The World Health Organization (WHO) issued a report late last month, which showed that increased access to HIV services and drugs resulted in a 15% decline in new infections during the past decade and a 22% decline in AIDS-related deaths in the last five years. “It has taken the world 10 years to achieve this level of momentum,” said Gottfried Hirnshcall, director of WHO’s HIV Department.,” in a Nov. 30, 2011, WHO press release. “There is now a real possibility of getting ahead of this epidemic. But this can only be achieved by both sustaining and accelerating this momentum over the next decade and beyond.” 

The WHO report noted that improved access to HIV testing services enabled 61% of pregnant women in eastern and southern Africa to receive counseling for HIV, up from 14% in 2005. Nearly half (48%) of pregnant women in need received effective medicines to prevent mother-to-child transmission of HIV in 2010. Antiretroviral therapy, which improves the health of infected people and also stops further transmission, is currently available for 6.65 million people in low- and middle-income countries, accounting for 47% of the 14.2 million people eligible to receive it. The improvement in health also has an improvement in economic development. The report says that investment in HIV services could lead to total gains up to $34 million by 2020 in increased economic activity and productivity, more than offsetting the cost of antiviral therapies. 

Despite these gains, however, the WHO report acknowledges that more needs to be done and continued investment in HIV services and drugs is required. “2011 has been a game-changing year,” said Paul De Lay, deputy executive director with UNAIDS, in the WHO release. “With new science, unprecedented political leadership, and continued progress in the AIDS response, countries have a window of opportunity to seize this momentum and take their responses to the next level. By investing wisely, countries can increase efficiencies, reduce costs, and improve on results. However, gains made to date are being threatened by a decline in resources for AIDS.” 

The report highlights certain key needs. More than half of the people who need antiviral therapy in low- and middle-income countries are still unable to access it or do not know if they are infected with HIV. Also, many countries are still not tailoring programs for at-risk groups, including adolescent girls. Worldwide, 64% of people aged 15-24 living with HIV are female. The rate is higher in Sub-Saharan Africa, where girls and women make up 71% of all young people living with HIV, according to the WHO analysis. The WHO report also points out that better services are needed to prevent mother-to-child transmission of HIV and to treat children. Only about one in four children in need of HIV treatment in low- and middle-income countries received it in 2010 as compared with one in two adults receiving treatment.  

At the end of 2010, 6.66 million people were receiving antiviral therapy in low- and middle-income countries, an increase of more than 1.4 million people, or 27% from December 2009. Overall, the estimated treatment coverage of antiviral therapies among adults and children in low- and middle-income countries continued to increase and was 47% of the 14.2 million people eligible for treatment at the end of 2010, up from 39% in December 2009. As of December 2010, 10 low- and middle-income countries, including three countries with generalized epidemics (Botswana, Nambia, and Rwanda) had already achieved universal access to therapy, defined as providing antiviral therapy to at least 80% of the people eligible for treatment. Seven additional countries, including two countries with generalized epidemics (Swaziland and Zambia) had estimated coverage levels between 70% and 90%.

On a regional basis, however, there are mixed signs for increased access to antiviral therapies. Sub-Saharan Africa recorded the largest overall increase, 30% in the number of people accessing antiviral therapies. The regional coverage rate for antiviral treatment  was 49% at the end of 2010 in Sub-Saharan Africa. It was 39% in Asia, 23% in Eastern Europe and Central Asia, only 10% in the Middle East and Africa, and 63% for adults and 39% for children in Latin America and the Caribbean.  

On the research front, there are approximately 88 medicines and vaccines in development to treat or prevent HIV/AIDS and related conditions, according to a recent report by the Pharmaceutical Research and Manufacturers of America (PhRMA). Of the 88 medicines and vaccines in development, 49 are antivirals and 27 are vaccines. These  medicines are either in clinical trials or awaiting review by FDA. The research efforts are focused in improving treatment regimes, more targeted therapies, and vaccines. The International AIDS Vaccine Initiative estimates that a vaccine that is 50%  effective and given to only 30% of the population could reduce new HIV infections by 24% over 15 years, according to the PhRMA report.

Articles

CSR and Sustainability Forum

International efforts, including improving access to medicines, have contributed to stemming the rise of HIV/AIDS in the developing world.

