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 PATENT VIEW 1    2016 
                              

 
Let's Read Together!

The table below gives examples of patent expirations, loss of protection for pharma products.
Pharma products may be protected by more than a single patent.

If complete, the expiration could give priority in coming inventions to further directions of:
original small molecules and generic followers...
original biotech products and biosimilar followers...
nucleotide sequences...
small molecules conjugated to target specific single chain proteins...

Considerations in view of personalized medicine:
Limits in application of small molecules and biotech pharma products: safety and efficacy?
Limits in application of Bio and Pharma 3D printing techniques: safety and efficacy?
Further developments?  Synthetic biology?  Diagnostic aspects?



15    .......................   16

Patent expiration / pharma industry / March-May, 2016
 source: drugpatentwatch.com
Patent  No
Filing*
Priority**
Expiration
***
Notes
US 6,423,342

04-05-1999 *
 02-03-1995** 
  01-03-2016***


ZELAPAR
selegiline hydrochloride  
tablet


Valeant Pharmaceuticals Intl.
Phenthylamine derivative, an additional component to the Levodopa/Carbidopa therapy for the symptomatic treatment of Parkinson's disease. It acts by inhibiting neurotransmitter degradation [irreversible inhibition of monoamine oxidase  (MAO-B)], enhancing thus dopaminerg activity of basal ganglia.

Bio perspective
:
  • Alim-Louis Benabid, a winner of the 'European Inventor Award 2016 (see No7 in Research category, Patent View 2016-2), inventor of high frequency stimulation by electrodes introduced into brain subthalamical level ('cerebral pacemaker') of patients with Parkinson's disease;
  • targeting of  in vitro constructed mDA neurons.
US 5,840,763
US 5,916,893

01-09-1995*

     01-03-2016***

FAMVIR

famciclovir
tablet

Novartis
For the symptomatic treatment of Herpes simplex virus (HSV-1, HSV-2) and Varicella zoster virus (VZV) infections. It acts by inhibiting viral DNA polymerase in infected cells, reducing thus the propagation of viruses.

Bio perspective
:
  VZV  vaccine  (attenuated living viruses) approved by the end of the year 2015 
US 6,034,267

08-03-1996*

 10-03-1995**
    08-03-2016***

METVIX

methyl aminolevulinate
hydrochloride
cream

Galderma Labs. L.P.
Photosensitizer (photodynamic) cream for the photochemotherapeutic treatment of keratosis actinica (k. solaris) with the help of red range light (Aktilite CL128) provoking cell necrosis, apoptosis by the generation of cytotoxic reactive intermediates, in  immunocompetent patients.

Bio perspective
:
 photodynamic  creams acting on the same principles (generics).
US 5,756,541

11-03-1996*
    11-03-2016***


VISUDYNE
verteporfin

powder, solution

Valeant Pharm. Luxembourg S.a.r.l.
Benzoporphyrin derivative, an adjunct for the photodynamic treatment of fungal infections in the eyes (histoplasmosis), for pathological myopia, for macula degeneration. Its combination with laser phototherapy results in the liberation of cytotoxic reactive oxygen intermediates, the harmful effects to endothelial cells, thus restricting subfoveal choroidalis neovascularisation.

Bio perspective
:
photodynamic generics acting on the same principles.
US 5,881,926

30-08-1993*

  11-03-1993**
    16-03-2016***


FLO-PRED

prednisolone acetate
oral suspension

Taro
Pharm. Ind. Ltd.
Antiinflammatory steroid (see:  steroid  action).

Bio perspective
:
targeted biotherapy (e.g. biosimilar recombinant antibodies), further search for natural substances.
US 5,854,290

21-09-1995*
    21-03-2016***


INTUNIV

guanfacine hydrochloride
tablet

Shire US Inc.
Selective agonist to central alpha2A-adrenergic receptors, an antihypertensive sympatholytic drug (decrease in impulses released from brain stem vasomotor center resulting in the decrease of peripheral resistance, sympathetic tone and, blood pressure).

