Starting with this fourth edition of our monthly life science patent highlights, we link patent identifiers to the new version of Espacenet at http://t1.espacenet.com/. To facilitate navigation with the commentaries, title patents and their base data now carry a yellow marker .
PLEASE CITE AS : Mucke HAM. Patent Highlights for March 2011. Published online on the H.M. Pharma Consultancy Blog (http://hmpharmacon.blogspot.com) on April 4, 2011. Contact us at office@hmpharmacon.com .
Elevated Procalcitonin – A Bad Sign
Like C-reactive protein, procalcitonin is a serum biomarker for systemic inflammation. Initial findings had focused on sepsis and bacterial infection ( J Clin Microbiol . 2010;48(7):2325-9; PubMed), but more recently it has been found that its concentrations can be elevated to the upper limit of normal in several conditions that are not primarily infectious in nature, including coronary artery disease and acute coronary syndromes. In WO 2011/023813 (Brahms [DE]; March 3, 2011) procalcitonin levels have been prospectively investigated as risk markers for adverse medical events (including death from any cause, excluding exogenous trauma) in 5,313 apparently healthy persons (mean age, 47.3 +/- 12 yr., normal blood pressure). It was found that elevated procalcitonin serum levels confer increased risk for cardiac and cerebrovascular events, cardiovascular mortality, cancer mortality, and overall mortality. Gender-specific effects were noted; men tended to have higher baseline levels than women. Optimal cut-off values are disclosed for various disease classes, including diabetes. This biomarker has attracted attention from many sides and for many purposes, including the Chinese military investigating mortality in heat stroke patients ( Emerg Med J 2011; PubMed)
Environmentally Friendly Alkaloid Extraction
Plant tissue remains the prime source for many of the chemically more complicated alkaloids with medical uses. For some, semisynthetic approaches are used; for others, extracted and synthetic material compete. A prime example for the last-mentioned case is galantamine, a cholinesterase inhibitor and nicotinic reptor modulator which used to be available only from limited agricultural sources in Bulgaria and Turkey for about $30,000 per kilogram until a fully synthetic version brought down the price to a fraction. Meanwhile, many new vendors (especially from China) have entered the market, but their processes are based either on toxic halogenated hydrocarbons or use supercritical carbon dioxide, which is environmentally friendly but energy-intense. WO 2011/026637 (Extranthis [DE]; March 10, 2011) demonstrates that extraction of galantamine, but also other alkaloids of medical utility, can be achieved at ambient or slightly elevated temperatures using virtually any industrial-quality plant oil, including rapeseed and sunflower oil. The oil can be used several times, and ultimately it can be combusted together with the plant material residues to generate much more heat than the limited amount that the process requires.
Earthworms For Drug Safety Tests
For scientific and ethical reasons, the Draize paradigm that tests drug and cosmetics candidates for their eye and skin irritation potential has been controversial for decades. Today’s routine versions are mild compared to what had been done to the experimental rabbits in the 1940s to 1960s, but alternatives that use non-vertebrates would be more than welcome. WO 2011/026841 (ViewPoint [FR]; March 10, 2011) claims just that: the company, which develops high-throughput motion analysis for behavioral testing, uses garden-variety earthworms in a simple container, a video camera, and PC software for motility analysis. Irritants produce hyperactivity. As with all alternatives to drug safety testing in animals, utility of this paradigm would hinge on whether regulatory authorities would accept it as valid, even if full validation can be proven.
Sequencing By Opposing Forces
WO 2011/028296 (Caerus Molecular Diagnostics [US]; March 10, 2011) might well contain another step towards the “$1,000 genome.” Millikan Sequencing, a label-free technology, represents a “ sequence by synthesis ” approach, which involves detection of the identity of each nucleotide immediately after its incorporation into a growing strand of DNA in a polymerase reaction. In this invention, opposing electrical, hydrodynamic and entropic forces are used to measure the increased charge as nucleotides are added to DNA templates attached to a tethered bead. Using analyzers such as those from 454 Life Sciences it can be multiplexed millionfold, allowing very fast sequence reading.
Growing Nerves In Vitro
Neurogenic cytokines can make neurites sprout, but that is not all there is to consider if you want to regenerate nerves; conduits are required that mimic the natural biological milieu. These must provide contact guidance and – especially if they are supposed to traverse long defects – they must be semi-permeable to allow access of nutrients. At the same time, these sheaths need to maximize the concentrations of neurotrophic agents and minimize inflammatory, molecule infiltration. Silicone tubing, bovine collagen and biodegradable materials have been used; each type has its drawbacks. WO 2011/028814 (Cleveland Clinic Foundation [US]; March 10, 2011) continues work disclosed in WO 2009/124170 by using naturally occurring epineural tubes that already express all neurotrophic and angiogenic factors (and optionally, bone marrow stromal cells). Details for isogenic and allogenic rat stromal cell-epineural conduits, which take about 14 days to grow prior to implantation, are presented. Maximal sensory recovery was achieved in all of 4 rats at week 5. Motor recovery as measured by toe-spread was robust with 3 out of 4 animals receiving a score of 2 by week 6. The principle of the technique has been known for years (see e.g., Ann Plast Surg. 2002;48(4):392-400 PubMed), and the question of its patentability should be interesting.
