSITA would have had a reasonable expectation of success because Mischley not only teaches treatment of PD with GSH in subjects in need where patients under go MRIs to determine treatment effectiveness but also Mischley teaches the effects of GSH dose as a delivery parameter administered in terms of GSH concentration quantified in the treated subjects.
Regarding limitation of a therapeutically-effective amount of about 100 mg to about 400 mg in instant claim 9, Mischley discloses a dose of 200 mg was self-administered. See abstract.
Regarding claims 11 and 13-14 and the limitations of an atomizer, and a pharmaceutically acceptable excipient, to form an aqueous solution, Mischley discloses the GSH was formulated as 200 mg GSH in 1cm3 of saline, using a device attached to a Mucosal Atomization Device, see page 5, column 2, under Study Medication.
Claim 19 recites the limitation of determining a change in the concentration of glutathione in the brain region over a period of time. Mischley discloses “After baseline GSH measurement, 200 mg (in) GSH was self-administered inside the scanner without repositioning, then serial GSH levels were obtained over ~1h, Statistical significance was determined by one-way repeated measures analysis of variance.” See Abstract.
Regarding claim 20 and the limitation wherein the administering increases the concentration of glutathione from about 20% to about 300%, Mischley discloses GSH levels were significantly higher than baseline at all of the remaining time points (P<0.05; Figure 3a,b). Mischley discloses between the baseline and the 45-min scan, there was a mean 269% increase in GSH/Cr (240% increase in absolute GSH). See P. 4, Fig. 3).
Claims 1-5, 7-14, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over MISCHLEY ET AL. Nature Partner Journals, 2016, 2, 16002, Pgs. 1-6 in view of WO 2019/084543.
Regarding claims 1 and 3 and administration of therapeutic agent (NAC derivative) in therapeutically effective amounts to a subject in need, and, quantification of glutathione by MRI Mischley discloses its objective 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 Parkinson’s disease, see abstract. As defined by the specification, GSH is a NAC derivative. See paragraph 29.
As required by claims 1, 4, 7 and 8 where the subject in need has a brain/CNS condition, i.e. Parkinson’s disease (PD, elected species), Mischley discloses treatment of PD, as defined by a lack of GSH. See abstract. Mischley teaches administration of therapeutically effective amounts of an agent are administered intranasally to a patient in need. See abstract.
While Mischley teaches the invention of main independent claim 1 as detailed above, it does not expressly teach the various species of the method of claim 1; the species of claim 2 (a species of N-acetylcysteine per se); claim 5 (species of treatment of mild traumatic brain injury); claim 10 (nasal pump for NAC or glutathione). However a PHOSITA would have a reasonable expectation in arriving at the claimed invention because 1) NAC is known to treat subjects in need, 2) treatment of mild traumatic brain injury is known and 3) nasal pumps are art known.
With regard to claims 1-3, Mischley discloses “intravenous NAC repletion” is seen “as a therapeutic strategy in PD,” despite some issues. See page 1, column 2 bridging to page 2, column 1. While Mischley does not teach NAC administered intranasally, WO 543 teaches treating CNS disorders comprising intranasally administering at least one antioxidant compound. See paragraph 90. WO 543 discloses the antioxidant compound is, inter alia, NAC or glutathione. See paragraph 91. Because Mischley and WO 543 are in the same space of treatment of conditions (brain conditions) with NAC or glutathione, one of ordinary skill in the art would have rationale to combine them.
Regarding claim 5, WO 543 discloses the CNS disorder is traumatic brain injury (TBI). See paragraph 95.
Regarding claim 10, WO 543 teaches devices for intranasal delivery include, inter alia, “Aptar Pharma nasal spray pump.” See paragraph 52.
Prior to the filing of the present patent application, a PHOSITA, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference in Mischley teachings steps a)-c) of claim 1 to modify with the second reference WO 543 teaching intranasal administration of NAC for the same patient population. The rationale to support a finding of obviousness are the prior art elements of Mischley combined with known methods, intranasal administration of therapeutic antioxidant agents such as NAC and NAC derivative GSH to subjects in need to treat brain conditions such Parkinson’s disease and mild traumatic brain injury.
Regarding claim 9’s limitation of a therapeutically-effective amount of about 100 mg to about 400 mg, Mischley discloses a dose of 200 mg was self-administered. See abstract.