Bio perspective
:
 protein scaffold  for the delivery of therapeutic small molecules.
US 5,811,436

30-01-1995*
  03-02-1994**
   22-03-2016
***

PAXIL
paroxetine hydrochloride
tablet

Apotex Technologies Inc.
Phenylpiperidine type antidepressant for the selective inhibition of serotonin transporters, leading to the blockade of serotonin reuptake, ending up in prolonged neurotransmission. 

Bio perspective
biotherapy targeting mTOR (serine/threonine kinases) signaling pathways (influence on cell metabolism, here: on synthesis of synaptic proteins > on translation initiation).
US 5,886,039

07-06-1995*
  02-09-1988**
    23-03-2016***

MUSE
alprostadil
urethral suppository

Meda Pharmaceuticals
Suppository for transurethral entry, containing prostaglandin E1 alike eicosanoid. In contrast to the indirect effects of PDE5 inhibitors, it directly results smooth muscle relaxation together with vasodilation of arteria cavernosa (correction of erectile dysfunction caused by damages in blood vessel wall, deficiencies in blood circulation and/or metabolism).
Developed formulation: gel for transdermal absorption.

Bio perspective
:
  alternative care.
US 6,387,946
US 6,372,780
US 6,331,635

28-04-1998*

  26-03-1996**
    26-03-2016***

JEVTANA KIT

cabazitaxel
infusion, solution


Sanofi Aventis US
Cytostatic drug, taxol derivative preventing the dynamic assembly of cytoskeletal microtubules, hence inhibiting cell division.

Bio perspective
:
  biotherapy   based on anomaly-related biomarker research (development of tumor  specific antibodies,  of  oncolytic viruses,  of vaccines ).
US 6,489,329

20-04-2001*
  08-04-1996**
     08-04-2016***


ZYRTEC-D  12 HOUR

cetirizine hydrochloride;
pseudoephedrine hydrochloride

tablet

J & J Consumer Inc.
A two-in-one combination of components for the alleviation of the symptoms in allergic and viral rhinitis. Component cetirizine is an antagonist to H1 receptors and an inverse agonist to H1 signalling pathways. Component pseudoephedrine is an agonist to alpha-adrenergic receptors. 
The latter acts by releasing norepinephrine of presynaptic vesicles into the synaptic cleft where primarily alpha-adrenergic receptors are stimulated. The stimulus results in vasoconstriction leading to decongestion of the nose and sinuses.

Bio perspective:
pre-seasonal preventive care with antihistamines acting on H1 receptors and H1 signalling pathways and, in an independent way suppressing gene expression of histidine decarboxylase, the enzyme regulating histamine synthesis.
US RE40183

  03-06-2005*
    04-08-1994**

      09-04-2016***

TYGACIL

tigecycline
iv. infusion

PF Prism C.V.
Tetracyclin derivative broad spectrum antibiotic with effects on Gram positive and Gram negative bacteria, too. Due to the emerging global spread of antibiotic resistance, further inventions are urged for the translation of inventive novelties into clinical practice.

Bio-perspective:
 synthetic and semisynthetic new substances.
US 5,998,380
US 6,503,884
US 7,498,311


13-10-1995*
09-11-1999*
06-01-2006*
  13-10-1995**
     13-04-2016***

TOPAMAX
topiramate

capsule, tablet
pediatric use

Janssen Pharmaceuticals Inc.
Anticonvulsant sulfamate derivative for the prophylaxis of periodically recurring, throbbing migraine pain (of non-epileptic patients). Currently, the development of migraine is traced back to the stimulated interactions of cranial nerve V and the cerebral cortex, and/or to neurovascular reasons manifesting in pain waves with or without aura.