World Health Organization Issues Progress Report on Combating HIV/AIDS

, a parasite found only in the Americas. Chagas disease is a neglected tropical disease that largely affects poor and rural populations. According to the US Centers for Disease Control and Prevention, as many as 11 million worldwide are affected with the disease. 

 initiative by awarding eight grants totaling $18.4 million to help communities and populations disproportionately affected by Type 2 diabetes. The grants will be used to develop solutions that integrate public health, healthcare services, and community supportive services to improve health outcomes and reduce disease burdens. The grants are part of an overall five-year $100 million initiative, 

Together on Diabetes: Communities Uniting to Meet America’s Diabetes Challenges

 awarded $2.34 million in grants to help prisoners with mental illness return to the community. The grants were made to the South Florida Behavioral Network and Valley Cities Counseling and Consultation in Washington. 

 is providing more than $4 million in additional funding to the 

Infectious Disease Research Institute (IDRI)

. The funding will allow IDRI to continue its early-phase drug-discovery efforts focused on identifying new and better therapies for treating tuberculosis, including multidrug-resistant tuberculosis. In addition, Lilly will provide more than $1 million in-kind for volunteer time from Lilly scientists and access to the company’s drug-discovery expertise, chemical libraries, and research tools. 

 contributed $12.3 million to the United Way, which represented contributions from the company’s US employees and retirees and a matching gift from the Lilly Foundation. The amount exceeded the company’s previous contribution of $12 million and was $800,000 above the 2011 donation goal.

International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

 highlighted two recent studies that provide global data on influenza vaccine provisions and the level of support for immunization policies. The IFPMA study published in the journal 

 measured seasonal influenza vaccine provisions worldwide and found coverage needs to continue to grow strongly to meet vaccination recommendations issued by public health authorities and organizations, such as the World Health Organization (WHO). The results showed that global vaccine supply increased by more than 70% to 449 million does during the study period (2004 to 2009), but only 20% of the 157 study countries reached the study’s low threshold level, which was based on WHO seasonal influenza immunization recommendations for the elderly only , not including other at-risk groups.  A second IFPMA study published in 

 showed that public health authorities around the world officially recommend and financially support seasonal influenza vaccination for healthcare workers. The IFPMA data surveyed 26 countries from each region of the world and showed that 88% of the countries recommended healthcare worker vaccination against seasonal influenza. 

, a global nonprofit healthcare group, to evaluate more than 30 promising technologies at various stages of development that address the two leading causes of maternal mortality, postpartum hemorrhage and preeclampsia, as well as family planning. The partnership, valued at $2.5 million, extends through the fall of 2012 and will integrate private- and public-sector expertise to evaluate affordable and easy-to-use maternal health technologies that work in resource-poor settings. The program is part of 

, a new 10-year, $500-million initiative focused on reducing maternal mortality caused by preventable complications of pregnancy and childbirth. 

 reported on progress in ending river blindness (i.e., onchocerciasis).  Merck is partnered with the Carter Center, founded by former President Jimmy Carter, through the center’s Onchocerciasis Elimination Program for the Americas (OEPA), which assists national ministries of health in six affected Latin American countries to conduct health education and distribute Merck’s Mectizan (ivermectin). At the 21st Inter-American Conference on Onchocerciasis, held in Bogota, Colombia, last month, public health officials announced that Colombia has eliminated river blindness from within its borders, making it the first Latin American country to reach that goal. Also, Guatemala and Mexico will end drug-treatment programs for the disease in 2012 and begin the three-year postmonitoring program, already completed by Colombia, and required by the World Health Organization, to certify elimination of the disease. In Latin America, river blindness historically has affected Guatemala, Mexico, Colombia, Ecuador, Brazil, and Venezuela. Starting  in 2012, approximately 80% of the half-million at risk will no longer be in need of treatment. Brazil and Venezuela will continue treatment in the hopes of interrupting transmission by the end of next year. 

