Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application, filed 06/28/2023 Claims Priority from Provisional Application 63390563, filed 07/19/2022; and Priority from Provisional Application 63358104, filed 07/02/2022.
Status of Claims
Claims 1, 4-17, and 19-22 are pending as of the response filed on 6/21/26. Claims 2-3, 18, and 23-47 have been canceled.
Applicant’s election of disorders treated by increasing or restoring PGC-1alpha, and thermal hyperalgesia in the reply filed on 6/21/26 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). However, upon further consideration, the species election requirement is withdrawn.
Claims 1, 4-17, and 19-22 were examined and are rejected.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code; see pg. 25, last para of the specification. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections-35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-17, and 19-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Independent claims 1, 4, and 7 recite administering “first and second particulate metaxalones”, however, this language is confusing, as it’s uncertain what the terms “first” and “second” specifically are in reference to; how do they differ from each other? What distinguishes the “first” from the “second”; are there differences in particles size for instance, or concentration? The claims are therefore indefinite, and claims 5-6, 8-17, and 19-22 are similarly rejected for depending on the rejected independent claims and not providing further clarity.
For the sake of providing compact prosecution and prior art searching, the examiner has interpreted “first and second particulate metaxalones” as differing from each other with respect to particle size distribution.
Claim Rejections-35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 7-10, 16, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pallio et. al., Int. J. Molecular Sci., vol. 22, 8425 (pp. 1-11), publ. 8/5/2021, in view of Dodd et. al., WO 2010121324 A1, publ. 10/28/2010.
Pallio teaches research suggests neurological disorders involve CNS neuroinflammation, and in particular microglia inflammation has been implicated in fibromyalgia (abstract; pp. 1-2, intro para). Pallio further teaches metaxalone as an approved muscle relaxant, purported to have MAO-A inhibitory action (pp. 1-2, intro para). Pallio teaches metaxalone was found to reduce an inflammatory phenotype in HMC3 microglial cells, and effectively reduced TNF-alpha, and IL-6 expression, while enhancing IL-13 mRNA (p. 5, para 3.1 & Fig. 1). Pallio further teaches metaxalone significantly upregulated Nrf2 expression and stimulated PGC-1alpha activation, while significantly reducing NF-ĸβ mRNA expression (p. 6 of 11, Fig. 2 and para 3.3). Additionally, metaxalone was confirmed to reduce MAO-A expression and activity induced by IL-1β in microglial cells (pp. 6-7, para 3.4). MAO related oxidative stress is taught to lead subsequently to mitochondrial dysfunction (p. 2 of 11). Pallio teaches CNS neuroinflammation may have an important role in amplifying pain perception, while fibromyalgia patients experience increased IL and TNF-alpha levels in serum and plasma, which exacerbate the inflammatory response and contribute to pain (p. 8, 1st 2 para under sec 4). Pallio concludes that metaxalone has important anti-inflammatory and antioxidant effects, which indicates therapeutic use for managing neuroinflammation and pain, including in fibromyalgia patients (p. 9, last 2 para).
Pallio doesn’t teach or suggest an oral dosage form of metaxalone, or first and second particulate metaxalone.
Dodd teaches methods of producing particulate metaxalone and pharmaceutical compositions comprising particulate metaxalone (title & abstract). Dodd teaches metaxalone as a medicament for the treatment of acute, painful musculoskeletal conditions, and prior studies have indicated reduction of particle size leads to higher rates of absorption and bioavailability (p. 3, lines 11-20). Dodd teaches a process of dry milling particles of an active agent, e.g., metaxalone, to provide a particle size equal to or less than 2000 nm, wherein the crystallinity of the active agent is unchanged (p. 4, lines 8-17). Dodd further teaches an embodiment wherein preferably, 50%, up to 100% of the particles have a particle size < 2000 nm, or < 1000 nm (p. 19, line 16-p. 20, line 4). Dodd further teaches a method of treating a human in need of treatment an effective amount of a composition comprising particulate metaxalone (p. 21, lines 13-31), and that the particulate compositions have an improved dissolution profile (p. 29, lines 5-36) as well as increased bioavailability (p. 46, lines 2-10). Dodd teaches the compositions are suitable for a variety of delivery routes, including orally, in dosage forms such as tablets, capsules, or powders (p. 48, lines 17-23). The compositions can further contain a wide variety of pharmaceutically acceptable excipients (p. 43, line 24-p. 45, line 2). Dodd teaches the inclusion of salts or other derivatives of metaxalone (p. 21, lines 13-20).