Bio-perspective:
 
  • active substance: melatonin prophylaxis
  • formulation/delivery: different from tablet and spray, intranasal delivery of medication for enhancing its efficacy and tolerability (lower dose, faster absorption).
US 5,869,082

12-04-1996*

    16-04-2016***

NITROMIST

nitroglycerin
sublingual aerosol

Mist Pharmaceuticals LLC
Bypassing first pass effect, buccal transmucosal accelerated delivery of nitroglycerin (GTN) dissolved in non-polar hydrocarbon, formulated in a biocompatible, hydrocarbon-miscible propellent. When in use, the propellent evaporates, the active substance in form of small droplets create a coat on the buccal mucosal (sublingual) surface and the penetration of the drug follows, resulting in systemic greater bioavailability compared to delivery per os. As an organic nitrate, nitroglycerin (GTN) is an antihypertensive substance with vasodilatory effects (NO/cGMP signalling pathways mediated smooth muscle relaxation in the blood vessel wall). Indication of use: relief/prophylaxis of acute angina attacks in CAD patients.

Bio-perspective:

  • active substance: nitroglycerin (TGN) has pleiotropic effects; chronic administration of it ise also to tolerance and endothelial cell damage. To avoid or minimize these effects, personalized supplementary medication (antioxidants, sulfhydryl group donors, ACE inhibitors, PDE inhibitors....) is suggested.
  • formulation/delivery: inventive novelty steps in further development of buccal transmucosal drug delivery (nanoparticle carriers, bioadhesive/mucoadhesive surfaces)
US 6,022,562

17-10-1995*
  18-10-1994**
    17-04-2016
***

COREG CR

calvedilol phosphate
extended release capsule


SB Pharmco Puerto Rico, Inc.
Technological solution comprising drug (nutrient) carrier polymer microcapsules formulated in tablets/powder/gelatin capsules for per os delivery of extended release substances (preferred residence time in small intestine is 8h - 24h).
In case of nonselective beta-adrenoceptor (beta1-, beta2-, + alpha1-adrenoceptor) antagonist and slightly antioxidant COREG CR/calvedilol, the technology serves for the controlled management of chronic heart failure (systolic anomalies) and hypertension, supplementing the treatment with thiazide type diuretics, with ACE inhibitors, or with digitalis.

Bio-perspective:
  • active substance:  ID No. NCT02012075 Phase III clinical trial started in december, 2013 aiming the comparative interpretation of the extended release nonselective beta-adrenoceptor antagonist Carvedilol Sulfate (carbazoles), and the sustained release cardioselective beta-1 adrenoceptor antagonist Metoprolol Succinate (tyrosols) therapies, in patients with chronic heart failure mentioned before. The evaluation of results are in process.  
  • formulation/delivery: implantable microchip based drug delivery, also in a biodegradable version.  
US 5,898,030

17-06-1994*
    27-04-2016***

ZORBTIVE
SEROSTIM
SAIZEN

somatropin recombinant
sc. / im. injection


EMD Serono, Inc.
Technological description of the composition of rHGH (recombinant human growth hormone) stabilized by the addition of saccharose/saccharose-mannitol. 
Indication: management of congenital or acquired HGH (somatotropin) deficiencies (pediatric, adult), maintenance of conditions with injured alimentary (e.g. short bowel syndrome) and anabolic pathways.

Bio-perspective:
  • need for clarification: childhood onset rHGH therapy deficiencies in young adults and adults.
  • rHGH liquid versus powder forms (a clinical trial): liquid formulation proved to be more beneficial in treating severe burns and skin donor areas.  
US 5,900,424

08-07-1994*
  09-07-1993**
     04-05-2016***


PRILOSEC

PRILOSEC OTC
omeprazole magnesium
capsule/granule
delayed release

AstraZeneca Pharmaceuticals  LP
Technological description of the pharmacological preparation of (class sulfinylbenzimidazoles) omeprazole magnesium salt, with emphasis on optimizing its assembly, purification, and  crystallization.
Indication: weak base omeprazole binds selectively to (activated) H+, K+-ATPase, the enzyme responsible for the last step in acid secretion of parietal cells in the gastric mucosa (proton pump inhibition). By inhibiting acid secretion in a dose dependent manner, the acid induced mucosa erosion (e.g. gastroesophageal reflux disease, Helicobacter pylori associated gastric ulcer, enhanced secretion of gastric acid in Zollinger-Ellison syndrome) is ameliorated.