Novartis Foundation for Sustainable Development

 held a symposium in early December to examine the impact of information and communication technology on democratization and development. The conference focused on the role of e-health applications in improving access to healthcare and in facilitating the achievement of the health-related objectives in the United Nations’ Millennium Development Goals. The symposium also discussed the role of social media platforms in the Arab Spring and the impact of mobile-phone penetration in African nations. 

 has received the 2011 Business Civic Leadership Center’s Corporate Citizenship Award in the Best International Ambassador category for Pfizer’s Global Health Partnership program. The awards honor excellence in corporate citizenship and civic leadership for initiatives in the United States and around the world. Pfizer’s Global Health Partnerships combines the philanthropic and in-kind resources of the Pfizer Foundation and Pfizer to combat noncommunicable diseases by strengthening healthcare systems and infrastructure toe support cancer- and tobacco-control efforts. 

 participated in the 10th Edition of the Pan-African Conference Against Malaria, which gathers the directors of 34 African National Malaria-Control Programs, representatives of the Global Fund to Fight Aids, Tuberculosis and Malaria, the World Health Organization, the Roll Back Malaria Partnership, and scientific experts. Speaking at the conference was Sanofi CEO Christopher A. Viehbacher, who discussed the value of private–public partnerships, nonprofit organizations, and public- and private-sector groups in combating the disease. Sanofi supplies several malaria drugs in support of malaria-control efforts and the health-related United Nations’ Millennium Development Goals. Key efforts by Sanofi include the Impact Malaria program to supply medicines and support healthcare education and information on malaria prevention and treatment, a partnership with the Drugs for Neglected Disease Initiative , a public–private partnership, which developed a fixed-dose combination drug to combat malaria, and various other research efforts for malaria treatment and prevention.. 

A roundup of developments in corporate social responsibility and sustainability from the bio/pharmaceutical industry, its suppliers, and other private and public organizations.

CSR and Sustainability in the News

Environmental sustainability is an important goal for companies, including pharmaceutical companies. Efforts in energy conservation, reduction of greenhouse-gas (GHS) emissions, and programs in green chemistry involving solvent reduction and water-based methods in manufacturing are some examples of how companies seek to meet goals in environmental sustainability 

In September 2011, Merck & Co. issued its 2010 global corporate responsibility report, which highlighted its efforts in environmental sustainability. These efforts including setting specific goals, establishing metrics, adopting best practices, and implementing specific project work in the areas of energy efficiency, water conservation, and green chemistry. 

One area of focus is energy efficiency. Merck has a Center of Excellence in Energy that is responsible for identifying and implementing best practices for reducing energy use across the company. Because the majority of the company’s demand for energy occurs at manufacturing, warehousing, laboratory, and major office facilities, the company targets these types of facilities for programs for energy-demand reduction. In 2008, the Center of Excellence in Energy developed efficiency metrics for all major energy-using systems at Merck to evaluate performance. The company also developed a Best Practices Evaluation Tool, which sites use to evaluate how well they meet best practices and identify opportunities to improve. The tool looks at 14 categories of energy demand, including HVAC, steam distribution, meters, lighting, and compressed air. In 2005, the company adopted a corporate goal to reduce the intensity of its energy demand at its research, manufacturing, and other major office facilities by 25% per unit area (measured in millions of BTUs/ft

) by the end of 2008 from a baseline year of 2004. The company exceeded that goal by reducing its energy demand by 28% in that timeframe. In 2009, the company established an improvement target of 10% for the period of 2009 to 2015, using 2009 performance as a baseline. Projects being developed and used to reach that goal include multiple renewable energy initiatives, installation of variable speed drives, reassessment of production, green research and office buildings, and the use of free cooling and heat recovery from recirculating water systems, according to the report. 

With respect to GHS emissions, Merck reports GHS through the Carbon Disclosure Project, an annual reporting of listed companies of their GHS emissions.  In February 2008, Merck announced a corporate goal to reduce GHS emissions from the company’s global facilities and automobiles by 12% by the end of 2012 from a baseline year of 2004. In 2009, Merck achieved and exceeded this GHG reduction. The company set a second-phase GHS reduction goal of an additional 10% by 2015, based on 2009 performance, according to its report. 