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have treated a chronic or acute condition associated with neuroinflammation in a human; to have increased PGC-1alpha; treated fibromyalgia; and inhibited NF-ĸβ comprising administering an oral dosage form comprising: a therapeutic dose of first and second particulate metaxalone in free form or a pharmaceutically acceptable salt, in view of Pallio and Dodd. Pallio teaches metaxalone reduce an inflammatory phenotype in HMC3 microglial cells, and effectively reduced TNF-alpha, and IL-6 expression; upregulated IL-13 and Nrf2 expression and stimulated PGC-1alpha activation, while significantly reducing NF-ĸβ mRNA expression; and reduced MAO-A expression and activity. Pallio further teaches metaxalone as a medicament for managing neuroinflammation and pain, including in fibromyalgia patients. Although Pallio doesn’t teach particulate metaxalone, Dodd teaches particulate metaxalone having improved dissolution profile and bioavailability, in pharmaceutical compositions, including oral dosage forms. Dodd further teaches an embodiment wherein preferably, 50%, up to 100% of the particles have a particle size < 2000 nm, or < 1000 nm. As such, one of ordinary skill in the art would have readily envisaged particulate metaxalone having two different particulate size ranges, e.g., 50% having a particle size <1000 nm, and 50% having a particle size greater than 1000 nm but < 2000 nm, a first and second particulate. One of ordinary skill in the art would have been motivated to have administered the particulate metaxalone composition taught by Dodd to reduce TNF-alpha and IL-6 expression; upregulate IL-13, and Nrf2 expression and stimulate PGC-1alpha activation; reduce NF-ĸβ mRNA expression; and reduce MAO-A expression and activity in a human patient experiencing neuroinflammation, for the benefit of improved dissolution and bioavailability. Moreover, as Pallio teaches metaxalone for managing pain and inflammation in neuroinflammatory conditions such as fibromyalgia, it would have been prima facie obvious to have administered the particulate metaxalone composition of Dodd to treat a human patient having fibromyalgia, pain caused by a nerve injury, or for preventing pain chronification caused by a burn injury, and have had a reasonable expectation of success.
As Pallio teaches MAO related oxidative stress is taught to lead subsequently to mitochondrial dysfunction, it would have further been prima facie obvious to have administered the particulate metaxalone composition of Dodd to ameliorate mitochondrial dysfunction and restore mitochondrial biogenesis as recited by claim 10, and have had a reasonable expectation of success.
Regarding claim 9, “wherein said neuropathic pain…”, it is noted that the claim doesn’t explicitly require the condition to be treated to be limited to neuropathic pain, and it is cited only in the alternative in claim 8, from which it depends.
Claim(s) 11, 20, and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pallio et. al., Int. J. Molecular Sci., vol. 22, 8425 (pp. 1-11), publ. 8/5/2021, in view of Dodd et. al., WO 2010121324 A1, publ. 10/28/2010 as applied to claims 1, 7-10, 16, and 19 above, and further in view of Kang et. al., Journal Sport & Health Sci., vol. 2, pp. 81-86, publ. 2013.
The teachings of Pallio and Dodd as discussed previously are incorporated herein. However, neither explicitly teaches or suggests stimulation of NRF-1 and NRF2; revitalizing muscle strength; and regeneration of muscle tissue as claimed.
Kang teaches PGC-1alpha as a key transcriptional coactivator that stimulates mitochondrial biogenesis, gene expression of superoxide dismutase-2, catalase, and glutathione peroxidase 1 (abstract; p. 81, 2nd para). Decreased mitochondrial content and functional capacity are also implicated in the development of mitochondrial myopathy (p. 81, 1st para). In particular, PGC-1alpha coactivates NRF-1 and NRF-2 (p. 82, para under sec 2.1). PGC-1alpha downregulation is observed in muscle atrophy, and PGC-1alpha is suggested to exert a protective role against muscle wasting, as changes characteristic of muscle sarcopenia were ameliorated with PGC-1alpha overexpression (p. 83, right col., last para-p. 84, right col., top para). Moreover, PGC-1alpha reduction in signaling appears to initiate the aging cascade in skeletal muscle, while PGC-1alpha elevation appears to be vital to restoring muscle (p. 84, left col., last para-right col., top para).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have administered the particulate metaxalone composition of Dodd to a human subject in need of treatment and increasing PGC-1alpha, to stimulate NRF-1 and NRF-2; revitalize muscle strength; and initiate regeneration of muscle tissue, in consideration of the combined teachings of Pallio, Dodd, and Kang. Pallio, as discussed previously teaches metaxalone stimulated PGC-1alpha activation and upregulated NRF-2 expression, while Kang teaches PGC-1alpha as a coactivator of both NRF-1 and NRF-2. Therefore, it would have been reasonably obvious that administration of the metaxalone particulate composition taught by Dodd would have resulted in stimulation of PGC-1alpha, leading to stimulation of NRF-1 and -2. Furthermore, Kang teaches PGC-1alpha elevation appears to be vital to restoring muscle, while downregulation is associated with skeletal muscle atrophy and sarcopenia. Thus, it would have been prima facie obvious to one of ordinary skill in the art that administration of the metaxalone particulate composition taught by Dodd would have resulted in stimulation of PGC-1alpha, leading to revitalization of muscle strength and initiation of muscle tissue regeneration.
