Patent Highlights April–May 2019

Abstract

Pharmaceutical Patent AnalystVol. 8, No. 5 Patent HighlightsFree AccessPatent Highlights April–May 2019Hermann AM MuckeHermann AM Mucke *Author for correspondence: E-mail Address: h.mucke@hmpharmacon.comhttps://orcid.org/0000-0002-1491-6250H.M. Pharma Consultancy, A-1160 Wien, AustriaSearch for more papers by this authorPublished Online:15 Oct 2019https://doi.org/10.4155/ppa-2019-0015AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit A snapshot of noteworthy recent developments in the patent literature of relevance to pharmaceutical and medical research and development.WO/2019/063955Agents inhibiting TCTP protein for the treatment of proliferative diseases, infectious diseases, allergies, inflammation &/or asthmaInventors: Messaoudi S, Alami M, Brion J-D, Chabrier A, Telerman A, Amson RAssignee: Universite Paris-Sud, Orsey (France); CNRS, Paris (France); INSERM, Paris (France)Language: FrenchThe translationally controlled tumor protein (TCTP) is a highly conserved protein that is widely expressed in all eukaryotes. Although it is associated with malignancy and chemoresistance [1], it has implications far beyond oncology. Its cytokine-like functions (release of histamine, induction of TH2 cytokines and chemoattractants, augmentation of B-cell proliferation) also puts it firmly in the realm of allergy [2]. The fact that the P. falciparum TCTP homolog has a binding site for artemisinin [3] provides a possible explanation why this drug is active not only in malaria but also in cancers. Having shown in WO/2004/080445 and discussed in a much later paper [4] that TCTP can also be inactivated by the selective serotonin reuptake inhibitor, sertraline the inventors have now progressed to derivatives of sertraline that improve on the relatively low affinity (Kd = 198 μM) of the parent compound to TCTP. The highest-affinity derivative (Kd 7 ± 3 μM) is also one of the chemically simplest, 1,2,3,4-tetrahydro-1,2′-binaphthalene; at 10 μM it induces p53 overexpression in HCT116 human colon cancer cells with the same profile as sertraline but more effectively. A close chemical relative, N-(1,2,3, 4-tetrahydro-1,2′- binaphthalen]-4-yl) benzenesulfonamide (AC070) is slightly less inhibitory than sertraline on cell growth but also less cytotoxic, making it interesting as a potential tumor reversion agent. In mice it acts against injected sarcoma cells at 30 mg/kg.Published: 4 April 2019MeSH Keywords: histamine releasing factor / sertraline / translationally-controlled tumor proteinWO/2019/065794Analgesic drug using Pac1 receptor antagonistic drugInventors: Kurihara T, Takasaki I, Toyooka N, Gouda HAssignee: Kagoshima University, Kagoshima (Japan); National University Corp. University of Toyama, Toyama (Japan); Showa University, Tokyo (Japan)Language: JapanesePACAP is an adenylate-cyclase-activating polypeptide, highly homologous to the vasoactive intestinal peptide; both act on three G-protein coupled receptors (Pac1, Vpac1 and -2) that are also highly homologous to each other [5]. Biased antagonists to Pac1-mediated endosomal signaling control neuronal excitability [6] and may offer therapeutic options for chronic pain and stress-related disorders [7] but so far all such antagonists have been peptidic. The invention centers on two small-molecule antagonists (PA-8, a pyridopyrimidine; and PA-9, a lactam) that were identified through in silico screening and are active at low-nanomolar concentrations, and derivatives thereof. Extensive data from mouse models of neuropathic pain and mechanical allodynia are provided; some compounds are active at 100 pM. For the peer review companion papers see Takasaki et al. [8,9].Published: 4 April 2019MeSH Keywords: chronic pain / ion channels / pituitary adenylate cyclase-activating polypeptideWO/2019/070685Methods & compositions for inhibiting ADAM10 biological activitiesInventors: Moss ML, Rasmussen R, Prince CAssignee: Verra Therapeutics, Ithaca (NY, USA)Language: EnglishOver 30 members of the ADAM disintegrin and metalloproteinase family are currently known in humans. They cleave membrane-spanning proteins from cells to generate soluble mature proteins that are involved in cell adhesion, migration, development and signaling [10]. ADAM10 prevents β-amyloid formation [11], promotes production of soluble EGF ligands, generates soluble Notch and