Water conservation also is an important goal. Merck established a goal to reduce its demand for water by 15% between 2009 and 2015 and by 25% between 2009 and 2020. The company’s strategy for improving water-use efficiency includes reducing overall demand for water, controlling water discharge, and understanding the water-related challenges in the regions in which the company operates. During 2010, the company used 9 billion gallons of water compared to 8.1 billion gallons in 2009. The increase was due to the addition of a new operating facility that uses 1.9 billion gallons of surface water. Facilities that were operating in 2009 and continue to operate in 2010 achieved an 11% decrease in water demand during 2010, according to the report. Approximately 69% of the total water the company uses is from surface and ground water. A large use of water is for utility systems in API manufacturing plants, which require large volumes of cooling water. In 2010, approximately 53% of its water usage globally was for once-through noncontact cooling, where water is pumped into the plant, circulated through heat-exchange piping to cool processes, and then discharged. 

Strategies to reduce water usage include assignment of a waste manager at each major site who is responsible for identifying water-reduction opportunities, implementing best practices, and conducting water audits to identify leaks and opportunities to reduce water use. Some examples of best practices include controlling cooling systems operations, repairing steam-distribution systems and traps, recovering and reusing steam condensate and water-purification reject water, optimizing production of process water, avoiding the use of water in mechanical seals, such as in pumps, and considering the total cost of water in project evaluation, according to the report. 

On a green-chemistry basis, the company has several initiatives in place, including solvent reduction, the use of water-based methods in pharmaceutical manufacturing, and ongoing programs for reducing emissions, effluents, and wastes. 

Other companies also are pursuing sustainability goals and practices. A specific example of sustainability at work at a production facility is Pfizer’s facility in Freiburg, Germany. Pfizer Manufacturing Deutschland GmbH recently won the 2011 Facility of the Year Award for Sustainability for its Strategic Plant Restructuring and Energy Master Plan (SPRING and E-MAP) project for its facility in Freiburg, Germany. The Facility of the Years Award program, which is awarded by the International Society for Pharmaceutical Engineers (ISPE), recognizes pharmaceutical manufacturing projects that use new and innovative technologies to enhance quality as well as reduce the cost of producing pharmaceuticals. Now in its seventh year, the awards program accepted submissions from more than 25 countries and territories. An independent judging panel consisting of global senior-level executives from the industry reviewed the submissions, according to a Nov. 7, 2011 ISPE press release. 

In earning the award, the Pfizer’s Freiburg facility was recognized for innovative technologies and automation as part of a long-term sustainability program. Some highlights include a fully automated material flow system, multipurpose automation systems, paperless order documentation, the facility’s use of computer-integrated manufacturing systems, a wood-pellet boiler system for powering air-conditioning systems, and other advanced manufacturing and energy-efficiency practices and design. These elements were cited for contributing to an overall sustainability program and cost-efficient production. Additional analysis of the Freiburg facility will be examined in an upcoming edition of  

, Neuland Laboratories will examine an eco-friendly route to the manufacture of rufinamide.

A roundup of pharmaceutical companies' sustainability objectives and key projects.

Pharmaceutical Companies Target Green Manufacturing

Antibody drug conjugates represent a niche area of drug development. Antibody drug conjugates combine a small-molecule, often a cytotoxic compound, to a monoclonal antibody. Grant E. Boldt, PhD, director of European business development for SAFC, discusses manufacturing considerations in producing antibody drug conjugates with Patricia Van Arnum, executive editor of 

APIs

A podcast moderated by Patricia Van Arnum, executive editor of Pharmaceutical Technology.

Technical Perspectives: Antibody Drug Conjugates

In September 2011, President Barack Obama signed into law the 

 (Public Law 112–29), which represented a major overhaul of the US patent system. Patent reform will affect all stages of the patent process, from prefiling activities to post-grant challenges to patent litigation, and many of these changes will have a particular impact on the pharmaceutical industry. At the front-end of the patent process, the changes to 35 

 102 shift the “prior art” paradigm from a “first-to-invent” system toward a “first-to-file” system. At the other end, the new post-grant review procedures will enable a competitor to challenge a granted patent on any basis, while the new 

 review procedures will apply to previously granted patents that currently are not subject to 

 reexamination. Additionally, the new supplemental examination procedures will offer patent owners a way to inoculate their own patents against certain inequitable conduct charges. The new law made several immediate changes related to patent litigation, of which the newly expanded prior-use defense may be particularly relevant to the pharmaceutical industry. It is important for pharmaceutical companies to be aware of these changes so that they can evaluate their publication, patenting, and competitive intelligence programs in view of the new laws and continue to leverage their intellectual property to maximize value and retain their competitive edge. 

