The Andhra Journal of Industrial News
(An International Electronic Digest Published from the United States of America)
(Dedicated to Andhra, My Mother's Homeland)

Chief Editor: Sreenivasarao Vepachedu, MS, JD, PhD, LLM
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Issue 73

5112 Kali EraVikruthi Year, Chaitra month
2068 Vikramarka Era, Vikruthi Year, Phalguna month
1932 Salivahana Era
Vikruthi Year, Phalguna month
 2010 AD, April





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Alzheimer’s Disease
Many preventive measures for cognitive decline and for preventing Alzheimer's disease -- mental stimulation, exercise, and a variety of dietary supplements -- have been studied over the years. However, an independent panel convened this week by the National Institutes of Health determined that the value of these strategies for delaying the onset and/or reducing the severity of decline or disease hasn't been demonstrated in rigorous studies.

The panel's assessment of the available evidence revealed that progress to understand how the onset of these conditions might be delayed or prevented is limited by inconsistent definitions of what constitutes Alzheimer's disease and cognitive decline. Other factors include incomplete understanding of the natural history of the disease and limited understanding of the aging process in general. The panel recommended that the research community and clinicians collaborate to develop, test, and uniformly adopt objective measures of baseline cognitive function and changes over time.

Although many non-modifiable risk factors have been examined, age is the strongest known risk factor for Alzheimer's disease. Additionally, a genetic variant of a cholesterol-ferrying protein (apolipoprotein E), has strong evidence of association with the risk for developing Alzheimer's disease. Although it is hoped that improved understanding of genetic risk factors may ultimately lead to effective therapies, currently these associations are primarily useful in the clinical research setting.

The panel determined that there is currently no evidence of even moderate scientific quality supporting the association of any modifiable factor-dietary supplement intake, use of prescription or non-prescription drugs, diet, exercise, and social engagement-with reduced risk of Alzheimer's disease. The evidence surrounding risk reduction for cognitive decline is similarly limited. Low-grade evidence shows weak associations between many lifestyle choices and reduced risk of Alzheimer's disease and cognitive decline.

Although there is little evidence that these interventions lessen cognitive decline, some are not necessarily harmful and may confer other benefits. However, the panel also emphasized the need for enhanced public understanding that these proposed prevention strategies are currently, at best, only loosely associated with improved outcomes. This means that carefully-designed randomized studies may reveal that these modifiable factors enhance, detract, or have no effect on preventing Alzheimer's disease and cognitive decline.

Software to Replace Chemist
Bill Gates’ $10 million investment in Schrodinger, a Portland-based drug development software outfit, could give him a strategic position in the quest to use powerful computers and state-of-the-art software to reengineer the development of pharmaceuticals.  Schrodinger is a company with a staff of 140 and a mission to create software that can be used to simulate the lab work that chemists perform during the discovery stage.  The field caught fire in the ‘90s but then burned and crashed to earth a decade ago.
The soaring cost of drug development, combined with a meager productivity rate from Big Pharma pipelines, has focused new attention on the field. For Gates, the key connection was meeting Schrodinger co-founder and Columbia professor Richard Friesner while playing bridge.

Gates’ Revolutionary Research
In a radical departure from traditional research funding standards, the Bill & Melinda Gates Foundation is handing out 81 grants of $100,000 each to researchers who are thinking big about revolutionary new approaches to protecting people from disease. And the Foundation's scientists know going in that as many as 90 percent of the projects will fail.  Based on nothing more than a two-page outline with no requirement for data, researchers around the world have been lining up for these Grand Challenges Explorations grants, which come with the promise of $1 million more if the initial research proves promising. Projects from 17 countries have been selected. They include work on giving mosquitoes a cold to prevent them from biting people, developing tomatoes that can therapeutically target viruses and using laser technology to enhance the human immune response triggered by a vaccine.
In an open letter, the fulltime philanthropist promised to shell out $3.8 billion this year, seven percent of the foundation's wealth and a significant increase over the $3.3 billion spent last year.  Gates highlighted the foundation's success in helping advance a late-stage malaria vaccine, an ongoing effort on HIV/AIDS and an ambitiopus effort to rid the world of polio. But Gates’ billions have earned criticism, as well.
Read more:

