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 .
Claim of Foreign Priority
Foreign priority is not claimed.
Status of the Claims
Claims 1-20 are pending and examined.
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.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Askansas et al., (US2014/0206763), in view of Cohen et al., (US2025/0017946), in view of Chiaramello et al., (US2018/0263935), in view of Lee et al., “Muscle membrane dysfunction in inclusion body myopathy studied by muscle velocity recovery cycles,” Journal of Neurology, Neurosurgery & Psychiatry 2017;88:e1, in view of Shah et al., “Detection of Changes in Mitochondrial Membrane Potential in T cells Using JC-1 Dye,” NCL Method ITA-33, February 2019, in view of Kholmukhamedov et al., “MitoTracker Probes and Mitochondrial Membrane Potential,” Shock. 2013 June ; 39(6): 543, in view of Shounan et al., “Apoptosis detection by annexin V binding: a novel method for the quantitation of cell-mediated cytotoxicity,” Journal of Immunological Methods 217 1998 61–70, in view of Hamivand et al., “Expression of Bax and Bcl2 Genes in Peripheral Blood Lymphocytes of Patients with Differentiated Thyroid Cancer,” J Med Phys 2018, Jan-Mar;43(1):41-45, and in view of Cao et al., “Oxygen-radical absorbance capacity assay for antioxidants,” Free Redic Biol Med. 1993 Mar;14(3):303-311.
Askansas teaches treating sporadic inclusion-body myositis (s-IBM) by administering phenylbutyrate. See prior art claim 1. Treatment is intended to improve muscle function or slow or stop progression of the present muscle weakness. Treatment with phenylbutyrate improves this. See par 47. Adults and children can safely take and tolerate phenylbutyrate long term. See par. 8.
Cohen teaches claims a method of treating at symptom of a neurodegenerative disease comprising administering sodium phenylbutyrate. See prior art claim 23, The disease can be inclusion body myositis. See prior art claim 26. Further, the dosage of sodium phenylbutyrate can be from about 0.5 to about 10 grams per day. See prior art claim 32. This is almost identical to the claimed dosage. Further, the compounds can be administered daily, weekly, monthly, or quarterly. See par. 117. Treatment can even be administered multiple times daily. See par. 135.
Chiaramello teaches treating mitochondrial diseases by administering a butyrate compound to increase mitochondrial membrane potential. See par.’s 1 and 40, and prior art claim 4.
Askansas and Cohen teach treating the claimed subject with the claimed API at the claimed dosage.
Lee teaches: “Sporadic inclusion body myositis (sIBM) is a relentlessly progressive inflammatory myopathy of unclear aetiology. We used a novel technique to assess muscle velocity recovery cycles (MVRC) that provides information on the polarization state and T-tubule function of myocytes.” Moreover, Lee concluded that changes were consistent with depolarization of the resting muscle membrane potential of tibialis anterior and rectus femoris was found in sIBM patients when compared to normal controls in this cross-sectional study.
Shah teaches a protocol for measuring changes in mitochondrial membrane potential wherein changes can lead to accumulation of ROS leading to apoptosis. “The combination of mitochondrial membrane potential loss and mitochondrial ROS lead to organelle specific toxicity that ultimately cause cell death.” See p3, 1st par. In the described protocol, T-lymphocytes are isolated after blood is obtained from healthy donors. Nanoparticles are used to test the changes in membrane potential in T cells using a cell permeable fluorogenic probe. See p3, 2nd par. Purified T cells were used. See p8, line 5. It allows for apoptosis to be visualized for an accurate quantification of apoptotic cells. Isolated T-cells are incubated with test-nanoparticles and charges are detected using a fluorogenic probe. See p3, 2nd par.
Lee and Shah teach, among other things, IBM involves depolarization and changes in membrane potential that can yield an accumulation of ROS leading to apoptosis. Mitochondrial membrane potential loss and mitochondrial ROS lead to organelle specific toxicity that ultimately cause cell death.
The following references indicate that measuring membrane potential with the claimed tools, measuring apoptosis with the claimed tools, and measuring Bax, Bcl-2 and their ratios, as well as oxygen-radical absorbing capacity are each known and establish assays. They are each linked to apoptosis, which can be caused by an accumulation of ROS secondary to a decrease and/or loss of membrane potential. This is characteristic of sporadic inclusion-body myositis
Kholmukhamedov teaches MitoTracker probes for mitochondrial membrane potential, which include cationic fluorophores that accumulate in response to negative potential. MitoTracker dyes possess a reactive chloromethyl group that covalently bonds to proteins and peptides. See Abstract. The accumulation occurs electrophoretically.