Regarding claims 11 and 13-14 and the limitations of an atomizer, and a pharmaceutically acceptable excipient, to form an aqueous solution, Mischley discloses the GSH was formulated as 200 mg GSH in 1cm3 of saline, using a device attached to a Mucosal Atomization Device, see page 5, column 2, under Study Medication.
With regard to claim 12 and the limitation of wherein the administering is repeated at least one time, Mischley teaches the treatment of Parkinson’s disease, a long term debilitating CNS disorder, requiring a lifetime of treatment. See abstract and paragraph 95 of WO 543. While not expressly reciting a repeat administration of GSH or NAC of at least once, one skill in the art would repeat the GSH or NAC treatment at least once due to the lifelong nature of Parkinson’s disease.
Regarding claim 19 and measurement of changes of glutathione in the brain over time, Mischley discloses “After baseline GSH measurement [followed by]. . . . then serial GSH levels were obtained over~ 1 h. . . .” See Abstract. With regard to the amendment of claim 19, wherein the selected delivery parameter is based on the determined change in the concentration of GSH, it would be routine for a PHOSITA to optimize the selection of the delivery parameter of dosages of GSH based on determined changes of GSH concentration, where Table 2 discloses corresponding GSH levels in response to a given dose of GSH administered intranasally.
Regarding claim 20 and the limitation wherein the administering increases the concentration of glutathione from about 20% to about 300%, Mischley discloses GSH levels were significantly higher than baseline at all of the remaining time points (P<0.05; Figure 3a,b). Mischley discloses between the baseline and the 45-min scan, there was a mean 269% increase in GSH/Cr (240% increase in absolute GSH). See P. 4, Fig. 3).
Claims 1, 3, 4, 6-9, 11, 13, 14, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over MISCHLEY ET AL. Nature Partner Journals, 2016, 2, 16002, Pgs. 1-6 in view of U.S. 2015/0148423 A1.
The teachings of Mischley are as applied supra (see 35 U.S.C. 103 rejection above), and are herein incorporated by reference in their entirety, rendering Claims 1 (steps a), b) and c) of claim 1) and dependent claims 3,4, 7-9, 11, 13, 14, 19 and 20 prima facie obvious. However, the species of method of claim 6 differs from the combined teachings of Mischley in so far as it does not disclose treatment of cancer per claim 6.
Regarding claim 6, US Pub 423 discloses the intranasal administration of NAC to a subject, where the brain condition to be treated is cancer, see paragraphs 42, 44 and 15. The motivation to combine the cited prior art is the fact that Mischley discloses nasal administration of the “essential intracellular antioxidant GSH” and the use of NAC also, see above. Further, US Pub 423 discloses both NAC and GSH for its antioxidant activity (see paragraphs 2-4).
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference Mischley (with regard to steps a)-c) of claim 1 and dependent claims) as modified by the secondary reference US 423 in order to treat species of brain cancer via intranasal administration of NAC. The rationale to support a finding of obviousness is the combination of prior art elements according to known methods to yield predictable results, i.e. intranasal administration of GSH or NAC to treat in injury (as per Mischley) and to treat brain cancer (as per US Pub 423).
Claims 1, 3, 4, 7-9, 11 and 13-21 are rejected under 35 U.S.C. 103 as being unpatentable over MISCHLEY ET AL. Nature Partner Journals, 2016, 2, 16002, Pgs. 1-6 in view of Duncan et al. (Movement Disorders Volume 28 Issue 4 April 2013). Duncan is listed on the PTO-892 form.
The teachings of Mischley are as applied supra (see 35 U.S.C. 103 rejection above), and are herein incorporated by reference in their entirety, rendering Claims 1 (steps a), b) and c) of claim 1) and dependent claims 3,4, 7-9, 11, 13, 14, 19 and 20 prima facie obvious. The species of method of claims 15-18 differ from the combined teachings of Mischley in so far as it does not disclose treatment of brain regions of the cerebrum, a frontal lobe, an occipital lobe and the occipital cortex, per claims 15-18 and 21.