Big Pharma’s Love for China
Big Pharma's need to cut development spending and boost its presence in big new markets is driving sizzling hot growth rates for China's contract research organizations (CROs).  There are at least 138 CROs in China.  Frost & Sullivan projects that China's CROs devoted to late-stage research will boom along at an 18 percent annual growth rate, with revenue projected to grow from $145 million to $240 million by 2012.  The early work that they offered in biology and chemistry is making way for more lucrative contracts to undertake preclinical drug studies and human trials.  The U.S.-based CROs like Charles River are going to China.  The company has already built one facility in Shanghai and is now blueprinting a second.

Humanized Antibodies
The new crop of mAbs represents a resounding level of validation for the HuMab transgenic mouse technology developed by Nils Lonberg, initially at Palo Alto, California–based GenPharm, and then at Medarex, which acquired GenPharm in 1997. The platform was further extended, after a cross-licensing agreement with the Tokyo-based beer company Kirin, which had independently developed a TransChromo mouse strain. UltiMab is based on so-called KM mice, bred from these two lines.

The four 2009 approvals bring to six the total of fully human mAbs on the market. Before 2009, Amgen's Vectibix (panitumumab), an inhibitor of epidermal growth factor receptor approved for colon cancer, and Humira (adalimumab), a TNF-α inhibitor marketed by Abbott Laboratories, of Abbott Park, Illinois, for autoimmune disorders, were the sole representatives of this category. Vectibix was generated by means of the XenoMouse technology developed by Abgenix, of Fremont, California, and now owned by Amgen, of Thousand Oaks, California. Humira's origins lie in the phage display technology developed by Cambridge Antibody Technology, of Cambridge, UK, and now owned by AstraZeneca, of London.

And there's more to come. “The four drugs approved in 2009 really represent only the tip of the iceberg for our transgenic mouse platform. There are a lot of exciting drugs behind these in clinical development, and we continue to use the platform for drug discovery,” says Lonberg, now senior vice president, biologics discovery at BMS. UltiMab's new owner is continuing to invest in further development of the platform. “We continue to make new strains of engineered mice that add to the basic platform, but, just as important, we also continue to invest in the infrastructure necessary to characterize and identify lead drugs derived from the mice. And we have developed our own proprietary antibody-drug conjugate technology that extends the range of applications for human antibody–based drugs,” Lonberg says. For example, MDX-1203, an anti-CD70 antibody conjugated via a peptide-based linker to a prodrug of CC-1065 (rachelmycin), entered phase 1 testing for advanced/recurrent renal cell carcinoma and relapsed/refractory B-cell non-Hodgkin's lymphoma last July.

Copenhagen-based Genmab is another beneficiary of UltiMab's recent coming of age. Formed in 1999 as a European spin-out from Medarex, Genmab also holds rights to the UltiMab platform, and it can lay direct claim to one of last year's four antibody approvals, Arzerra (ofatumumab). It licensed the compound, an anti-CD20 mAb, to London-based GlaxoSmithKline in late 2006. The entire development process, from generating a hybridoma cell line to final approval, took seven years, seven months and five days, says Jan van de Winkel, Genmab's chief scientific officer.

All of the antibodies approved in 2009 are being commercialized by large pharmaceutical companies. Ilaris (canakinumab), an interleukin-1β inhibitor, was fully developed in-house at the Boston headquarters of the Novartis Institutes of Biomedical Research (NIBR). Ilaris is not a first-in-class drug, as two other IL-1β inhibitors already exist. Kineret (anakinra), a recombinant version of the naturally occurring protein IL-1 receptor antagonist, was originally developed by Amgen and is now marketed by Stockholm-based Orphan Biovitrum. The fusion protein Arcalyst (rilonacept), an IL-1 trap that acts as a soluble decoy receptor, is also marketed by Regeneron Pharmaceuticals, of Tarrytown, New York.