 The US patent system has been unique in the world by granting patents to the “first inventor” rather than the first person to file a patent application. For example, current 35 

102 (a) provides that certain disclosures qualify as prior art only if they were made “before the invention thereof by the applicant,” and current 35 

102 (g) provides that a patent may not be granted if someone else made the invention first as established during an “interference” proceeding. In other countries, any publication made before the application filing date usually qualifies as prior art (although some countries have a grace period for an inventor’s own disclosures), and no investigation is made into relative dates of invention.

Patent reform will bring the US closer in line with other countries, by deleting the first-to-invent terms of the statute and placing more emphasis on an application’s filing date. The new law will not create a true first-to-file system, however. There still will be a one-year grace period after an inventor’s own public disclosure, but such a disclosure may put foreign patent rights at risk. Nevertheless, under the new US system, an inventor disclosure could shield an application filed within the grace period from an independent third-party disclosure made after the inventor’s disclosure but before the inventor’s filing date. The new law also includes provisions that protect inventors from third-party disclosures and patent applications that are based on information obtained from the inventor, by excluding such inventor-based events from the definition of prior art. On the other hand, the new law eliminates the ability to “swear behind” an independent, third-party disclosure by proving an earlier date of invention.


The new law expands the realm of prior art by eliminating provisions that required certain events to occur in the US in order to qualify as prior art. Thus, a public use or sale anywhere in the world will qualify as invalidating prior art, whereas the parallel provision in the current law is limited to US activities. Similarly, published US patent applications will qualify as prior art as of their earliest filing dates, regardless of whether that date is based on a foreign or US application. On the other hand, the new law eliminates the risk embodied in current 35 

102 (g)(2) that an inventor will not be able to obtain a patent because some one else invented the subject matter earlier, but never disclosed it.

The ability to cite patent applications based on their filing dates creates a cache of “secret” prior art because most patent applications are not published until 18 months after their earliest filing date. The US uses such secret prior art much more expansively than foreign countries. In most countries, patent applications that were filed but not published before the filing date of the application at issue can be cited as of their filing date only if they fully describe the invention at issue. That is, they can be cited if they destroy novelty, but cannot be cited if they only impact inventive step or obviousness. In contrast, in the US, such applications are citable for any reason, including being cited in combination with other references to establish obviousness. The new law extends the reach of unpublished US patent applications back to their foreign filing dates, whereas under current law an unpublished US patent application is only citable as of its earliest US filing date. Pharmaceutical companies may be able to mitigate the effects of this expanded cache of secret prior art by obtaining evidence that weighs against obviousness, such as experimental data reflecting any unexpected results associated with their inventions.

 
 The first-to-file changes take effect on Mar. 16, 2013, and will apply to applications with an effective filing date on or after that date. However, because they impact the scope of the one-year grace period and the ability to swear behind third party publications, any disclosures made after Mar. 16, 2012 could have a greater impact than they would have had without patent reform. With this in mind, pharmaceutical companies should review their publication and patenting policies now, to ensure that they have strict prepublication review policies, maintain good records on all disclosures, and streamline their patenting processes to reflect the importance of securing an early application filing date. 

 Patent reform changes the way third parties can challenge granted patents within the US Patent and Trademark Office (“Patent Office”) by creating new post-grant review proceedings and by replacing the current 

 review proceedings. The two new types of proceedings will be complementary in that post-grant review and will be available only within a nine-month window after a patent’s issue date while 

 review will be available only after that nine-month window has closed, or after any post-grant review proceeding has terminated.

The availability of post-grant review could be significant for the pharmaceutical industry because it will permit third parties to challenge a patent on any ground, including written description, enablement, and patent-eligibility, which currently only can be raised in a court proceeding. In order to institute post-grant review, the petitioner will have to show that it is “more likely than not” that one of the challenged claims is “unpatentable,” or that the petition raises a novel or unsettled question of law. Unlike court proceedings where a patent is entitled to a presumption of validity and the challenger must prove otherwise by clear and convincing evidence, the petitioner in a post-grant review proceeding will have to make its case by only a preponderance of the evidence. Except for certain business-method patents, post-grant review will be available only against patents granted from applications with an effective filing date on or after Mar. 16, 2013.Thus, it could be several years before the first post-grant review proceedings are underway. 