Bio-perspective:
  omeprazole has already long history, and, in our days too, is considered a well tolerated preparation.
  • The metabolism of omeprazole is stereo-selective, compared to the R-isomer the S-isomer (esomeprazole) has better pharmacokinetics and pharmacodynamics (it reaches  pH > 6 level faster). 
  • There are significant differences in omeprazole metabolism of distinct ethnic groups (e.g. frequency of poor metabolizers in chinese and japan populations > frequency of poor metabolizers in caucasian and african populations) moreover, intragroup/interindividual differences are also observed (CYP-450 2C19 genetic polymorphism - SNP dependent enzyme activity). According to experiences so far, the pharmacodynamics of esomeprazole is less influenced by genetic polymorphism mentioned before. Supporting clinical data are further required. 
  • Meta-analysis: comparative assessment of proton pump inhibitors (PPI) therapy and H2 receptor antagonists (H2RA) therapy following successful endoscopic intervention for the prevention of recurrent upper gastrointestinal bleeding associated with H.pylori infection, with the use of nonsteroid antiinflammatory drugs.  PPI proved to be more efficient in preventing recurrent bleeding, however, in mortality, PPI and H2RA did not show significant differences. In clinical studies mentioned, PPI=omeprazole, pantoprazole;  H2RA=cimetidine, famotidine, ranitidine.  Supporting clinical data are further required.  
CA 2 191 475

06-05-1996*
  08-05-1995**
     06-05-2016***


A DRUG, CONTAINING ONE OR MORE PLASMA DERIVATIVES

quality-assurance method

Baxalta Inc. USA
,
Baxalta GmbH
Dual-target (= oligo primers for different target sequences) Southern blot-PCR (DTS-PCR) and laser induced fluorescent PCR tests (with fluorescent labelled oligos > LIF-PCR)  for the detection of haematogen viruses HAV, HBV, HCV, HIV, HPVB19 in starting material, intermediate products, and final products of manufacturing blood plasma and blood plasma derivatives (e.g. albumin, immunoglobulins, blood clotting components), meanwhile serological standard methods and procedures for virus removal/virus inactivation (nanofiltration, heat-inactivation, enzymatic treatments, organic solvents, surfactants, chromatography, ultracentrifugation) are retained.
Endpoint PCR tests mentioned above target sequences in conserved regions of the viral genome.

Bio-perspective:
in current European Guideline (2015) the necessity of serological and nucleic acid based tests (NAT) in quality assurance of manufacturing blood plasma and blood plasma derivatives, are emphasized.
Development of NAT/PCR method in detecting the presence of viruses:
  • Real-time PCR (RT-PCR): presence of virus, kinetics of virus replication, quantification of virus load (first half 1990s).
  • Sensitivity of detection: 400-500 copies/ml (1990s) ..... 40-50 copies/ml (2000s) 
  • Transcription  mediated PCR amplification (TMA): isothermal method, preferred for RNA virus detection.
  • Single genome amplification (SGA): avoiding discommodities of bulk PCR (recombination, sampling errors) and, determination of phenotypic markers (e.g. viral envelope specialties).
  • Digital PCR (1999) now in its renaissance: single cell genome level amplification for all-or -none decisions (e.g. integration of provirus into the genome of retrovirus infected cell). By Digital PCR  the exponential and analogue PCR reaction is transformed into linear, digital signal.
  • Question: in quality assurance of blood and blood products, serology based on phenotypic features will be replaced by pheno-genotyping?
CA 2 223 694

07-05-1996*
  07-06-1995**
     07-05-2016***

ISOLATED NUCLEIC ACID MOLECULES, PEPTIDES WHICH FORM COMPLEXES WITH MHC MOLECULE HLA-A2 AND USES THEREOF
immunotechnology for
diagnostic and therapeutic purposes
Ludwig Institute for Cancer Research
U.S.A.
//
Inserm
France
Isolation of HLA-A2 (human leukocyte antigen MHC2A) coding nucleic acid sequences and/or  tumor rejection antigen (TRA, here: melanoma antigen) precursor/peptide coding defined  nucleic acid sequences > integration into expression vectors (bacterial/viral) > transformation/transfection of prokaryotic (e.g. E.coli) or eukaryotic (e.g. CHO, COS, melanoma) cells  > in vitro culturing of autologous cytolytic T lymphocytes (CTLs) specific for the HLA-A2-peptide expression complex.