J&J's Centocor Ortho Biotech arm can claim another two of the six biologic approvals, one of which, Stelara (ustekinumab), is a first-in-class drug. It inhibits the pro-inflammatory cytokines IL-12 and IL-23 by binding the p40 subunit common to each. That prevents their binding to the cell-surface receptor chain, IL-12 β1, and triggers their respective immunological cascades. The two cascades are ultimately distinct, as the IL-12 p35 and the IL-23 p19 subunits recognize different receptors and activate alternative inflammatory pathways. IL-12 is associated with a T-helper (Th) type 1 response (Th1), whereas IL-23, which has variously been described as the master switch in both psoriasis and Crohn's, is associated with a Th17 response. Stelara has gained approval initially as a treatment for plaque psoriasis, but studies in Crohn's disease and psoriatic arthritis are also underway. However, the molecule failed to demonstrate efficacy in multiple sclerosis4. Its long-term safety profile is not well understood, either. The FDA approval required J&J to put in place a Risk Evaluation and Mitigation Strategy to evaluate and mitigate the risk of serious infection, malignancy and the development of reversible posterior leukoencephalopathy syndrome, a neurological condition associated with taking chemotherapy and transplant rejection drugs.

Simponi, J&J's second biologic to gain approval in 2009, is the fifth TNF-α inhibitor to reach what is now a lucrative but crowded market. It is going up against several mature product franchises, including Amgen's Enbrel (etanercept), Abbott's Humira and Remicade, marketed in the US by J&J and in Europe by Merck of Whitehouse Station, New Jersey, following its acquisition of Kenilworth, New Jersey–based Schering-Plough. It is also pitted against a more recent newcomer: Cimzia (certolizumab pegol), a pegylated Fab' antibody fragment, marketed by UCB, of Brussels. Stelara, which is administered by subcutaneous injection, can, like Cimzia, be self-administered by patients. It also offers a more convenient dosing schedule than other TNF-α inhibitors, as only five injections per year are necessary. However, it is not expected to offer significant clinical advantages over its longer-established competitors5.

Nucleotide Sequence Patents
Judge Robert W. Sweet of the U.S. District Court for the Southern District of New York ruled in favor of the plaintiffs on March 29, 2010 in Association for Molecular Pathology, et al. v. United States Patent and Trademark Office, et al, invalidating Myriad’s patents. The PTO currently grants patents on nucleotide sequences provided that the sequences are "isolated" nucleotide sequences and the isolated nucleotide sequence is novel (the particular sequence had not been previously described), is non-obvious and is useful. According to Judge Sweet, the basis of this policy was that nucleotide sequence was being treated the same as any other chemical compound.

The Court highlighted the similarities between natural nucleotide sequence and isolated nucleotide sequences: both are chemical substances and both serve as physical carriers of information. According to Judge Sweet, since the same structural and functional qualities are identifiable in both native DNA and isolated DNA, isolated DNA is not "markedly different" from native DNA and thus does not constitute patentable subject matter under 35 U.S.C. §101. The Court acknowledged that "the identification of BRCA1 and BRCA2 gene sequences is unquestionably a valuable scientific achievement for which Myriad deserves recognition, but that it is not the same as concluding that it is something for which they are entitled to a patent."  However, the judge conveniently forgot that the human DNA existed for as long as humans existed and nobody developed Myriad’s isolated sequences in the past several millions of years to test breast cancer, and why humanity cannot grant monopoly to Myriad’s cancer test for a trivial 20 years to incentivize such innovations, particularly in this case the remaining life of the patents in question is about 5 years only.

This is just the beginning of the debate on whether nucleotide sequences and other molecules such as antibodies, vaccines etc constitute patentable subject matter.

Pharmaceutical Industry and HealthCare Reform Law
On March 30, 2010, President Barak Hussein Obama made law of the final chapter of health care reform when he signed the reconciliation bill (H.R. 4872, the "Health Care and Education Affordability Reconciliation Act of 2010" or "Reconciliation Bill") passed by both houses of Congress on March 25, 2010, which amended the landmark health reform legislation, H.R. 3590 (the "Patient Protection and Affordable Care Act") signed by the President on March 23, 2010.