Regarding claims 15-18 and 21, it is noted that the cerebrum is divided into frontal, parietal, occipital and temporal lobes/cortex and substantia nigra. Duncan discloses MR imaging to investigate cognitive decline in PD, outline limitations of those studies, and suggest directions for future research. See abstract. Duncan discloses various MRI studies in Parkinson’s disease and cognitive impairment, including regions of the brain such as the frontal lobe as per Beyer et al. (2007), see Table 1; the left occipital lobe, see Burton et al. (2004), Table 1; the occipital cortex, see Melzer et al. (2012), Table 1. See also page 426, column 1 noting the presence of Lewy bodies (associated with PD) in the substantia nigra.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference Mischley (with regard to steps a)-c) of claim 1 and dependent claims) as modified by the secondary reference US 423 in order to investigate these areas of the brain via MRI, as they are associated with Parkinson’s Disease as per Duncan, where Mischley disclosed the use of MRI in measuring the levels of GSH to treat Parkinson’s disease. The rationale to support a finding of obviousness is the combination of prior art elements according to known methods to yield predictable results, i.e. intranasal administration of GSH or NAC to treat in injury (as per Mischley in combination with Duncan, MRI technology is used to diagnose, research and evaluate Parkinson’s disease in the claimed areas of the brain).
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response argues that optimization is not a simple observation but a deliberate, multi-step feedback process that would include the 5 points recited therein.2
In response to applicant's argument that the references fail to show certain features of applicant’s invention, it is noted that the features upon which applicant relies (i.e., bullet points 1-5) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
More specifically, 1) determination of a geometric pattern and droplet spray of a device to affect different brain regions, 2) analysis of drug concentration over time for optimal dosing frequency, 3) dose titration, 4) different drug formulation evaluation, 5) confirmation of parameters are NOT specifically recited in the claims as filed.
In fact, as detailed above, with regard to step c) and the parameters of drug concentration analysis over time, dose titration and different drug formulation with respect to confirmation of said parameters, are arguably disclosed by Mischley above, as detailed in the rejection. In particular, Mischley teaches its study was the first to demonstrate an increase an increase in CNS GSH levels with a noninvasive GSH augmentation, See page 3, column 1, Discussion, a person having ordinary skill in the art (PHOSITA) would routinely optimize the selection of a dose and/or formulation for any subsequent intranasal administration based on glutathione concentrations in said subject.
Mischley teaches in its study, it was able to demonstrate that previous obstacles of inability to assess human CNS GSH concentrations in vivo and poor oral absorption of GSH were overcome by its H-MRS editing method to measure CNS GSH levels and a noninvasive (intranasal) GSH administration strategy as a therapeutic approach for only on PD but also other CNS GSH deficiency disorders. See page 3. Mischley teaches in particular, the selection of dose delivery parameter for subsequent intranasal administration throughout its disclosure. For example, Table 2 demonstrates changes in brain GSH levels (GSH/cr peak ratios) relative to baseline after 200 mg nasally administered GSH. See page 3, top of page. Based off the teachings of Mischley, for example Table 2, where a 200 mg intranasal dose of GSH resulted in various GSH/Cr peak ratios over time, a PHOSITA would routinely optimize the delivery parameter of dose with potential subsequent intranasal administration to optimize GSH levels based on resulting GSH levels measured.
The Attorney response points to paragraph 40, Example 10 etc. to argue these particulars of the specification are to be read into “optimizing a therapeutic regimen” as claimed so as to differentiate from its characterization of Mischley being a single-dose, proof of concept of study.
The Attorney response states there is “no teaching or suggestion of using the results of this one-time measurement to then inform and optimize a further course of treatment,” such as selection of a new dose, different formulation or an alternative delivery device. As detailed above, optimization of dosing, whether higher or lower than the 200 mg intranasal taught be Mischley would be readily apparent to a PHOSITA, as a clinician of ordinary skill in the art would no doubt lower or increase doses of GSH, based on teachings of Mischley (Table 2) to achieve desired clinical profiles to treat the subject in need via intranasal administration.
The Attorney response further argues the alleged deficiencies of Mischley are not corrected by the teachings of Duncan, WO 543 or US 423. In response, Mischley nonetheless teaches the amended claim 1 with regard to step c) and in particular the dose delivery parameter
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.
