Issue 31

Contents

Gleevec and the Faltering Indian Patent Regime
USPTO Accelerated Examination: PTO Training Session
Research in Alternative Medicine
NIH Research on Berries
Misoprostol may Save Women in India
Drug Coated Stents
10 Worst Polluted Cities
Energy Wasters League
Diabetes
Rayataz for HIV
Viagra for pulmonary arterial hypertension
Seroquel for Bipolar Disorder
Aricept
Nexium
Noxafil
Allegra
FDA Approval of Generic Drugs
Oil Hunger

Gleevec and the Faltering Indian Patent Regime
Gleevec/Glivec® (imatinib mesylate) tablets have received approval in the U.S. for five additional disorders. This marks the first time a regulatory authority has simultaneously approved one targeted medicine for so many disorders, Novartis reports. The additional indications include one solid tumor and four blood disorders. Gleevec is already in the market for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors (GIST) in the U.S.  The FDA approvals are based on data from Novartis-sponsored clinical studies and clinical data from independent medical researchers, according to the company.

Gleevec targets the activity of proteins called tyrosine kinases that appear to play important roles within some cancer cells, explains Novartis. It has been shown to inhibit the function of the tyrosine kinase Bcr-Abl in patients with certain forms of blood cancer—Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)—and the receptor tyrosine kinase Kit in Kit-positive GIST. Researchers have found Gleevec also inhibits other tyrosine kinases, including platelet-derived growth factor receptor, which seem to be activated in disease pathways that underlie a number of rare hematologic diseases as well as some solid tumors. The new diseases for which Gleevec received approval are dermatofibrosarcoma protuberans, relapsed/refractory Ph+ ALL, certain forms of myelodysplastic/myeloproliferative diseases, hypereosinophilic syndrome/chronic eosinophilic leukemia, and aggressive systemic mastocytosis. The company is also awaiting approval for treating patients newly diagnosed with Ph+ ALL.

Researchers reported in the journal Nature Medicine in July that there was evidence Gleevec caused heart failure in 10 patients. They said other drugs in the same class, called tyrosine kinase inhibitors, may damage the heart too.  Patients with heart disease or risk factors for cardiac failure should be monitored carefully, the U.S. Food and Drug Administration said in a notice on its Web site. Any patients with signs of cardiac failure should be evaluated and treated, the FDA added.

The $2-billion Gleevec is a drug crucial to prolonging the life of patients suffering from chronic myeloid leukemia (blood cancer). Novartis sells Gleevec at Rs 14.4 lakh ($26,000) per patient per year. Generic drug companies who didn't spend millions of dollars and years of research in developing the drug can sell illegitimate versions of the drug for cheap.  Yet these generic companies make a lot of profit, due to the fact that they didn't incur any cost in developing.  Still, these greedy generic companies sell Gleevec at a price, which is unaffordable for 90% of the population.  Generic Veenat (imatinib mesylate) is available in India for about Rs 96,000 ($2100) per patient per year, while the average income in India is about $ 450 per year. (http://cee45q.stanford.edu/2003/briefing_book/india.html).  What is the purpose of selling a generic drug that costs 5 times more than the average annual income of an Indian? Is this drug for the poor, as claimed by various organizations? The tall claim that dilution of product patent regime is to help the poor in India is bogus. This is a game plan by the generic drug industry, which does not want to develop new branded drugs by spending money on R&D, but wants to make profit from the hard work of other innovative entities outside the country.

Unfortunately, costs of developing new drugs are high.  Companies like Novartis, Pfizer, AstraZeneca etc. take the risk and develop new drugs.  For example, AstraZeneca is forced to abandon its late-stage therapy (spending millions of dollars in developing it) for stroke after a clinical trial failed to demonstrate any significant benefit over a placebo. NYX-059 was considered one of the company's biggest and brightest hopes for achieving blockbuster status and its failure at this stage sent AstraZeneca shares down. The news proved a disaster for Renovis, which had licensed the therapy to AstraZeneca. Its shares lost three quarters of their value after the news hit. Whereas the generic drug companies in the third world lost nothing in this venture so far, while waiting for the drug to be developed, so that they can make profit by snatching it from the developer.