The Healthcare Reform Law imposes an annual fee on any "covered entity engaged in the business of manufacturing or importing branded prescription drugs" beginning in 2011. Branded prescription drugs and biologics covered include (i) any prescription drug approved under section 505(b) of the Federal Food, Drug, and Cosmetic Act; and (ii) any biological product for which an application was submitted under section 351(a) of the Public Health Service Act.

"Covered entity" is defined broadly, and includes "any manufacturer or importer with gross receipts from branded prescription drug sales." This annual fee, for any individual pharmaceutical manufacturer (or importer), is based on a calculation intended to reflect the market share of the manufacturer. "Branded prescription drug sales" is defined to include sales of branded prescription drugs to specified government programs (Medicare, Medicaid, the Department of Veterans Affairs (VA), the Department of Defense (DOD), and the TRICARE retail pharmacy program under 10 U.S.C. § 1074g) or "pursuant to coverage under any of those programs."1 Significantly, based on the statutory language and application to only "branded" drugs, sales of generic drug products will not affect the calculation of the annual fee.

In determining the annual fee, the government programs that either purchase or provide coverage for the branded drugs (i.e., Medicare, Medicaid, VA, and DOD/TRICARE) will provide a yearly report to the Department of the Treasury, indicating the prior year's sales (or units of drugs dispensed to beneficiaries and corresponding payment amount) for each branded drug for all manufacturers covered by the program. Dividing the industry into tiers of branded sales, the Secretary of the Treasury will calculate the annual fee for each pharmaceutical manufacturer or importer based on reports from other specified federal government agencies based on a ratio of its branded drug sales to the branded drug sales of all covered entities for the prior year (i.e., market share).2 The annual fee is a step-wise annual increase, starting at $2.5 billion in 2011, increasing to a maximum of $4.1 billion in 2018, and decreasing to $2.8 billion in 2019 and onward.

In addition, section 10609 of the Healthcare Reform Law is intended to increase access to lower-cost generic drugs by preventing brand name manufacturers from delaying approval of generic products by making label changes to the brand name or listed drug. Prior to the Law, the labeling of a generic drug was required to match the labeling of the referenced brand name or listed drug, or would not be approved.  Under the new law, a generic application can be approved despite last-minute changes to the labeling of the listed drug, so long as the labeling change to the listed drug is approved 60 days prior to the date of expiration of the listed drug's patent or exclusivity period, and provided that the labeling change does not affect the "Warnings" section of the listed drug's labeling.

Comparative Effectiveness: Drug manufacturers should keep abreast of comparative effectiveness research activities initiated under the Healthcare Reform Law and assess whether their products may be impacted. The law creates a new public-private Patient- Centered Outcomes Research Institute tasked with identifying comparative effectiveness research priorities, establishing a research project agenda, and contracting with entities to conduct the research in accordance with the agenda. Research findings published by the Institute will be publicly disseminated. However, the law imposes restrictions on CMS's ability to use such findings to make decisions related to coverage, reimbursement, or incentive programs. Additional information on comparative effectiveness will be available in a forthcoming Morgan Lewis LawFlash.

Fraud and Abuse: Drug manufacturers also will be affected by Healthcare Reform Law amendments related to fraud and abuse, including amendments to the Anti-Kickback Statute, False Claims Act, healthcare fraud criminal statute, and program integrity provisions. Additional information on these amendments is available in our March 31, 2010 LawFlash, "Healthcare Reform Law: Healthcare Fraud and Abuse and Program Integrity Provisions," available at

Transparency Initiatives: Drug manufacturers will need to establish systems and controls to ensure compliance with new transparency provisions, which require reporting of (1) payments and other transfers of value to physicians and teaching hospitals for values of $10 or more (or $100 aggregate in a calendar year), and (2) physician ownership of or investments in drug manufacturers. The statutory language is limited to applicable manufacturers of devices, drugs, biologics, and medical supplies for which "payment is available" from certain designated federal healthcare programs and does not appear to include by its terms indirect payments or funding. The information reported will be publicly available through an Internet website in a searchable format. Additional information on the new transparency requirements is available in our March 29, 2010 LawFlash, "Healthcare Reform Law Delivers New Transparency Requirements for the Health Industry," available at LF_29mar10.pdf.