 review proceedings will be similar to current 

 reexamination in many respects. For example, like 

 review will be limited to prior art issues raised by patents or printed publications. Patent reform immediately changed the standard for instituting 

 reexamination from raising a “substantial new question of patentability” to showing that there is “a reasonable likelihood that the requestor would prevail” with respect to at least one of the challenged claims. (Note the subtle difference between the post-grant review standard, which may be a slightly higher threshold). This change will be carried forward for 

 review and should, in theory, make it harder to institute these proceedings, and consequently increase the certainty associated with obtaining a granted patent. 

 review is available on Sept. 16, 2012, it will be available against patents granted previously, including patents based on applications filed before Nov. 29, 1999, which currently are not subject to 

 reexamination. Competitors who would like to invalidate such patents in a Patent Office proceeding may want to evaluate the potential risks and rewards of pursuing 

 review, and patent holders may want to consider whether they have any valuable patents that may be particularly vulnerable to such a challenge. 

Other differences between the current and new proceedings strike a balance between the interests of patent owners and the interests of competitors. For example, both post-grant review and 

 review will be conducted by the (newly named) Patent Office Trial and Appeal Board, and are statutorily mandated to be completed within one year. They both have estoppel provisions that prevent a petitioner from raising in litigation an issue that was or reasonably could have been raised in the Patent Office proceeding and other provisions that restrict the relative timing and conduct of litigation.

These new proceedings will offer competitors several different ways to challenge patents with a promise of prompt resolution of patentability questions. As patent holders, pharmaceutical companies should be prepared to defend their important patents in these new proceedings. As competitors, pharmaceutical companies may want to monitor competitor applications and prepare to promptly challenge questionable patents under appropriate circumstances. Parties on both sides of the patent table will need to have their arguments and evidence prepared in advance and be ready to hit the ground running to obtain a favorable decision in the statutorily mandated short timeframe.


 Supplemental examination is a new type of proceeding within the Patent Office that only patent owners will be able to use. Supplemental examination will be similar to current e

 reexamination proceedings, but can be based on any “information” that raises a “substantial new question of patentability,” not just prior art. The “information” itself need not be new. Rather, supplemental examination can be pursued to obtain reconsideration of “information” already of record in the patent. If supplemental examination is obtained before the patent is involved in litigation or before it is the subject of an abbreviated new drug application (ANDA) Paragraph IV certification letter, the patent cannot be held unenforceable based on information that was considered, reconsidered, or corrected during supplemental examination although the Patent Office can pursue any questions of material fraud that arise during supplemental examination.

 Although supplemental examination will not be available until Sept. 16, 2012, once it is available it can be pursued with respect to patents granted previously. Pharmaceutical companies with patents listed in the 

pproved Drug Products with Therapeutic Equivalence Evaluations

, which identifies drug products approved on the basis of safety and effectiveness by FDA under the Federal Food, Drug, and Cosmetic Act) and/or preparing to enforce their patents may want to consider whether pursuing supplemental examination is advisable to inoculate the patents from any foreseeable inequitable conduct charges. On the other hand, patent owners should keep in mind that claim amendments made during supplemental examination can give rise to intervening rights around any amended or new claims. 


 Pharmaceutical companies may be particularly interested in the expanded prior commercial use defense that is available against any patent granted on or after Sept. 16, 2011. The previous defense was available only against method claims, but the new defense applies both to a process and to “a machine, manufacture, or composition of matter used in manufacturing or other commercial processes.” Thus, for example, the expanded defense conceivably could encompass reagents or intermediates used in commercial processes. Directly relevant to the pharmaceutical industry, the statute expressly defines commercial use as including premarketing regulatory review. This means that pharmaceutical companies may be able to invoke this defense based on activities undertaken to conduct safety and efficacy studies before they have a commercial product on the market. On the other hand, the revised law provides that the defense cannot be used against certain university-owned inventions. 

In order to invoke this defense, a pharmaceutical company will have to be able to show by clear and convincing evidence that it was commercially using the subject matter at issue in the US at least one year before the earliest filing date of the application claiming the invention or, in some circumstances, one year before the grace period of the application. The defense is personal, nontransferable, does not invalidate the patent, and generally is limited in scope to the prior commercial use. The expansion of this defense gives pharmaceutical companies further reasons to maintain good records of their internal processes as the availability of this defense could prove very valuable in a patent-infringement litigation. 