RESPONSE TO ATTORNEY ARGUMENTS OF THE PROVISIONAL OBVIOUSNESS DOUBLE PATENTING REJECTIONS:
The Attorney response requests the provisional ODP rejections over 18/509,935 and 18/792,836 be held in abeyance. In response, the request to hold rejections in abeyance is NOT a proper rebuttal of the ODP rejections. Therefore, the ODP rejections are maintained and/or newly applied to amended claims 1, 19 and new claim 21, see below.
Claims 1-5, 9-13 and 15-21 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-15 and 19-20 of copending Application No. 18/509,935 in view of MISCHLEY et al. Nature Partner Journals, 2016, 2, 16002, Pgs. 1-6.
Examined claims 1-5 disclose administration of therapeutic agent to a subject in need, with a brain/CNS condition such, mild traumatic brain injury where the agent is NAC or derivative, where claim 1 requires quantifying glutathione in the brain by magnetic spectroscopy (such as MRI).
The reference application generally claims treating traumatic brain injury in a subject, the method comprising intranasally administering a dose of N-acetylcysteine (NAC). See reference claim 1, in humans as per reference claim 2. Reference claim 3 discloses a condition such as a concussion. It is noted that the reference application does not teach quantifying glutathione by MRI as per claim 1.
However one of ordinary skill in the art would do so with a reasonable expectation of success as such technique is known in the art. As required by claim 1, Mischley discloses its objective 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, see abstract. As defined by the specification, GSH is a NAC derivative. See paragraph 29.
Regarding claim 9 reciting a range of about 100-400 mg, reference claim 15 discloses an overlapping dose that is about 50-350 mg.
Claims 10-11 recite nasal pump and an atomizer. Reference application teaches a nebulizer (a form of nasal pump claim 19) and atomizer (claim 20).
With regard to claim 12 and the limitation of wherein the administering is repeated at least one time, while not expressly reciting a repeat administration of GSH or NAC of at least once, one skilled in the art would have a rationale to repeat the GSH or NAC treatment at least once due to the nature of traumatic brain injury likely requiring repeat dosing to cure the subject.
Claim 13 discloses a composition comprising pharmaceutically acceptable excipient(s). These limitations are taught by reference claims 4-14.
Claims 15-18 and 21 are directed to regions of the brain, the cerebrum, frontal lobe, occipital lobe, occipital cortex and substantia nigra. While not expressly claimed by the reference patent, it would be obvious to scan these regions of the brain via magnetic resonance spectroscopy as the mild traumatic brain injury of traumatic brain injury (concussion) would affect these brain regions.
Regarding claim 19 and measurement of changes of glutathione in the brain over time, Mischley discloses “After baseline GSH measurement [followed by]. . . . then serial GSH levels were obtained over~ 1 h. . . .” See Abstract. . With regard to the amendment of claim 19, wherein the selected delivery parameter is based on the determined change in the concentration of GSH, it would be routine for a PHOSITA to optimize the selection of the delivery parameter of dosages of GSH based on determined changes of GSH concentration, where Table 2 discloses corresponding GSH levels in response to a given dose of GSH administered intranasally.
Regarding claim 20 wherein the administering increases the concentration of glutathione from about 20% to about 300%, Mischley discloses between the baseline and the 45-min scan, there was a mean 269% increase in GSH/Cr (240% increase in absolute GSH). See P. 4, Fig.3).
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Claims 1-5 and 7-21 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-25 of copending Application No. 18/792,836 in view of MISCHLEY et al., Nature Partner Journals, 2016, 2, 16002, Pgs. 1-6.
Claims 1-5 and 7-8 disclose administration of therapeutic agent to a subject in need, with a brain/CNS condition such as Parkinson’s, mild traumatic brain injury and cancer where the agent is NAC or derivative, where claim 1 requires quantifying glutathione in the brain by magnetic spectroscopy (such as MRI).
Regarding claims 1-5 and 7-8, the reference application teaches treatment of brain disorder in a subject with GSH (a known NAC derivative) where doses are administered via first the olfactory pathway and second the trigeminal pathway of the subject. See claim 1. Reference application claims 2-10 and 22 disclose disorders such as mild traumatic brain injury, Parkinson’s disease, etc.
Regarding claim 9, the reference application teaches a therapeutically effective amount from about 100-400 mg. See claim 18.