Greedy generic drug companies and their allies in the third world are not willing to let a drug developer have its legitimate monopoly to recover the costs sunk into the development of the new drugs.  Nobody disputes that fact that generic drugs are very important.  However, they should be sold only after the expiry of the patents.  This is fundamental to the development of new drugs and products.

Pharmaceutical companies seek to use patentability of polymorphs as a means to extend the monopoly protection of a known active ingredient already patented. However, such forms can be deemed within the prior art, and therefore non-patentable, if they were obtained following the process of the basic patent on the active ingredient or were covered by a previous product patent. Patent offices should be aware of the possible unjustified extension of the term of protection arising from the successive patenting of the active ingredient and its polymorphs.

However, Gleevec ran into problems in India on several levels, including the basic issues concerning patentability of polymorphs.  Generic companies who have invested nothing in developing the drug have an immense interest in making a profit by selling the generic version of the drug.  To do so, Gleevec should not be patented in India.  Patients, public interest groups and international groups like Doctors without Borders have an interest in keeping the drug not patented in India.  Their immediate concern is to provide cheap drugs to the poor.  They have no concern for the long-term effects of an ineffective patent regime on the new drug development in India, which has not developed a single branded drug so far for the world's rich or poor.  Populist political parties and the various interest groups have effectively managed to have a clause in Indian patent law, which does not allow issue of a patent for Gleevec.

The section that is the culprit for Gleevec's problems in India is section 3(d) of the Indian Patent Law, which was exploited by the interest groups in preventing the issue of the patent.

Pharmaceutical companies are becoming increasingly aware of the importance of gaining patent protection for specific crystal forms of API's.  Polymorphs and isomers are an important aspect of drug development.  Accordingly, the EPO and USPTO recognize polymorphs as patentable, if they show unexpected properties. Even if a chemical compound is known, it may be possible to obtain patent protection upon a given crystal form or polymorph. Indeed, patent applications are commonly filed on the polymorphs of an active pharmaceutical so as to extend patent protection on the pharmaceutical or as a supplementary patent.  The process by which an optimal solid form is selected involves an appreciation of the pharmaceutical development process and the requirements of the drug substance and drug product.

Polymorphism has become a concern in today's pharmaceutical research labs as it affects a number of issues in pharmaceutical systems varying from processing characteristics to bioavailability. During the pre-formulation stage of drug development, polymorph screening is a tedious and time-consuming but essential process. Discovering this polymorphic behavior is crucial, as the case of Norvir (ritonavir) demonstrates. The drug, a protease inhibitor from Abbott Laboratories, Abbott Park, Ill., had to be pulled from the market in 1998 and reformulated after the emergence of a polymorph cut the drug's bioavailability by half.

Since polymorphs and solvates differ in crystal structure, and also differ in some, or all of their properties, these characteristics lead to patentable inventions, which can become the subject of litigations. Some recent case histories of high visibility patent litigations of pharmaceutical products demonstrate some of the chemical issues involved, and the implications for future discovery and patent preparation.

One of the principal regulatory concerns with respect to pharmaceutical solid polymorphism is based upon the potential effect it may have on drug product bioequivalence/ bioavailablity, and hence upon therapeutic efficacy. These concepts form the foundation for the scientific and regulatory aspects that pertain to polymorphism and drug substance "sameness".

Indian laws and the Constitution are inherently against incentives for innovation and R&D spending, so far.  The Constitution of India guarantees right to health and life, but does not guarantee new innovative therapies by providing for short-term monopolies for the inventor, in return for the disclosure of the invention for the benefit of the society. In the past half century of independent India, there has not been a single groundbreaking therapy or drug developed that would help the world's poor or rich, because the Indian patent regime has been very unfriendly to innovation, research and development.