Axl which are known promoters of tumor proliferation, and also generates soluble CD23, a low-affinity receptor for IgE. [12,13] Selective ADAM10 inhibitors could offer interesting new approaches to the treatment of cancers, allergy and infection. This has yet to be achieved with small-molecule inhibitors: hydroxamates developed by GlaxoSmithKline and Incyte also inhibit other matrix metalloproteinases, and possibly other ADAM family members. The inventors have exploited the fact that ADAMs are expressed as zymogens with the prodomains maintaining the enzymes in a latent state [14]. They created PEGylated peptides corresponding to the human ADAM10 prodomain but with modifications that annihilate one or both of the two furin recognition sequences at amino acids 26–29 and/or 52–55, which otherwise would allow the peptide to be quickly degraded. The same was accomplished for one or more of the six meprin recognition sites in the prodomain-equivalent peptides, also endowing them with enhanced resistance against cleavage and resulting in much improved pharmacokinetic properties. The peptides have nanomolar IC50 values for ADAM10 but do not significantly inhibit ADAMs 8, 9 or 17 at concentrations up to 10 μM.Published: 11 April 2019MeSH Keywords: ADAM10 protein / allergy and immunology / neoplasmsWO/2019/071007Methods and compositions for targeting vascular mimicryInventors: Hannon G, Cannell IAssignee: New York Genome Center, Inc., New York (NY, USA)Language: EnglishHeterogeneous tumors can employ several alternative mechanisms of vascularization, which includes a process termed vascular mimicry: tumor cells differentiate into endothelial-like cells to form extra-cellular matrix-rich tubular structures that are essentially pseudo blood vessels [15]. Their occurrence uniformly indicates an unfavorable prognosis [16], because standard anti-angiogenic agents cannot suppress their formation. Two secreted proteins, Serpine2 and Slpi, are necessary and sufficient to program tumor cells for vascular mimicry, and also ensure perfusion of the pseudovessels by acting as anticoagulants [17]. Working with RNA profiling of core biopsies taken immediately prior and 2 weeks post bevacizumab therapy of previously untreated ductal breast cancer patients, the inventors have identified additional critical pathways for vascular mimicry that are centered on a Forkhead box protein (FOXC2) and IRE1. Suppression of mimicry via low dose tunicamycin (an IRE1 activator) enhanced response of tumors to standard anti-angiogenic therapy. Gene ontology analysis of genes that were significantly downregulated by tunicamycin and significantly upregulated by IRE1 inhibition were enriched for regulators of vasculature development and genes affiliated with extracellular matrix formation. The claims extend to any compound that activates IRE1 (including acetaminophen, amiodarone, arsenic trioxide, bleomycin, bortezimib, cisplatin, clozapine, olanzapine, cyclosporin, diclofenac, indomethacin, efavirenz, zidovudine, sertraline, troglitazone, erlotinib, and doxorubicin) and to any compound that inhibits FOXC2 or the FOXC2 pathway (inhibitors of p38 MAPK, protein kinases A or D, and many others).Published: 11 April 2019MeSH Keywords: Forkhead transcription factors / inositol requiring enzyme 1alpha, human / neoplasms / tumor microenvironmentWO/2019/071355Products & methods associated with multiple sclerosis as a transmissible protein misfolding diseaseInventors: Stys P, Zamponi GW, Tsutsui SAssignee: UTI Limited Partnership, Calgary (AB, Canada)Language: EnglishIn this provocative patent application the inventors, who have argued before that multiple sclerosis is more like a primary neurodegenerative disorder than an autoimmune disease [18], demonstrate that brains of patients with primary progressive multiple sclerosis have widespread deposition of abnormally aggregated amyloid, presumably caused by human prion protein (PrP). The aggregates are generally invisible to conventional histopathological examination but detectable using a conformationally-sensitive fluorescent amyloid probe (pFTAA) and spectral microscopy. Their evidence is that transgenic tg650 mice overexpressing PrP that are injected with brain homogenate from a primary progressive multiple sclerosis patient-developed brain atrophy and ventriculomegaly (commonly seen in multiple sclerosis (MS) patients) as well as plaque-like PrP deposits not seen in controls. Passaging and transmission of an MS-like pathology was also observed by injecting naive transgenic mice intraperitoneally with brain homogenate from infected mice. The tg650 mice also exhibited abnormal behaviors including deficits in spatial learning and memory as well as decreased exploratory behavior and increased anxiety. The hypothesis is that at least this subtype of multiple sclerosis is caused by misfolding of normal PrPc into an aggregation-prone conformer, PrPMS, which accumulates in the brain and causes dysregulation of myelinic glutamate receptors, followed by non-immune demyelination. Agents that have been shown to interfere with PrP misfolding (quinacrine, tetracyclines, tacrolimus, pentosan polysulfate) are claimed, but no in vivo data are presented. Note that similar reasoning has been put forward by researchers at the University of Milan [19]; and that the MS drug, copaxone is known to interfere with the initial PrPSc infection process in scrapie [20].Published: 18 April 2019MeSH Keywords: amyloid / multiple sclerosis, chronic progressive / prion proteinsWO/2019/075453Memory manipulation via modification of protein kinase C zeta activityInventors: Acevedo-Duncan M, Sacktor TAssignee: The Research Foundation for the State University of New York, New York (NY, USA)Language: EnglishPKMζ, an atypical protein kinase C isoform expressed in neurons, is constitutively active (because it lacks the autoinhibitory N-terminus) and contributes to long-term memory under physiological conditions by maintaining newly strengthened connections between neurons [21]. Selective inhibitors that penetrate the blood–brain barrier and cell membranes could help with the treatment of post-traumatic stress disorder, other mood disorders and (only slightly less obviously) neuropathic pain [22]. Here the inventors claim the first small molecule that achieves this: 1-naphthol-3,6,8-trisulphonic acid (ζ-Stat) binds and inhibits the unique PKMζ catalytic domain with an IC50 of approx. 100–200 nM, without having an effect on PKCι/λ (isoforms which can compensate for PKMζ deficiency) at doses up to 10 μM. At 10 μM ζ-Stat reverses maintenance of long-term potentiation induced by tetanizing stimulation in hippocampal slices from wild-type mice when applied 3 hours post-tetanization. Microinjection of 5 nmol into the hippocampus of wild-type mice one day after active place-avoidance training (a time period during which long-term memory processes related to memory maintenance are active) inhibited memory retention when tested 2 days later. Subsequently acquired long-term memory was not affected, indicating that ζ-Stat does not damage the hippocampus or cause other permanent interference with mechanisms of learning or long-term memory formation. No derivatives of this compound are claimed, which is quite unusual. In papers published after the October 2017 priority date of this document, ζ-Stat has been reported by the inventors in the context of melanoma and colon carcinoma [23,24]. Also see the inventor's US patent application 2017348336.Published: 18 April 2019MeSH Keywords: memory consolidation / naphthalenesulfonates / protein kinase C zetaWO/2019/076633Nucleoside analogs for the treatment of parasitic infectionsInventors: Hulpia F, Van Calenbergh S, Caljon G, Maes LAssignee: Universiteit Gent, Gent (Belgium); Universiteit Antwerpen, Antwerpen (Belgium)Language: EnglishThe subject matter of this patent application has a rich and long history: PubMed shows the first peer review paper in May 1956, describing the effect of the nucleoside analog puromycin against Entamoeba histolytica and other intestinal parasites [25]. Since then hundreds of papers have reported on nucleoside analogs to treat parasitic infections, mostly by kinetoplastid (genera Trypanosoma and Leishmania) and apicomplexan (Plasmodium spp. and Toxoplasma gondii) protozoans because these lack the enzymes for de novo purine synthesis. The inventors focused on C7-phenyl substituted purine ribofuranosyl compounds (derivatives of 7-deaza-adenosine, known as tubercidin, a template used for decades [26]) with antitrypanosomal action. Their initial subset produced weakly active analogs, with TH1012 being the most active one (low μM EC50). Further derivatization focused on electron-poor and/or lipophilic