Options for application:  
  • Diagnostics: detection of tumor antigens in in vitro test. Marker: release of Tumor Necrosis Factor (TNF).  
  • Adoptive transfer of CTLs specific for the HLA-A2-peptide expression complex.
  • HLA-A2-peptide expression complex: component for vaccine assembly.
Bio-perspective:  

HLA (  MHC) presented immunopeptidome analysis: application of the robust  SWATH mass spectrometry for the reproducible detection and quantitation of immunopeptides specific for pathogens and tumors,  aiming the elaboration of personalized immunotherapy.
US 5,955,488
US 6,063,802
US 5,854,270


28-04-1998*
  22-11-1994**
    14-05-2016***
28-01-1998*
  22-11-1994**
    14-05-2016***
20-11-1995*
  22-11-1994**
    20-05-2016***

ZOFRAN  ODT
ondansetron
free base in
freeze-dried form

ZOFRAN ODT
ondansetron
free base in
freeze-dried form


ZOFRAN
ondansetron hydrochloride
liquid

Novartis Pharmaceuticals Corp.
Antiemetic drug for preventing nausea/vomiting, mainly in surgical and/or chemotherapeutical and/or radiological care of tumor patients. A selective antagonist for serotoninergic 5-HT3 receptors (at nerve endings of peripheral nervus vagus, at chemoreceptor trigger zone of central area postrema - medulla oblongata).
The afferent emetogenic pathway to dampen is: antineoplastic substance > serotonin release from small intestine enterochromaffin cells > degenerative changes in the gastrointestinal tract > 5-HT3 mediated stimulation of nervus vagus and nervus splanchnicus fibers > impulses reaching the medullar vomiting center // impulses reaching the chemoreceptor trigger zone of
area postrema.

Bio-perspective:
personalized regimens for antiemetic therapy related to antineoplastic  medication of high, medium, and low (or minimal) emetogenic potential
.
US 5,567,817

01-05-1995*
  02-02-1990**
    24-05-2016***


VFEND

voriconazole
oral suspension
iv. injection
tablet

PF  PRISM  C.V.
Synthetic triazole antimicotic (fungistaticinhibition of growth); administered mainly in Aspergillus, Candida, Fusarium and  Scedosporium fungal infections (aspergillosis, esophageal  candidiasis...). Mechanism of action > restraining synthesis of cell membrane component ergosterol by the selective inhibition of the enzyme CYP450 dependent 14-alpha lanosterol demethylase > disruption in cell membrane integrity, ending up in changes of permeability, of survival capacity.

Bio-perspective:
a new objective is the dispruption of cell wall for the exploration of correspondance between cell wall and signaling pathways in order to construct substances efficient and specific in interfering with fungal vitality.
CA 2 226 488

28-05-1996*
  17-07-1995**
    28-05-2016***


POLYSACCHARIDE GEL
COMPOSITION
technology-method
for extended/continuous release of bioactive substances

Q-Med AB
Sweden
Preparation of water soluble biocompatible polisaccharide gel by crosslinking glucose amino glycan (hyaluronate) units. Crosslinking (aldehydes/epoxides/...) happens in two phases. First phase: to reach a pre-gel status. At this stage the gelling process is halted by steric inhibition, i.e. by diluting the system. This stage favours the inclusion (by dispersing/dissolving) of the bioactive component chosen. Second phase: suspension of steric inhibition by concentration, and the ongoing crosslinking leads to a visco-elastic gel, the depot vehicle of bioactive substances included (hormones, cytokines, vaccines, tissue-augmenting components, components in wound care ...).

Bio-perspective along with applications above
: electronic sensors embedded in biocompatible hydrogel 
matrix > use on body surfaces as bandage in 'interactive' care for wounds and injuries > use by delivery into the body to perform sensory functions in metabolism, neuronal activities.





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