New research is needed to find new drugs for cancer.  The Food and Drug Administration (FDA) approved Gleevec as a treatment for CML about six years ago. Since then, a significant number of patients who initially responded well to Gleevec have acquired additional mutations and developed resistance to the drug. In these patients, white blood cells continue to proliferate. If left unchecked, it leads to the final, acute stage, called the blast crisis, where immature white blood cells infiltrate the blood and the bone marrow.  Indian drug industry and the government don't have any specific research programs to address the drug resistance to Gleevec.  What is the outcome of developing a patent regime that doesn't protect new polymorphs and isomers that would help generate resources for the research necessary to discover new remedies?

Researchers in the US tested the effects of forskolin on normal, Gleevec-sensitive and Gleevec-resistant CML cells, and discovered that the forskolin reduced the cancer cells' ability to grow by up to 90 percent and induced leukemic cell death and differentiation. The ayurvedic herb forskolin, which comes from the root of the plant Coleus Forskohlii (Makandi), is a member of the mint (Lamiaceae) family, and has been part of the Indian medicine for centuries.  The current patent regime in India would not allow expensive research, development and clinical studies of a new drug based on forskolin, because the regime is against providing protection for derivatives of known molecules.  Who are the losers in the long run? All Indians, rich and poor, are the losers in this game of "rich against poor" played by the generic drug industry in collusion with organizations like Doctors without Borders (Medicines Sans Frontiers), whose survival depends on the profits form selling drugs to the poor in the third world. (Especially by selling the generic drug Veenat (imatinib mesylate) that costs 5 times the annual income of an average Indian.)

Research in Alternative Medicine
A plant used widely in China is the focus of a national clinical trial that aims to see if it could help treat Alzheimer's disease and other types of dementia.  The University of North Carolina Hospitals are participating in the national clinical trial on Chinese club moss, which is already being sold in stores with nutritional supplements and is used in China as a treatment for cognitive disorders. The study, sponsored by the National Institute on Aging, is one of a growing number of federally funded research studies focused on natural and alternative therapies. The centers of the National Institutes of Health expect to spend $300.5 million in complementary and alternative medicine research in the 2007 budget year.  Even with the recent financial commitment, research in that area is limited, making it difficult for doctors to get information that is essential to understanding the risks and benefits of certain treatments.

NIH Research on Berries
Every year millions of people (mostly women) suffer with urinary tract infections (UTIs). Nearly 90% of these infections are caused by the bacteria E. coli, which is actually considered a “good” bacteria when it remains in the gastrointestinal tract where it belongs. Problems occur when E. coli leaves the GI tract and finds its way up the urethra and into the bladder, where it multiplies and spreads. Once the infection takes hold, uncomfortable symptoms usually follow. These may include: A frequent urge to urinate, Painful urination (a “burning” sensation), Strong, unpleasant urine odor, Cloudy urine, Uncomfortable pressure in the lower abdomen.  Most patients diagnosed with a UTI are prescribed a course of antibiotics, which can wreak havoc on the body in several ways. Antibiotics kill the “friendly” bacteria in the GI tract, which may result in diarrhea, nausea, and/or constipation. These friendly bacteria also prevent the overgrowth of yeast, so when they are killed off, a vaginal yeast infection often results, requiring yet another medication to “cure”. And one more thing to consider: the overuse of antibiotics can encourage the mutation of bacteria, creating antibiotic-resistant strains.

The good news is that you may never need an antibiotic for a UTI again. There is an all-natural product available which may prove just as effective as an antibiotic, without any side effects whatsoever. It is inexpensive, easy to use, and does not require a doctor’s prescription.

Current belief is that the prevention of UTI is achieved by inhibiting adhesion of the infecting bacteria, E. coli, to uroepithelial cells. Bacterial adherence to these cells is a critical step in the development of infection. It is facilitated by fimbriae (proteinaceous fibers on the bacterial cell well). Fimbriae produce adhesins which attach to receptors on uroepithelial cells. It is hypothesized that cranberry constituents act by preventing adhesion. Thus, the causative bacteria are flushed, preventing their colonization of the urinary tract. In addition, there has been a report of the potential of cranberry juice to weaken attachment of E. coli to inert (nonliving) surfaces for control of biofilm formation on urinary catheters. Two components of cranberry juice have been shown to inhibit the adherence of E. coli to uroepithelial cells in vitro. The first is fructose which may not survive absorption and metabolism intact to reach the urinary bladder. The second is a group of polymeric proanthocyanidins; the chemical structures of three have been elucidated. Fructose inhibits the adherence of type-1 fimbriated E. coli and proanthocyanidins inhibit the adherence of P-fimbriated E. coli to uroepithelial cells.