Regarding claims 10-11, the reference application teaches a nasal pump and atomizer. See claim 19.
With regard to claim 12 wherein the administering is repeated at least one time, while not expressly reciting a repeat administration of GSH or NAC of at least once, one skilled in the art would have a rationale to repeat the GSH or NAC treatment at least once due to the nature of traumatic brain injury and/or Parkinson’s disease likely requiring repeat dosing to cure the patient.
Regarding claim 13 and the limitation of a pharmaceutical composition that further comprises a pharmaceutically acceptable excipient, these limitations are taught by reference claims 1-25, as the methods of the application administering a therapeutic agent to a subject in need, by virtue of this method by its nature, requires a pharmaceutical composition that must pharmaceutically acceptable excipients.
Regarding claim 14 and the limitation of an aqueous solution administered, reference claim 19 discloses a nasal pump. By their nature, nasal pumps administer liquid formulations, such as aqueous solutions. Therefore, it would be routine for one skilled in the art optimize and formulate an aqueous therapeutic agent composition as claimed.
Claims 15-18 and 21 are directed to regions of the brain, such as the cerebrum, frontal lobe, occipital lobe, occipital cortex and substantia nigra. While not expressly claimed by the reference patent, it would be obvious to scan these regions of the brain via magnetic resonance spectroscopy as the prior art brain disorders would affect these regions of the brain.
Regarding claim 19 and measurement of changes of glutathione in the brain over time, Mischley discloses “After baseline GSH measurement [followed by]. . . . then serial GSH levels were obtained over~ 1 h. . . .” See Abstract. . With regard to the amendment of claim 19, wherein the selected delivery parameter is based on the determined change in the concentration of GSH, it would be routine for a PHOSITA to optimize the selection of the delivery parameter of dosages of GSH based on determined changes of GSH concentration, where Table 2 discloses corresponding GSH levels in response to a given dose of GSH administered intranasally.
Regarding claim 20 wherein the administering increases the concentration of glutathione from about 20% to about 300%, Mischley discloses between the baseline and the 45-min scan, there was a mean 269% increase in GSH/Cr (240% increase in absolute GSH). See P. 4, Fig.3).
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
RESPONSE TO ATTORNEY ARGUMENTS WITH REGARD TO ODP REJECTIONS OVER THE ‘278 PATENT, THE ‘939 PATENT AND THE ‘130 PATENT:
The Attorney response argues the newly amended claim 1 render the invention patentably distinct from the claims of the conflict patent.
For the reasons cited above, where Mischley details and teaches the limitations of amended claim 1’s step c), the claims remain rejected over the conflict patents listed in view of Mischley.
Claims 1-5, 9-13 and 15-20 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-16 of US 11,660,278 B2 in view of MISCHLEY et al., Nature Partner Journals, 2016, 2, 16002, Pgs. 1-6.
Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to treating a subject in need with NAC and/or an NAC derivative.
Examined Claims 1-5 disclose administration of therapeutic agent to a subject in need, with a brain/CNS condition such, mild traumatic brain injury where the agent is NAC or derivative, where claim 1 requires quantifying glutathione in the brain by magnetic spectroscopy (such as MRI).
The reference patent generally claims treating post-concussion syndrome in a brain of a subject in need thereof, the method comprising intranasally administering to the subject a dose of N-acetylcysteine (NAC), wherein the intranasal administration provides a therapeutically-effective amount of the NAC to the brain through a nasal cavity of the subject, wherein the dose is about 50 mg to about 350 mg. See reference claim 1, in human as per claim 2. It is noted that the reference patent does not teach quantifying glutathione by MRI as per claim 1.
Mischley discloses its objective 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, see abstract. As defined by the specification, GSH is a NAC derivative. See paragraph 29.
Mischley teaches in particular, the selection of dose delivery parameter for subsequent intranasal administration throughout its disclosure. See Abstract and page 3, column 1 Discussion. For example, Table 2 demonstrates changes in brain GSH levels (GSH/cr peak ratios) relative to baseline after 200 mg nasally administered GSH. See page 3, top of page. Based off the teachings of Mischley, for example Table 2, where a 200 mg intranasal dose of GSH resulted in various GSH/Cr peak ratios over time, a PHOSITA would routinely optimize the delivery parameter of dose with potential subsequent intranasal administration to optimize GSH levels based on resulting GSH levels measured. Optimization of dosing, whether higher or lower than the 200 mg intranasal taught be Mischley would be readily apparent to a PHOSITA, as a clinician of ordinary skill in the art would no doubt lower or increase doses of GSH, based on teachings of Mischley (Table 2) to achieve desired clinical profiles to treat the subject in need via intranasal administration.