phenyl analogs, with the 3,4-dichloro analog FH3147 displaying an EC50 of 3.0 μM against T. brucei. A bio-isosteric replacement for the phenyl group with a pyridine moiety as an electron-poor substituent was then tried. Of the three possible isomers, the 2-substituted pyridine TH1008 showed nanomolar antitrypanosomal activity with reasonable selectivity indices vs. human cells (50 for T. b. brucei and 500 for T. b. rhodesiense). Continued investigation into electron deficient 6-membered heteroaromatics failed to produce anything equivalent or better. For the peer review companion paper see Hulpia et al. [27]Published: 25 April 2019MeSH Keywords: nucleoside analogs / Plasmodium; toxoplasmaWO/2019/080842Uronic acid compound preparation method therefor & use thereofInventors: Li H, Zhang XAssignee: Wuhan University, Wuhan (Hubei, China)Language: ChineseThe fatal consequences of reperfusion injury following alleviation of ischemia were first described in the early 1960s but the matter gained real traction only after organ transplantation, and later thrombolysis after stroke or myocardial infarction, became possible. Although the mechanisms are quite clear, no single drug has ever been approved for this specific purpose. The inventors present an unusual candidate, N-(1,3-benzothiazol-2-yl)-4-[(2-glucuronyl-3-methoxy-yl)benzylamine] benzenesulfonamide, which does not seem to appear anywhere in the peer review literature or in chemical databases; the synthesis is described in detail. The therapeutic focus is on hepatic and lung injury, with quite convincing mouse data. No mechanistic rationale is presented, leaving us to speculate that the uronic acid residue might have a quite pronounced antioxidant and multitarget effect, perhaps similar to that of scutellarin which is an herbal flavonoid glucuronide that has been used clinically to treat stroke, myocardial infarction and diabetic complications [28].Published: 2 May 2019MeSH Keywords: glucuronides / reperfusion injuryWO/2019/087162Polycyclic hERG activatorsInventors: Bebernitz GR, Day RF, Patel T, Quian M, Zecri FAssignee: Novartis AG, Basel (Switzerland)Language: EnglishCardiac repolarization is primarily by the slow delayed rectifier current, IKs (mediated by the potassium ion channel Kv7.1) and the rapid delayed rectifier current IKr, which is conducted by the hERG channel. Blockade of hERG delays cardiac repolarization, leads to excessive prolongation of the action potential duration and associated QT interval, which predisposes to potentially lethal torsades de pointes arrhythmia [29]; such a finding during safety pharmacology testing often means the death knell for a drug candidate. Certain potassium channel mutations (e.g., in Lange–Nielsen syndrome) will also cause long QT syndrome, which is potentially treatable by hERG channel activators that act by altering channel activation, inactivation or deactivation. Such drugs may also function as general antiarrhythmics since they reportedly reduce electrical heterogeneity in the myocardium [30]. Novartis presents a new class of hERG activators built around a benzofuran-6-carboxamide or benzofuran-2-carboxylic acid core. In the standard automated patch clamp assay with CHO cells recombinantly expressing hERG channels, 6- [((3-chloro-4-((trifluoromethyl)thio)phenyl)carbamoyl)benzofuran-2-carbocylic acid was the most effective molecule, increasing hERG currents by 180% at 10 μM and by 338% at 30 μM. Also note companion application WO/2019/087163.Published: 9 May 2019MeSH Keywords: ERG1 potassium channel / Jervell-Lange Nielsen syndromeWO/2019/089335Fused triazole agonists of the APJ receptorInventors: Dransfield PJ, Harvey JS, Ma Z, Sharma AAssignee: Amgen, Inc., Thousand Oaks (CA, USA)Language: EnglishThe APJ receptor, whose endogenous ligands are the apelin and Elabela/Toddler peptides, is a G-protein coupled receptor that is closely related to the angiotensin II Type 1 receptor (with 50% homology in the transmembrane domain). Although the apelin system is involved not only in cardiovascular diseases but also in cancer, obesity and other conditions [31,32] the interest in the APJ receptor has mostly focused on agonists for heart disease because it is widely expressed in blood vessels, heart and cardiovascular regulatory regions of the brain, and mediates vasorelaxation when stimulated [33,34]. The first such