But the FDA has not yet approved it as a medical treatment. This is largely because as a naturally-occurring and well-known sugar, it cannot be patented.  Who would spend millions of dollars on an unpatentable product to get it approved by FDA? Government or generic drug industry would not do that.  Naturally, the large drug companies have no incentive to spend the millions of dollars it would take to do the large-scale controlled study which would be required for FDA approval.  Generic companies and the third world governments that are against product patent regimes have no money or interest to do the research and clinical trials for the benefit of poor people.

However, US Federal Government spends millions of dollars in research into alternative medicines.  For more on research support provided American government visit:
http://grants.nih.gov/grants/guide/rfa-files/RFA-AT-03-004.html

Misoprostol may Save Women in the Indian Continent
An estimated 500,000 women die annually from complications during pregnancy and childbirth, and the most common cause of death is postpartum bleeding.  In developed countries, where most births take place in hospitals and emergency care is available, deaths from such hemorrhages are rare. But in rural India, where a study was conducted between September 2002 and December 2005, about half of all births occur without a doctor, and poor families often lack the means and the transport to take a woman to the hospital in an emergency.  The estimated maternal death rate in India is 407 per 100,000 births, with postpartum hemorrhage responsible for about 30 percent of those fatalities, the study said. In the United States, that number is about 10 per 100,000, with such hemorrhages accounting for only 17 percent of the deaths.  Though other, more expensive drugs are used to prevent excessive bleeding in the developed world, misoprostol costs as little as 14 cents per pill and requires no refrigeration and no special training to administer.  The drug stops bleeding in the uterus by causing it to contract. Misoprstol, normally used to treat ulcers, was effective in preventing excessive postpartum bleeding in women in poor areas.  The discovery that may save the lives of thousands who die annually from complications of childbirth, a British medical journal reported. The study, which appeared in The Lancet, showed the drug, misoprostol, reduced the likelihood of having such hemorrhages by 50 percent over the three-year period during which the research was conducted in rural India.

Drug Coated Stents
A French study published in the New England Journal of Medicine found that a therapy that uses stents to clear blockages in the carotid artery carried twice the risk of stroke and sudden death compared to the standard surgical treatment. Carotid stents be considered only for patients with at least 70% blockage who have symptoms and are at high risk for standard surgery.

Recently, drug-coated stents have been shadowed by a flurry of news about their long-term side effects.  Doctors have found that a small number of patients develop blood clots inside drug-coated stents long after they are implanted. Such late-forming clots, which are frequently fatal, almost never appear in bare-metal stents. As more evidence emerges that suggests drug-coated stents have caused higher rates of blood clots than the older generation of bare-metal stents, doctors at many hospitals have recently begun shifting toward the older, bare-metal stents they replaced according to figures provided to the Globe by Goodroe Healthcare Solutions LLC.

10 Worst Polluted Cities
More than 10 million people are at risk for lung infection, cancer and shortened life expectancy because they live in the 10 worst-polluted cities in the world, according to a report published by the Blacksmith Institute, an international environmental research group. Three Russian cities are among the most polluted -- Dzherzhinsk, Norilsk and Rudnaya Pristan. The other cities are Linfen, China; Haina, Dominican Republic; Ranipet, India; Mayluu-Suu, Kyrgyzstan; La Oroya, Peru; Chernobyl, Ukraine; and Kabwe, Zambia. According to the report the cities are reminders of an early industrial era, with most pollution stemming from relics such as unregulated lead and coal mines or unrefined nuclear weapons manufacturing plants. The top 10 list was compiled from more than 300 areas nominated by non-governmental agencies, local communities and international environmental authorities. The list of criteria included the size of the affected population, severity of the toxins involved and reliable evidence of health impacts.