It would have been prima facie obvious to a PHOSITA following the teachings of the primary reference in Mischley teachings steps a) and b) of claim 1 (administration of therapeutic agent (GSH) to a subject to treat a condition such as PD,) to modify with the secondary teachings of Mischley (selection of dose delivery parameter) so as to routinely optimize treatment based on quantified GSH concentrations in the subject.
The PHOSITA would have had a reasonable expectation of success because Mischley not only teaches treatment of PD with GSH in subjects in need where patients under go MRIs to determine treatment effectiveness but also Mischley teaches the effects of GSH dose as a delivery parameter administered in terms of GSH concentration quantified in the treated subjects.
Claim 9 discloses a therapeutically effective amount from about 100-400 mg. Reference patent claim 1 discloses an overlapping dose that is about 50-100 mg.
Examined claims 10-11 claim a nasal pump and an atomizer. These limitations are taught by reference patent claims 16 (nebulizer, a form of nasal pump) and claim 21 (atomizer).
With regard to claim 12 and the limitation of wherein the administering is repeated at least one time, while not expressly reciting a repeat administration of GSH or NAC of at least once, one skilled in the art would have a rationale to repeat the GSH or NAC treatment at least once due to the nature of traumatic brain injury likely requiring repeat dosing to cure the subject.
Claim 13 discloses a pharmaceutical composition comprising pharmaceutically acceptable excipient(s). These limitations are taught by reference claims 3-15.
Claims 15-18 are directed to regions of the brain, such as the cerebrum, frontal lobe, occipital lobe and occipital cortex. While not expressly claimed by the reference patent, it would be obvious to scan these regions of the brain via magnetic resonance spectroscopy as the mild traumatic brain injury of post-concussion syndrome would affect these regions of the brain.
Regarding claim 19 and measurement of changes of glutathione in the brain over time, Mischley discloses “After baseline GSH measurement [followed by]. . . . then serial GSH levels were obtained over~ 1 h. . . .” See Abstract. . With regard to the amendment of claim 19, wherein the selected delivery parameter is based on the determined change in the concentration of GSH, it would be routine for a PHOSITA to optimize the selection of the delivery parameter of dosages of GSH based on determined changes of GSH concentration, where Table 2 discloses corresponding GSH levels in response to a given dose of GSH administered intranasally.
Regarding claim 20 wherein the administering increases the concentration of glutathione from about 20% to about 300%, Mischley discloses between the baseline and the 45-min scan, there was a mean 269% increase in GSH/Cr (240% increase in absolute GSH). See P. 4, Fig.3).
Claims 1-4, 8-10, and 12-14 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-21 of US Patent 11,963,939 in view of MISCHLEY et al., Nature Partner Journals, 2016, 2, 16002, Pgs. 1-6.
Although the conflicting claims are not identical, they are not patentably distinct from each other because both inventions are directed towards treatment of a brain condition with a therapeutic agent.
Examined claims 1-4 and 8 disclose administration of therapeutic agent to a subject in need, with a brain/CNS condition such, mild traumatic brain injury where the agent is NAC or derivative, where claim 1 requires quantifying glutathione in the brain by magnetic spectroscopy (such as MRI).
The reference patent generally claims treating Parkinson’s disease in a subject in need thereof, the method comprising intranasally administering to the subject a dose of N-acetylcysteine (NAC), wherein administering to the subject’s brain through the nasal cavity a dose of about 100 mg to about 350 mg. See reference claim 1, in human as per claim 2. See also reference 19. It is noted that the reference patent does not teach quantifying glutathione by MRI as per claim 1.
Mischley discloses its objective 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, see abstract. As defined by the specification, GSH is a NAC derivative. See paragraph 29.