Claim(s) 13-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pallio et. al., Int. J. Molecular Sci., vol. 22, 8425 (pp. 1-11), publ. 8/5/2021, in view of Dodd et. al., WO 2010121324 A1, publ. 10/28/2010 as applied to claims 1, 7-10, 16, and 19 above, and further in view of Thirupathi et. al., J. Physiol. Biochem., vol. 73, pp. 487-494, publ. 7/14/2017.
The teachings of Pallio and Dodd as discussed previously are incorporated herein. However, neither explicitly teaches or suggests stimulation of AMPK or bolstering gene expression and protein syntheses of MnSOD and catalase as claimed.
Thirupathi teaches PGC-1alpha as an important transcription coactivator that supports the activation of other transcription factors including NRF-1 and NRF-2, and upregulation of gene expression of mitochondrial biogenesis (p. 490, para beginning with title “Role of PGC-1 α…”). Thirupathi further teaches PGC-1alpha increases the stimulation of dismutase-2 (also known as MnSOD) and catalase, while AMPK and p38 MAPK induce PGC-1alpha expression (p. 490, para beginning with title “Role of PGC-1 α…”). Additionally, PGC-1alpha is activated by AMPK and SIRT1 (p. 491, Fig. 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have administered the particulate metaxalone composition of Dodd to a human subject in need of treatment and increasing PGC-1alpha, to stimulate AMPK, and bolstering gene expression and protein synthesis of MnSOD and catalase, in consideration of the combined teachings of Pallio, Dodd, and Thirupathi. Pallio, as discussed previously teaches metaxalone stimulated PGC-1alpha activation and upregulated NRF-2 expression, while Thirupathi teaches PGC-1alpha as a stimulator of SOD2 (MnSOD) and catalase. Furthermore, AMPK is taught to increase PGC-1alpha. Therefore, it would have been reasonably expected that administration of the metaxalone particulate composition taught by Dodd would have resulted in stimulation of PGC-1alpha via AMPK signaling, leading to stimulation of MnSOD and catalase.
Claim(s) 4-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pallio et. al., Int. J. Molecular Sci., vol. 22, 8425 (pp. 1-11), publ. 8/5/2021, in view of Dodd et. al., WO 2010121324 A1, publ. 10/28/2010 as applied to claims 1, 7-10, 16, and 19 above, and further in view of Chen et. al., J. Neuroinflammation, vol. 19, pp. 1-28, publ. 5/16/2022.
The teachings of Pallio and Dodd as discussed previously are incorporated herein. While Pallio teaches metaxalone enhanced IL-13 expression, neither explicitly teaches or suggests inhibition of STAT3 and increasing white matter growth and development as claimed.
Chen teaches IL-13 as an anti-inflammatory cytokine that regulates microglia/macrophage polarization towards an anti-inflammatory phenotype, at least partially by inhibition of STAT3 (abstract; p. 2 of 28, right col., 1st full para). Furthermore, Chen teaches enhancement of IL-13 improved brain inflammation and promoted white matter repair and integrity after ischemic stroke (p. 2 of 28, right col., 1st para; p. 10 of 28, left col., last para-right col., top para). Chen teaches white matter demyelination as a key component in the pathological processes that occur in response to ischemic stroke, contributing significantly to long-term sensorimotor and cognitive deficits, and that IL-13 treatment attenuated demyelination of myelinated fibers after a model of ischemic stroke (p. 10 of 28, left col., last para-right col., 3rd para).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have administered the particulate metaxalone composition of Dodd to a human subject in need of treatment and increasing PGC-1alpha, to stimulate IL-13 and inhibit STAT3; increase white matter growth and development; for treating a demyelination disorder, in consideration of the combined teachings of Pallio, Dodd, and Chen. Pallio, as discussed previously teaches metaxalone stimulated PGC-1alpha activation and enhanced IL-13 expression, while Chen teaches IL-13 enhancement to inhibit STAT3 and promote white matter growth and recovery after a model of ischemic stroke. Chen further teaches IL-13 treatment attenuated demyelination of myelinated fibers after a model of ischemic stroke. Therefore, it would have been reasonably obvious that administration of the metaxalone particulate composition taught by Dodd would have resulted in stimulation of IL-13 and inhibition of STAT3, resulting in the promotion of white matter development and growth. As IL-13 is taught to attenuate demyelination, and metaxalone stimulates IL-13, one of ordinary skill in the art would have been motivated to have administered the particulate metaxalone composition of Dodd to stimulate IL-13 and inhibit STAT3 in a human having a demyelinating disorder, with the reasonable expectation metaxalone treatment would have attenuated demyelination.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH PIHONAK whose telephone number is (571)270-7710. The examiner can normally be reached Monday-Friday 9:00-5:30 EST.
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SARAH . PIHONAK
Primary Examiner
Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627
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