Shounan teaches the annexin V binding assay is an early detector of apoptosis. Primed human lymphocytes were examined as the annexin V binding by indirect immunofluorescence was fast and sensitive. Annexin V was used as a superior assay for detecting and visualizing the presence of apoptosis in lymphocytes cells derived from human blood.
Kholmukhamedov and Shounan teach an ability to test for changes in mitochondrial membrane potential and early detection of apoptosis including in human lymphocytes. Apoptosis is a specific harm that is taught to be caused by accumulation of ROS as a result of a loss of membrane potential.
Hamivand teaches measuring the changes in expression levels of apoptotic Bax and Bcl-2 and the ratio of Bax/Bcl-2, in the peripheral blood lymphocytes (PBLs). Significant changes were observed in apoptotic cells compared to the control. This was the case for Bax and the ratio of Bac/Bcl-2. The relationship is described as follows:
The Bcl-2 protein is placed in the cover of core and mitochondria; and it functions through the connection to Bax.[16] The Bax protein in terms of structural is Bcl-2 homologous, and it is considered to be a promoter of apoptosis that is placed in the cytoplasm or the cellular membrane, and hence, in terms of performance, this antagonist protein has a protective role for Bcl-2.
The process for such measurement included isolation of lymphocytes from the peripheral blood and extracting RNA, primers were used to evaluated Bcl-2, Bax and Bax/Bcl-2 ratio. See p43, 6th par. The measurements were used to identify the incidence of apoptosis. See p44, 3rd par.
Cao teaches a relatively simple but sensitive and reliable method of quantitating the oxygen-radical absorbing capacity (ORAC) of antioxidants in serum. Results are quantified by measuring the protection produced by antioxidants.
With regard to claims 19 and 20, there is no indication that individuals less than 18 years old are being treated and there is no reason to believe that the subject populations taught to have sIBM and have a condition described therein. The methods of treatment taught by Cohen and Askansas do not require a condition/symptom of than inclusion body myositis.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods in view of the teachings of the cited prior art. One would be motivated to do so because phenylbutyrate at the claimed dosage is taught to treat the claimed condition. Lee explains that loss of muscle function in sIBM is related to a loss of membrane potential, such as resting muscle membrane potential. A subject treated for sIBM would be determined to have sIBM. Shah explains that a loss of membrane potential is responsible for an accumulation of ROS and mitochondrial ROS leads to organelle specific toxicity that ultimately causes apoptosis. Thus, a POSA would immediately understand that these are consequences of membrane depolarization associated with sIBM. Kholmukhamedov teaches MitoTracker probes for assaying mitochondrial membrane potential and Shounan teaches the annexin V binding assay is an early detector of apoptosis. Using these two particular assays would be obvious to determine and monitor the efficacy of treatment in a condition characterized by membrane potential and apoptosis. Hamivand provides an additional assay for measuring apoptosis, which entails an assay of Bax and Bcl-2, as well as the ratio of Bax/Bcl-2 in the peripheral blood lymphocytes (PBLs). Such assay can be used to identify the incidence of apoptosis. Finally, Cao teaches the ability to measure the protection produced by antioxidants in a subject’s serum. This is important because ROS accumulation, as noted above leads to apoptosis. As such, the prior art teaches treating the claimed subject with the claimed agent at the claimed dosage. The steps for measuring membrane potential could be used to evaluate treatment and/or to identify symptoms in a subject. The steps for measuring apoptosis and/or a subject’s antioxidant potential can be used to evaluate the need to mitigate or understand the degree to which ROS are causing apoptosis and how effective the treatment has been in countering these effects. It would be logical to measure apoptosis and membrane potential as well as an ability to mitigate ROS when a subject has a condition that is characterized by a loss of membrane potential, an accumulation of ROS, and a potential apoptosis of cells as a direct result of the accumulation of ROS. Further, butyrate compounds are known to treat the claimed condition and taught to increase membrane potential. Thus, determining a subject has a low potential prior to administering a butyrate compound is also logical. As such, there is a reasonable and predictable expectation of success in arriving at the claimed methods in view of the cited prior art and the state of the art as a whole.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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