Mischley teaches in particular, the selection of dose delivery parameter for subsequent intranasal administration throughout its disclosure. See Abstract and page 3, column 1 Discussion. For example, Table 2 demonstrates changes in brain GSH levels (GSH/cr peak ratios) relative to baseline after 200 mg nasally administered GSH. See page 3, top of page. Based off the teachings of Mischley, for example Table 2, where a 200 mg intranasal dose of GSH resulted in various GSH/Cr peak ratios over time, a PHOSITA would routinely optimize the delivery parameter of dose with potential subsequent intranasal administration to optimize GSH levels based on resulting GSH levels measured. Optimization of dosing, whether higher or lower than the 200 mg intranasal taught be Mischley would be readily apparent to a PHOSITA, as a clinician of ordinary skill in the art would no doubt lower or increase doses of GSH, based on teachings of Mischley (Table 2) to achieve desired clinical profiles to treat the subject in need via intranasal administration.
It would have been prima facie obvious to a PHOSITA following the teachings of the primary reference in Mischley teachings steps a) and b) of claim 1 (administration of therapeutic agent (GSH) to a subject to treat a condition such as PD,) to modify with the secondary teachings of Mischley (selection of dose delivery parameter) so as to routinely optimize treatment based on quantified GSH concentrations in the subject.
The PHOSITA would have had a reasonable expectation of success because Mischley not only teaches treatment of PD with GSH in subjects in need where patients under go MRIs to determine treatment effectiveness but also Mischley teaches the effects of GSH dose as a delivery parameter administered in terms of GSH concentration quantified in the treated subjects.
Regarding claim 9 and the dose therein, the reference application teaches an overlapping dose of about 100 mg to about 350 mg. See claims 1 and 19.
Examined claim 10 claim a nasal pump. Reference patent claims 20-21 teach a nasal sprayer comprising a spray pump.
With regard to claim 12 and the limitation of wherein the administering is repeated at least one time, while not expressly reciting a repeat administration of GSH or NAC of at least once, one skill in the art would have a rationale to repeat the GSH or NAC treatment at least once due to Parkinson’s disease being a life-long condition requiring repeat dosing to cure the subject.
Claim 13 discloses a composition comprising pharmaceutically acceptable excipient(s). These limitations are taught by reference claims 3-18.
Regarding claim 14 and the limitation of an aqueous solution, this taught by claims 16-18, noting liquid compositions, where it one of ordinary skill in the art would routinely optimize formulation of aqueous solutions where the art teaches liquid formulations.
Claims 15-18 are directed to regions of the brain, such as the cerebrum, frontal lobe, occipital lobe and occipital cortex. While not expressly claimed by the reference patent, it would be obvious to scan these regions of the brain via magnetic resonance spectroscopy as Parkinson’s disease would affect these regions of the brain.
Regarding claim 19 and measurement of changes of glutathione in the brain over time, Mischley discloses “After baseline GSH measurement [followed by]. . . . then serial GSH levels were obtained over~ 1 h. . . .” See Abstract. . With regard to the amendment of claim 19, wherein the selected delivery parameter is based on the determined change in the concentration of GSH, it would be routine for a PHOSITA to optimize the selection of the delivery parameter of dosages of GSH based on determined changes of GSH concentration, where Table 2 discloses corresponding GSH levels in response to a given dose of GSH administered intranasally.
Regarding claim 20 wherein the administering increases the concentration of glutathione from about 20% to about 300%, Mischley discloses between the baseline and the 45-min scan, there was a mean 269% increase in GSH/Cr (240% increase in absolute GSH). See P. 4, Fig.3).
Claims 1-5 and 7-20 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-24 of US Patent 12,090,130 in view of MISCHLEY et al., Nature Partner Journals, 2016, 2, 16002, Pgs. 1-6.
Although the claims at issue are not identical, they are not patentably distinct from each other because they are both directed to methods of treating brain disorders with NAC and/or derivatives thereof.
Claims 1-8 disclose administration of therapeutic agent to a subject in need, with a brain/CNS condition such as Parkinson’s, mild traumatic brain injury and cancer where the agent is NAC or derivative, where claim 1 requires quantifying glutathione in the brain by magnetic spectroscopy (such as MRI).
Regarding claims 1-8, the reference patent teaches treatment of brain disorders, including concussion, post-concussion syndrome, mild traumatic brain injury athletic injury brain injury, dementia, neurodegenerative disease, Parkinson’s disease and stroke. See reference claims 1-11. It is noted that the reference patent does not teach quantifying glutathione by MRI as per claim 1.