ENERGY WASTERS' LEAGUE
1. UK
2. Italy
3. France
4. Spain
5. Germany
Britons are the worst energy wasters in Europe with bad habits which could cost £11bn by 2010, a survey of Europe's five most populous nations suggests.  Leaving mobile phone chargers plugged in, appliances on standby and lights on are among their most common failings. Almost half (48%) of Britons admit to using the car for short journeys rather than public transport, walking or cycling. If the levels of wastage continue, an extra 43m tonnes of carbon dioxide will be pumped into the atmosphere by then, the Energy Saving Trust said.

Diabetes
People with type 2 diabetes have a new treatment option. The Food and Drug Administration this week approved a new drug that boosts the body's ability to lower blood sugar. The once-daily pill, Januvia, simultaneously increases insulin production and decreases glucose production in the liver. Januvia's manufacturer, Merck and Co., said that in a 1-year trial the drug lowered blood sugar levels just as much as an older medication, glipizide, but without the weight gain and episodes of extremely low blood sugar associated with the older therapy. The most common side effects seen with Januvia were upper respiratory tract infection, sore throat and diarrhea. Januvia is approved for use alone or in combination with other type 2 diabetes drugs.

Rayataz for HIV
Bristol-Myers Squibb Company announced that the U.S. Food and Drug Administration (FDA) has granted approval of a new 300 mg single capsule formulation of REYATAZ(R) (atazanavir sulfate) for the treatment of HIV-1 infection in adults as part of combination therapy. Taken once daily along with ritonavir and food as part of a anti-HIV drug regimen, the REYATAZ 300 mg single capsule formulation can replace two REYATAZ 150 mg capsules for: patients who have previously received anti-HIV medicines, patients who will be receiving tenofovir disoproxil fumarate, and patients who have never taken anti-HIV medicines that require SUSTIVA(R) (efavirenz) as part of their anti-HIV drug regimen.

Viagra for pulmonary arterial hypertension
The drug sildenafil, popularly known as Viagra, may help people with chronic obstructive pulmonary disease control the illness-related blood pressure spikes in the heart's pulmonary artery, a new study found.  The medication, in addition to its use as a popular treatment for impotence, has already been approved by the U.S. Food and Drug Administration for the treatment of the chronic version of such blood pressure spikes, known as pulmonary arterial hypertension (PAH). The drug has been marketed specifically for this purpose under the trade name Revatio. Another drug -- bosentan -- is also approved for similar purposes.  The new research suggests that sildenafil may help all chronic obstructive pulmonary disease (COPD) patients, even those not diagnosed with full-blown PAH, who experience potentially dangerous pulmonary arterial blood pressure increases both at rest and following exercise.

Seroquel for Bipolar Disorder
More than seven million American adults are affected by bipolar disorder, a serious psychiatric condition also known as manic depressive illness. Patients with bipolar disorder are symptomatic almost half of their lives, and approximately two-thirds of that time is spent in the depressed phase of the illness. For many people with bipolar disorder, the depressive symptoms are significantly more debilitating than the manic symptoms associated with the illness.
AstraZeneca announced that the U.S. Food and Drug Administration (FDA) has approved SEROQUEL(R) (quetiapine fumarate) for the treatment of patients with depressive episodes associated with bipolar disorder. SEROQUEL already is approved for the treatment of acute manic episodes associated with bipolar I disorder and for the treatment of schizophrenia. SEROQUEL is now the first and only single medication approved by the FDA to treat both depressive and acute manic episodes associated with bipolar disorder.