agonists to be reported were cyclic analogs of apelins, or contained unnatural amino acids; small molecules have only recently been reported [35]. This document continues from Amgen's triazole sulfonamides disclosed in WO/2016/187308, progressing to tricyclic-fused molecules such as (1S,2S)-N-((5R)-5-(methoxymethyl)-5,6-dihydro[1,2,4]triazolo[4,3-d][1,4]benzoxazepine-3-yl)1-(5-methyl-2-pyrimidinyl)-1-(propanyloxy)-2-propanesulfonamide (EC50 in CHO cells recombinantly expressing the human APJ receptor, 17 nM). In cells expressing both APJ and the AT1 angiotensin receptor, addition of APJ agonists at different concentrations increased the maximal response to angiotensin-II and also shifted the potency to the left, with a ceiling effect which is a hallmark for allosteric cooperativity between the two receptors.Published: 9 May 2019MeSH Keywords: apelin receptors / heart diseasesWO/2019/091847Substituted 2,4-dihydro-3H-1,2,4-triazol-3-ones & use of sameInventors: Biber N, Brockschnieder D, Kölling F et al.Assignee: Bayer AG, Leverkusen (Germany); Bayer Pharma AG, Berlin (Germany)Language: GermanProlyl oligopeptidase, which cleaves peptides of up to 30 amino acids length at a proline residue, is one of the endopeptidases that are constitutively expressed in most tissues and can be induced by inflammatory mediators. Due to its role in cell signaling pathways, it is proposed as a target for treatment of neuropsychiatric disorders and cancer [36], but it also has a distinct and detrimental function in chronic obstructive pulmonary disease and other forms of emphysema. Induced by inflammation, prolyl oligopeptidase contributes to the breakdown of the proline-rich extracellular collagen matrix and generates the tripeptide proline-glycine-proline (PGP), which is a neutrophil chemoattractant. This exacerbates airway inflammation and creates a vicious cycle [37,38]. There are no specifically approved inhibitors, but the chronic obstructive pulmonary disease (COPD) drug roflumilast (a PDE-4 inhibitor) can decrease prolyl oligopeptidase and PGP levels by around 50% when added to standard therapy [39]. Bayer's new prolyl oligopeptidase inhibitors are built around 4-methylbenzyl)-5-(pyrrolidin-1-ylcarbonyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3(2H)-one. In in vitro assays with the recombinant enzyme they show IC50 values in the low nanomolar or even high picomolar range. Experiments with mice exposed to cigarette smoke are described, but without presenting results. Such compounds could also be useful in inflammatory bowel disease where conditions resemble the lung to a certain degree as far as PGP is concerned [40].Published: 16 May 2019MeSH Keywords: CD4 antigens / chronic obstructive pulmonary disease / inflammatory bowel diseases / prolyl oligopeptidaseWO/2019/094469Small molecule inhibitors of shared epitope calreticulin interactions & methods of useInventors: Holoshitz J, White AAssignee: The Regents of the University of Michigan, Ann Arbor (MI, USA)Language: EnglishRheumatoid arthritis and periodontal disease seem quite dissimilar at first sight (rheumatoid arthritis [RA] being an autoimmune disease and periodontitis being caused by bacteria), but they are both characterized by chronic inflammation and bone erosions. On the molecular level, both diseases are associated with HLA-DRB1 alleles coding a five amino acid sequence motif called the ‘shared epitope’ in the region 70–74 of the DR β-chain, which functions as a signal transduction ligand that binds to cell surface calreticulin in a strictly allele-specific manner, expands the pool of Th17 T cells producing IL-17 and the nuclear factor-κB ligand RANKL, and activates nitric oxide-mediated pro-oxidative signaling [41–43]. Its presence indicates a risk for more severe bone destruction. The inventors have identified (R,E)-(1-((1-(3-(1-methyl-1H-pyrazol-4-yl)acryloyl)piperidin-3-yl)methyl)-1H-1,2,3 triazol-4-yl)methanaminium (HL840) as a moderately orally bioavailable modulator of the interaction of the shared epitope with calreticulin and potent anti-osteoclast activity (the S-enantiomer in the commercially available racemate is inactive). Further experiments identified additional small molecules having a similar triazole-methyl-piperidinyl-pyrolyl-propenone structure which function as modulators of shared epitope-calreticulin binding and/or interaction. In