Mischley discloses its objective 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, see abstract. As defined by the specification, GSH is a NAC derivative. See paragraph 29.
Mischley teaches in particular, the selection of dose delivery parameter for subsequent intranasal administration throughout its disclosure. See Abstract and page 3, column 1 Discussion. For example, Table 2 demonstrates changes in brain GSH levels (GSH/cr peak ratios) relative to baseline after 200 mg nasally administered GSH. See page 3, top of page. Based off the teachings of Mischley, for example Table 2, where a 200 mg intranasal dose of GSH resulted in various GSH/Cr peak ratios over time, a PHOSITA would routinely optimize the delivery parameter of dose with potential subsequent intranasal administration to optimize GSH levels based on resulting GSH levels measured. Optimization of dosing, whether higher or lower than the 200 mg intranasal taught be Mischley would be readily apparent to a PHOSITA, as a clinician of ordinary skill in the art would no doubt lower or increase doses of GSH, based on teachings of Mischley (Table 2) to achieve desired clinical profiles to treat the subject in need via intranasal administration.
It would have been prima facie obvious to a PHOSITA following the teachings of the primary reference in Mischley teachings steps a) and b) of claim 1 (administration of therapeutic agent (GSH) to a subject to treat a condition such as PD,) to modify with the secondary teachings of Mischley (selection of dose delivery parameter) so as to routinely optimize treatment based on quantified GSH concentrations in the subject.
The PHOSITA would have had a reasonable expectation of success because Mischley not only teaches treatment of PD with GSH in subjects in need where patients under go MRIs to determine treatment effectiveness but also Mischley teaches the effects of GSH dose as a delivery parameter administered in terms of GSH concentration quantified in the treated subjects.
Regarding the dose range limitation of claim 9, the reference patent discloses an overlapping range of about 100 mg to about 400 mg. See claim 18.
Regarding claims 10-11, the reference patent teaches a nasal pump (claim 19) and an atomizer (claim 20).
With regard to claim 12 and the limitation of wherein the administering is repeated at least one time, while not expressly reciting a repeat administration of GSH or NAC of at least once, one skill in the art would have a rationale to repeat the GSH or NAC treatment at least once due to nature of brain disorders (concussion, dementia, Parkinson’s disease, traumatic brain injury, etc.) likely requiring repeat dosing to cure the subject.
Regarding claim 13 and the limitation of a pharmaceutical composition comprising a pharmaceutically acceptable carrier, it is pointed out that claims 1-24 are methods of administering NAC/congeners/derivatives, etc. to a subject in need suffering from a brain disorder. By the very nature of such a method, active pharmaceutical ingredients, such as NAC, require formulation into pharmaceutical compositions which must be formulated with excipients to administer them to subjects. Therefore, the reference patent claims 1-24 render claim 13 obvious.
Regarding claim 14 and the limitation of an aqueous solution administered, reference claim 19 discloses a nasal pump. By their nature, nasal pumps administer liquid formulations, such as aqueous solutions. Therefore, it would be routine for one skilled in the art optimize and formulate an aqueous therapeutic agent composition as claimed.
Claims 15-18 are directed to regions of the brain, such as the cerebrum, frontal lobe, occipital lobe and occipital cortex. While not expressly claimed by the reference patent, it would be obvious to scan these regions of the brain via magnetic resonance spectroscopy as any of the brain disorders taught by the art would affect these brain regions.
Regarding claim 19 and measurement of changes of glutathione in the brain over time, Mischley discloses “After baseline GSH measurement [followed by]. . . . then serial GSH levels were obtained over~ 1 h. . . .” See Abstract. . With regard to the amendment of claim 19, wherein the selected delivery parameter is based on the determined change in the concentration of GSH, it would be routine for a PHOSITA to optimize the selection of the delivery parameter of dosages of GSH based on determined changes of GSH concentration, where Table 2 discloses corresponding GSH levels in response to a given dose of GSH administered intranasally.
Regarding claim 20 wherein the administering increases the concentration of glutathione from about 20% to about 300%, Mischley discloses between the baseline and the 45-min scan, there was a mean 269% increase in GSH/Cr (240% increase in abso