Galectin-3 As Biomarker In Cardiac Resynchronization Therapy
That galectin-3 (a multifunctional beta-galactoside-binding protein) may be a useful biomarker for decompensated heart failure has been reported before ( Curr Heart Fail Rep. 2010; 7(1):1-8 PubMed). But WO/2011/031493 (BG Medicine [US]; March 17, 2011) claims that measuring its serum levels can identify those heart failure patients who are better candidates for cardiac resynchronization therapy. Apparently the inventors analyzed samples from a long-concluded clinical study ( N Engl J Med. 2005; 352(15): 1539-49 PubMed) in which patients were randomized to optimized pharmacological therapy alone or combined with pacemaker implantation (InSync® III, Medtronic) in an open-label manner. Out of the 10 patients with the greatest reduction in galectin-3 levels between baseline and 3 months post-baseline, 6 (60%) died or were hospitalized for heart failure within 18 months. In contrast, of the other patients with a serum galectin-3 value at baseline and at 3 months after baseline and available information on adverse outcome, 81% (128 out of 159) suffered the adverse outcome of death or hospitalization for heart failure at 18 months. Baseline galectin-3 in the group of patients who did not receive CRT was not significantly associated with adverse outcome.
An Engineered Anti-Amyloid Antibody For Alzheimer’s
Blocking the active site of beta-secretase is a popular route of attack against amyloid plaques in Alzheimer’s disease; however, this is associated with side effects. WO 2011/031720 (Arizona State University [US]; March 17, 2011) presents a bispecific nanobody with dual activity. It blocks beta-secretase not by binding to the enzyme’s active site, but rather by binding to its substrate, amyloid precursor protein (APP), which allows the β-secretase enzyme to carry out other beneficial proteolytic functions. The nanobody’s other moiety has been engineered to cleave the α-secretase site of beta amyloid or APP, where targeted α-secretase activity permanently precludes Αβ formation. The nanobody is an engineered single chain antibody that is based on a recombinant antibody light chain, mk18, originally raised by immunization against vasoactive intestinal peptide. See the patent application’s companion paper, Biotechnol Prog . 2009; 25(4):1054-63 here.
Cancer Drug Delivery Liposomes Activated By sPLA2: Another Try
Constructing liposomes that encapsulate antiproliferative drugs and have a membrane that can be lysed by the elevated levels of secretory phospholipase A2 in cancerous tissue is not a new idea (see e.g. Curr Drug Deliv . 2005;2(4):353-62 PubMed). There is potential synergy: the products of sPLA2-mediated hydrolysis, a lysolipid and a fatty acid, should permeabilize the cancer cell membranes and increase cellular uptake of the drug cargo released from the liposomes. But elevated sPLA2 levels might occur elsewhere in the body too. In WO 2011/032563 (Bio-Bedst [DK]; March 24, 2011) the inventors tried to narrow the trigger range for sPLA2-mediated lysis by adding a polymer (3-6% mol/mol) that is conjugated to the head group of phospatidyl ethanolamine (which introduces an anionic charge), or to ceramide. In a Phase I dose escalation trial of cisplatin encapsulated in sPLA2 hydrolysable liposomes in patients with advanced or refractory tumors, the maximum tolerated dose was above 80 mg per 3-week treatment cycle, which was surprising in view of the MTD predicted from animal experiments. A superior safety and tolerability profile was noted compared to free cisplatin formulations in terms of nausea, diarrhea, vomiting, anemia, neuropathy, nephrotoxicity and ototoxicity. The preparation does not require hydration (in contrast to free cisplatin), and can can be administered on an outpatient basis.
Kinase Inhibitors For Down Syndrome
WO 2011/037962 (Neuronascent [US]; March 31, 2011) targets DYRK1A (dual-specificity tyrosine-Y phosphorylation regulated kinase 1A), a homolog of the Drosophila mnb (minibrain) gene, which is localized in the Down syndrome critical region of chromosome 21. Along with acetylcholinesterase, this kinase is considered to be a strong candidate gene for cognitive defects associated with this disorder because it inhibits neurogenesis during postnatal brain development, especially in the hippocampus ( J Neurochem . 2010; 115(3):574-84; PubMed). NNI-351 (see figure) is the parent compound of the Dyrk1a inhibitors that are presented here; the biological examples that are given are entirely prophetic. NNI-351 or its blood-brain barrier penetrating analogs will be administered to Ts65Dn mice (which produce Dyrk1a protein at the gene dosage found in human Down syndrome, and exhibit many of its behavioral features) at 0.1-1.0 µM i.p., starting at 7-9 weeks of age and continuing daily until four months of age. Brains will be flash frozen in liquid nitrogen and analyzed for hippocampal neurogenesis.A Neurotoxin For Osteoporosis
Years ago, before it began its diversification, Allergan, Inc. used to have only two main lines of business: ocular pharmacology, and a preparation of botulism neurotoxin A which marketed as BOTOX(TM) and has multiple uses, from spastic syndroms to foot sweating and cosmetics. In WO 2011/038015 (Allergan [US]; March 31, 2011) the company claims an appealing new application for the neurotoxin: osteoporosis; and the toxin is not injected but ingested (an established practice for the treatment of gastrointestinal spasticity). The rationale is inhibition of the production of gut-derived serotonin (GDS), which has a role in bone formation ( Curr Opin Pharmacol. 2011 Feb 12; PubMed ); long-term administration of selective serotonin re-uptake inhibitors, which increases GDS formation, can cause loss in cortical bone mass. The priority date of this application is from September 2009, a safe half-year earlier than the paper from Columbia University ( Nat Med . 2010;16(3):308-1; PubMed ) reporting the same findings. However, Allergan presents only two anecdotal single-case studies in support of its claims.