Avoiding hindsight in non-obviousness determination: case law review of pharmaceutical patents and guidance from the KSR v Teleflex decision.

Introduction: Hindsight bias is the tendency to estimate an outcome once it is known. Legal systems are often prone to hindsight bias. In patent law, the non-obviousness or inventive step is the most critical determinant of patentability and often subjected to hindsight bias.Areas covered: Scholarly literature confirms the existence of hindsight bias in different patent systems. This communication hence addresses factors, which lead to hindsight bias specifically in chemical and pharmaceutical arts, guidance from the case law that can be helpful in avoiding hindsight bias in non-obviousness determination.Expert opinion: The Supreme Court in 2007, advocated a more expansive and flexible approach to where the Teaching Suggestion or Motivation test could come from. In the case of chemical and pharmaceutical active compounds, the considerations such as i) was there sufficient motivation to modify the lead compound and arrive at the claimed compound and its properties, ii) was there a reasonable expectation of success to achieve the claimed property and other such considerations highlighted in this review may contribute to avoid hindsight bias in non-obviousness determination.

Secondary patents: innovator and generic strategies.

The global pharmaceutical industry consists of innovators and generics. Innovators focus on drug discovery, and bring new drugs into the marketplace after filing the new drug applications. In contrast, the generics enter the market by making a bioequivalent product by filing abbreviated new drug applications. In order to maximize their returns on R&D and maintain market share, the innovators introduce a wide range of drug products based on the same 'new molecular entity' and protect them against competition by filing what the industry term as secondary patents. The patents of four innovator viz., AstraZeneca, Takeda, Eisai and Wyeth related to the gastroesophageal reflux disease drugs and how their new molecular entity patents overcame the nonobviousness criteria is analyzed and studied in detail.

Unlocking the concealed targets using system biology mapping for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) constitutes a neural loss in histology of brain with involvement of complex genomic and environmental factors. Accumulation of amyloid beta (Aß) peptide and phosphorylated tau are indicative of progression and cognitive decline. Hence an understanding of the underlying biological pathways and targets along with associated mechanisms would be useful for the development of improved therapeutics for treating AD. In the present work, we aim to identify concealed targets for developing first line therapeutics and repositioning of validated targets as well as FDA- approved drugs using a system biology approach. METHODS: We have collated information pertaining to the biological targets as well as the approved drugs, from scientific literature and patents. RESULTS: In all, the imbalance in the functioning of around 79 proteins and genes were identified to be involved in Alzheimer's cascade. Amongst them, around 21 targets were found to be under therapeutic consideration for AD. Of the remaining, around 17 targets were reported as potential targets for AD, although they are under researcher's attention for other physio-pathological conditions. The analysis further revealed that ˜41 therapeutic targets are pharmacologically concealed but structurally validated targets and may constitute as potential therapeutic candidate for future drug discovery for AD. CONCLUSION: The biological pathway vs. drug mapping provides a complete overview about underlying biological pathways, therapeutic targets (explored and concealed), associated mechanisms, existing therapeutics and the information pertaining to molecules currently under active drug development for further drug discovery and drug re-positioning/repurposing approaches for AD management.

Nonobviousness of pharmaceutical inventions: implications for patent prosecution and litigation.

Nonobviousness is the most critical patentability criterion. Patents covering new molecular entities and second-generation molecules in the pharmaceutical industry are often challenged for prima facie obviousness during prosecution and/or litigation. In such situations, the patentee has to either reject or rebut the same by clear and convincing evidence or demonstrate unexpected results, to establish nonobviousness. This paper tries to show how the lead compound requirement is consistent with 35 U.S.C. § 103; the prima facie obviousness challenge can be overcome; the two-prong approach is consistent with the Supreme Court's KSR v. Teleflex, 2007 (KSR) decision. The showing is illustrated with the analysis of new molecular entities in the proton-pump inhibitor family.

Therapeutic and cosmetic applications of Evodiamine and its derivatives--A patent review.

Evodiamine, ((+)-(S)-8,13,13b,14-tetrahydro-14-methylindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one) indoloquinazoline alkaloid, is the major component isolated from the fruits of Evodia rutaecarpa, family Rutaceae. Broad spectrum of pharmacological activities of Evodiamine suggests its imperative role in treating a variety of diseases influencing the function of diverse targets. A comprehensive search was carried out to collect patent information regarding Evodiamine and its derivatives using different patent databases covering priority years to till date. The patents claiming therapeutic as well as cosmetic applications of Evodiamine and its derivatives were analyzed in detail and were classified technically based on the its application such as treatment of metabolic disorders, cancer, neurological disorders, and cardiovascular disorders, etc. The analysis revealed that the use and the mode of actions of Evodiamine and its derivatives in weight management treatments are currently well established. For example the fat reducing property of this alkaloid is primarily due to its mode of actions such as prevention of muscle protein catabolism, enhancement of thermogenesis and lipid oxidation. Apart from its use for treating obesity, Evodiamine and its derivatives are also experimentally explored for their anti-cancer, anti-diabetic and anti-inflammatory properties. The possible mechanisms related to its anti-cancer activity as illustrated by different experimental studies include its potential action as modulator of specific receptors such as topoisomerase I, NF-kappa B and B-cell lymphoma 2 (Bcl2). The analysis hence highlights that, clinical studies pertaining to the anti-cancer, anti-diabetes as well as anti-inflammatory activities of the Evodiamine and its derivatives would possess important market potential for the development of Evodiamine based therapeutics.

Natural Products based P-glycoprotein Activators for Improved ß-amyloid Clearance in Alzheimer's Disease: An in silico Approach.