the standard mouse model of collagen induced arthritis HL840 (25 μg/kg twice weekly) strongly inhibited disease development, decreased arthritis severity and prevented bone destruction. There are no animal data on periodontitis, which is however covered by the claims along with osteoporosis, osteomyelitis, bone metastasis and fracture healing. For a shared epitope peptidomimetic strongly interacting with calreticulin by the same group see Fu et al. [44]Published: 16 May 2019MeSH Keywords: arthritis, rheumatoid / calreticulin / osteoporosis / periodontitisWO/2019/098945Stapled peptide agonists & their use in treatment of behavioral disordersInventors: Dawe GS, Marwari SAssignee: National University of Singapore (Singapore)Language: EnglishThe neuropeptide relaxin-3 is a recently identified member of the insulin superfamily; its receptor is RXFP3 (formerly GPCR 135) [45]. The restricted localization of GABAergic neurons expressing relaxin-3 [46], and the broadly distributed relaxin-3 projections throughout the brain are remarkably similar to those of the serotonergic and noradrenergic pathways, suggesting that the relaxin-3/RXFP3 network might be contributing to the central stress response implicated in the etiology of anxiety and depression. The primary binding and activation sites of RXFP3 are within the surface of the helical domain of the B-chain; the A-chain does not have any functional role beyond enforcing the correct secondary structure of the B-chain. The inventors have developed a stapled peptide agonist (i.e., with intramolecular covalent inter-domain cross-links) [47] that is modelled on the relaxin-3 B-chain, with strong proteolytic resistance and full agonist activity at RXFP3. When it was infused into rat brains, or administered intranasally, in picomolar amounts it enhanced food intake and drinking behavior, making it superior to any existing relaxin-3 agonist. Antidepressant properties were evident in a repeat forced swim test following acute, subacute and chronic treatment. For the peer review companion paper see Marwari et al. [48]Published: 23 May 2019MeSH Keywords: antidepressive agents / relaxin / RXFP3 protein, humanWO/2019/104324GHSR1a antagonist for Prader-Willi syndrome treatmentInventors: Kamencka T, Lin H, Smith R, Griffin PR, Grande C, Kern AAssignee: The Scripps Research Institute, La Jolla (CA, USA)Language: EnglishDopamine (via the D2 receptor) and ghrelin (via the GHSR receptors) play important roles in regulating food intake and glucose homeostasis. Interfering with these pathways is not an option in ‘normal’ obesity induced by diet and/or diabetes. However, it could be promising in Prader–Willi syndrome, where the paternal SNORD116 gene cluster, which encodes a small nontranslated nucleolar RNA expressed abundantly in areas of the hypothalamus that controls feeding, is deleted, abolishing satiety signaling and causing extreme hyperphagia [49]. Working on the hypothesis that hyperphagia in Prader-Willi syndrome is caused by attenuated GHSR1a-dependent hypothalamic D2 receptor signaling mediated by heterodimerization and allosteric interactions between the two receptors exclusively in the hypothalamus [50], the inventors developed an agent (SR16281, modified from the GHSR1a antagonist YIL781) that enhances D2 receptor signaling selectively in appetite regulating neurons. This produces non-canonical signaling through phospholipase C and mobilization of intracellular Ca2+ instead of the canonical D2 receptor signaling, which inhibits cAMP production. SR16281 has good bioavailability and brain penetration after i.p. injection and decreases food intake in Snord116+/- mice (a genetic model of Prader-Willi syndrome). Analogs of SR16281 demonstrate antagonism of ghrelin-induced Ca2+ mobilization in cells expressing only GHSR1a, but in cells expressing the GHSR1a:DRD2 or GHSR1a:DRD1 heterodimers, they enhance dopamine-induced Ca2+ mobilization. The p-tolyl analog was >100-fold more potent on GHSR1a:DRD2 compared with YIL781. An increase in the size of the substituent at the para-position of the phenol ring in YIL781 leads to a remarkable shift in potency and selectivity for GHSR1a:DRD2 over GHSR1 a:DRD1.Published: 31 May 2019MeSH Keywords: appetite / ghrelin receptor / Prader-Willi syndrome / RNA, small nucleolar / SNORD116 RNA, humanFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.