Biosimilars: The Law authorizes FDA to create a new regulatory pathway for biosimilar biological products, allowing licensure of biological products as biosimilar or interchangeable to products with current licenses. Innovator manufacturers of reference biological products are granted 12 years of exclusive use before biosimilars can be approved for marketing in the United States. Because it establishes a new regulatory pathway for biosimilars, this aspect of the Healthcare Reform Law will have a broad impact on industry activities for both innovator and follow-on biological products. Additional information on the new transparency requirements is available in our April 15, 2010 LawFlash, "Healthcare Reform Law: A New Regulatory Pathway for Biosimilar Biological Products," available at ducts_LF_15apr10.pdf.

Dawn Raids in Germany
Patent owners can obtain an ex parte order from a German court granting them access to the premises of a competitor who is suspected of infringing their patent. This covers in particular production facilities, laboratories, and R&D sites, no matter how secret and protected the premises may be.  Such inspection proceedings or "dawn raids" are carried out by a court-appointed expert, accompanied by a court marshal or sometimes even police officers, and two to three attorneys as counsel for the patent owner, usually a litigation-focused attorney and a patent attorney. This larger team can appear without prior warning at the site that is to be inspected and enforce access, usually simultaneously serving a court order on the management of the facility. The expert will then proceed to inspect the allegedly patent-infringing device or process and may take pictures, partially dismantle devices, and take samples. After completing this inspection, the expert will summarize its findings in an expert opinion, which will be admissible as binding evidence in subsequent patent infringement proceedings….
The Federal Supreme Court has now, for the first time, confirmed that the inspection procedure developed under case law is in accordance with German law and balanced the interests of the patent owner and the suspected patent infringer (BGH X ZB 37/08 – Lichtbogenschnürung). The Court confirmed that a court order obliging attorneys to keep information confidential and not disclose it even to their own clients is permissible, thus allowing the release of expert opinions to plaintiff's counsel to comment on alleged business secrets in such opinions. The same rules apply with respect to counsel's observations during the inspection itself. With this ruling, the core structure of the inspection procedure has been confirmed, thereby allowing plaintiff's counsel to take part in the inspection. Furthermore, the Court provided a clear set of rules that have to be met in order to qualify information as a business secret, bringing the standard protection in line with long-tested provisions of German criminal law.

To protect the interests of the alleged infringer, the Court ruled that it is mandatory in every case to balance the interests of both parties. However, the Court also clarified that even if business secrets were contained in such expert opinion, they need not necessarily prevent the expert opinion from being released, as the impact of their disclosure on competition may in fact be more or less insignificant. It can be assumed that courts will follow the approach developed under existing case law, where the outcome of the expert opinion is a significant factor in determining the balance of interests: The greater the likelihood that a patent infringement has occurred, the greater the chance that the interests of the patent owner would prevail over any concerns of secrecy raised by the alleged infringer.

Source: The primary sources cited above,  BBC News, New York Times (NYT), Washington Post (WP), Mercury News,, Chicago Tribune, CNN, USA Today, Intellihealthnews, Deccan Chronicle (DC), the Hindu, Hindustan Times, Times of India, AP, Reuters, AFP,  Biospace etc.

Notice: The content of the articles is intended to provide general information. Specialist advice should be sought about your specific circumstances.

Copyright ©1998-2010
Vepachedu Educational Foundation, Inc
Copyright Vepachedu Educational Foundation Inc., 2009.  All rights reserved.  All information is intended for your general knowledge only and is not a substitute for medical advice or treatment for special medical conditions or any specific health issues or starting a new fitness regimen. Please read disclaimer.

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