Alzheimer's disease is an age related disorder and is defined to be progressive, irreversible neurodegenerative disease. The potential targets which are associated with the Alzheimer's disease are cholinesterases, N-methyl-D-aspartate receptor, Beta secretase 1, Pregnane X receptor (PXR) and P-glycoprotein (Pgp). P-glycoprotein is a member of the ATP binding cassette (ABC) transporter family, which is an important integral of the blood-brain, blood-cerebrospinal fluid and the blood-testis barrier. Reports from the literature provide evidences that the up-regulation of the efflux pump is liable for a decrease in ß -amyloid intracellular accumulation and is an important hallmark in Alzheimer's disease (AD). Thus, targeting ß-amyloid clearance by stimulating Pgp could be a useful strategy to prevent Alzheimer's advancement. Currently available drugs provide limited effectiveness and do not assure to cure Alzheimer's disease completely. On the other hand, the current research is now directed towards the development of synthetic or natural based therapeutics which can delay the onset or progression of Alzheimer's disease. Since ancient time medicinal plants such as Withania somnifera, Bacopa monieri, Nerium indicum have been used to prevent neurological disorders including Alzheimer's disease. Till today around 125 Indian medicinal plants have been screened on the basis of ethnopharmacology for their activity against neurological disorders. In this paper, we report bioactives from natural sources which show binding affinity towards the Pgp receptor using ligand based pharmacophore development, virtual screening, molecular docking and molecular dynamics simulation studies for the bioactives possessing acceptable ADME properties. These bioactives can thus be useful to treat Alzheimer's disease.

Patent analysis as a tool for research planning: study on natural based therapeutics against cancer stem cells.

Medicines developed from traditional systems are well known for their various important pharmaceutical uses. Cancer has been known since ancient times and has been mentioned in the ancient Ayurvedic books. Thus natural based products play a significant role in cancer chemotherapeutics. Further, approximately 70% of anticancer compounds are based on natural products or have been derived from their structural scaffolds. Hence, there is a growing interest for developing medicines from these natural resources. Amongst the methods of treating cancer, therapies targeting cancer stem cell are found to control metastatic tumor which is a newly identified factor associated with relapse. This patent review aims to highlight the use of natural products to treat cancer by targeting the cancer stem cells. The review will also provide insights into the reported mechanisms by which the natural products act in order to suppress or kill cancer stem cells. The analysis has been done using various criteria such as the patenting trend over the years, comparison of active assignee and a comparison of the technical aspects as disclosed in the different patent documents. The analysis further highlights different bioactives, the scaffolds of which could thus be a promising candidate in the development of anti-cancer drugs by targeting the cancer stem cells. The technical aspects covered in this review include: Bioactives and formulations comprising the extracts or bioactives, their mode of action and the type of assay considered to study the efficacy of the natural products. Further the mapping has helped us to identify potential therapeutic areas to evaluate herbs/bioactives and their uses for developing new formulations.

Therapeutic and cosmetic applications of mangiferin: a patent review.

INTRODUCTION: Mangiferin, a natural C-glucoside xanthone [2-C-ß-D-glucopyranosyl-1, 3, 6, 7-tetrahydroxyxanthone], is abundantly present in young leaves and stem bark of the mango tree. The xanthonoid structure of mangiferin with C-glycosyl linkage and polyhydroxy components contributes to its free radical-scavenging ability, leading to a potent antioxidant effect as well as multiple biological activities. AREAS COVERED: An extensive search was carried out to collect patent information on mangiferin and its derivatives using various patent databases spanning all priority years to date. The patents claiming therapeutic and cosmetic applications of mangiferin and its derivatives were analyzed in detail. The technology areas covered in this article include metabolic disorders, cosmeceuticals, multiple uses of the same compound, miscellaneous uses, infectious diseases, inflammation, cancer and autoimmune disorders, and neurological disorders. EXPERT OPINION: Mangiferin has the potential to modulate multiple molecular targets including nuclear factor-kappa B (NF-κB) signaling and cyclooxygenase-2 (COX-2) protein expression. Mangiferin exhibits antioxidant, antidiabetic, antihyperuricemic, antiviral, anticancer and antiinflammatory activities. The molecular structure of mangiferin fulfils the four Lipinski's requisites reported to favor high bioavailability by oral administration. There is no evidence of adverse side effects of mangiferin so far. Mangiferin could thus be a promising candidate for development of a multipotent drug.

Phyto-chemical and pharmacological applications of Berberis aristata.

In the recent years, the interest and research in medicinal plants have increased in a great deal. Ayurvedic medicines and formulations developed from ancient Indian herbal systems are renowned for their various important applications. Berberis aristata - an Indian medicinal plant, which belongs to the family Berberidaceae is an ayurvedic herb used since ancient times. It is also known as Indian berberi, Daruharidra, Daruhaldi, Darvi and Chitra. The plant is useful as anti-pyretic, anti-bacterial, anti-microbial, anti-hepatotoxic, anti-hyperglycaemic, anti-cancer, anti-oxidant and anti-lipidemic agent. B. aristata extracts and its formulations are also useful in the treatment of diarrhoea, haemorrhoids, gynaecological disorders, HIV-AIDS, osteoporosis, diabetes, eye and ear infections, wound healing, jaundice, skin diseases and malarial fever. This review aims to highlight the ethnobotany, pharmacognosy and pharmacological uses of B. aristata which will give insights in developing potentially new bioactives from the plant scaffolds. This review will also highlight the patenting trends, the new compositions developed using the actives from B. aristata and the different assignees involved in filing patents.