Aricept
Eisai and Pfizer Inc announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for ARICEPT(R) (donepezil HCl tablets) for treatment of severe Alzheimer's disease (AD).  With this approval, ARICEPT becomes the first and only prescription medication to treat the full spectrum of AD (mild, moderate and severe). ARICEPT, which is co-promoted in the United States by Eisai Inc. and Pfizer Inc, has been approved in the United States since 1996 for treatment of mild to moderate AD. While there is no cure for Alzheimer's disease, ARICEPT can help slow down the progression of symptoms, including memory loss. AD is a progressive brain disease that gradually destroys a person's memory and ability to learn, reason, make judgments, communicate and carry out daily activities. AD affects 4.5 million Americans. One in 10 persons over age 65 has AD, and as many as half of those over 85 have it. About 20 percent of people with Alzheimer's disease are in the severe stage.

Nexium
The US Food and Drug Administration (FDA) has approved a new indication for the prescription proton pump inhibitor NEXIUM® (esomeprazole magnesium) for the treatment of Zollinger-Ellison Syndrome (ZES). NEXIUM already is indicated for the treatment of gastroesophageal reflux disease (GERD) in adults and children ages 12 to 17, and to reduce the risk of NSAID-associated gastric ulcers in at-risk patients.
ZES is a rare but serious chronic condition characterized by the development of tumors that secrete excessive levels of gastrin, a hormone that stimulates acid production by the stomach.

Noxafil
Schering-Plough Corporation reported that the U.S. Food and Drug Administration (FDA) has approved NOXAFIL® (posaconazole) Oral Suspension for the treatment of oropharyngeal candidiasis (OPC), including infections refractory to itraconazole and/or fluconazole. OPC is a fungal infection of the mouth and throat caused by the yeast Candida. NOXAFIL is a novel triazole antifungal agent discovered and developed by Schering-Plough Research Institute.

Allegra
Sanofi-aventis U.S. announced that the U.S. Food and Drug Administration (FDA) has approved Allegra(R) (fexofenadine hydrochloride) Oral Suspension for the twice-daily treatment of symptoms associated with seasonal allergies in pediatric patients, 2 to 11 years of age, and for the treatment of chronic idiopathic urticaria in children 6 months to 11 years of age. This approval makes available a safe and effective seasonal allergy treatment option that is non-impairing to pediatric populations as young as 2 years old.

Seasonal allergic rhinitis is a common chronic condition in children. Symptoms of seasonal allergies include nasal drainage, sneezing, watery eyes and itchy nose, eyes and throat. Studies indicate that seasonal allergy inflammation as well as the impairing side effects of older antihistamines can be disruptive to a child and may affect cognitive skills and function.

FDA Approval of Generic Drugs
The FDA has a backlog of more than 800 generic drugs awaiting an approval decision under the current process that evaluates all applications in the order it receives them. In 2005, the median time for an approval was more than 16 months, according to the FDA.  Last year, the FDA received 766 generic applications, the agency said. About 40 applications a year are for those that, if approved, would be the first generic alternative to a branded drug.  At issue is a lack of staff and funding, the FDA and others have said. Reviews for brand name drugs are funded in part by company fees, but the FDA's work on generic bids is funded solely by the government.

The U.S. Food and Drug Administration will accelerate its reviews of certain generic drugs, a top agency official said on October 18.  Companies will be given priority if their application is the first one proposing a generic version of a brand name drug that is no longer protected by a patent or market exclusivity.  Applications filed before a patent or exclusivity ends would not be eligible under the new procedures now in effect.  Generic medicines that would address a public health emergency or nationwide shortage would also see faster reviews, he told a conference sponsored by the Generic Pharmaceutical Association.

Top generic drug makers include Teva Pharmaceutical Industries Ltd, Barr Pharmaceuticals Inc., Mylan Laboratories Inc., Watson Pharmaceuticals Inc. and Novartis AG's Sandoz unit.

Oil Hunger
A new study in The Engineering Economist says Americans are burning nearly 1 billion more gallons of gasoline each year than they did in 1960 because of their expanding waistlines. Simply put, more weight in the car means lower gas mileage -more gas guzzling.  Using recent gas prices of $2.20 a gallon, that translates to about $2.2 billion more spent on gas each year.  The bottom line is that our hunger for food and our hunger for oil are not independent. There is a relationship between the two.