 The new law made immediate changes in other litigation-related areas as well. False-marking cases brought by citizens on behalf of the US government were retroactively eliminated. Now, only the US government and parties suffering a commercial injury can bring a false marking claim. Additionally, marking a product with an expired patent number no longer amounts to false marking. So-called “patent troll” cases that named numerous defendants also should be less common, now that there are stricter requirements for joining defendants in an infringement suit. The new law also eliminated a “best mode” violation as a basis for invalidating a patent. Although disclosing the best mode remains a requirement for patentability, the Patent Office has indicated that examiners will not focus on best-mode issues. 

Adapting to the reformed US patent system


 The pharmaceutical industry is well-situated to adapt to the changes that patent reform will bring. Pharmaceutical companies already are patent-savvy, and most are familiar with the first-to-file patent systems of other countries. While the US system will be unique in some respects, most pharmaceutical companies already have publication controls and patenting procedures in place that may only need to be tweaked in view of the new US laws. Careful invention recordkeeping will remain important to establish that your public disclosure is prior art against a competitor, and not obtained from a competitor’s inventor, and to defeat a claim that your patent application was derived from someone else. Pharmaceutical companies also may want to revisit their competitive intelligence programs to ensure that they are positioned to take advantage of the new procedures for challenging competitor patents. Pharmaceutical companies already retain good records of internal manufacturing processes for regulatory purposes, and now may be able to leverage those records to establish a prior commercial use defense against a charge of patent infringement. Thus, while patent reform will affect all aspects of the US patent system, pharmaceutical companies who prepare for the changes now should be able to use them to their advantage to maximize the value of their intellectual property.

Courtenay C. Brinckerhoff (cbrinckerhoff@foley.com) is a partner of Foley & Lardner LLP, vice-chair of the firm's chemical, biotechnology and pharmaceutical practice, and editor of 

Global Feature

The author discusses the major changes in US patent laws as a result of the recently signed patent-reform law and the implications for pharmaceutical companies.

Patent Reform and the Pharmaceutical Industry: From First-To-File To Post-Grant Review And Beyond

Biosimilars manufacturers recognize that to compete and provide cost-savings relative to reference products, they must be cost-effective. Some improvements for biosimilar manufacturers will include: improved expression systems, higher titers to reduce capacity requirements, and better assay methods to permit process monitoring, and product characterization (1). 

. Biosimilars manufacturers will need to increase expression-system yields to enable use of smaller bioreactors and lower cost facilities. New expression-system technologies, along with large single-use bioreactors for late-stage and commercial manufacturing, may begin to displace stainless steel for commercial manufacture. This shift is particularly true for recombinant monoclonal antibodies (mAbs), where a large number of biosimilar products are in development. mAbs have high repeated dosing requirements, and large amounts of protein in the magnitude of hundreds of kilograms per year often are needed.   

New platforms (i.e., new host cells/organisms) and genetic-engineering advances applied to traditional platforms also can offer advantages in product yield, product quality, lower operating, purification, and infrastructure costs (2). Some newer technologies offer shorter times required to go from gene to transformed host cell line/organism to commercial-scale manufacture. Currently, there are just a few major players promoting new expression-system technologies, but there are a many advances ready for adoption, adaptation,  and further development.  

Higher titers to reduce capacity requirements.

The trend in increasing protein expression yields has had broad ramifications for biosimilars. From lowering construction requirements to increasing bottlenecks at the downstream end of production, the effects of upstream advances and the availability of more varied expression systems have created options and problems not previously seen. According to a recent BioPlan Associates analysis, the overall average yield reported for commercial mAB manufacture in 2011 is 2.18 g/L, up from 1.94 g/L in 2009 (see Figure 1). (1). It was not that long ago that mammalian-cell culture commercial production yields were lucky to achieve 1 g/L or greater (1).  

Figure 1: Annual change in titre, commercial, and clinical-scale production of monoclonal antibodies, 2008â2011 (1). (ALL FIGURES ARE COURTESY OF THE AUTHOR) 

The next generation of commercial products will have an even greater average yield. For late-stage clinical manufacture, the overall average in 2011 is 2.68 g/L, up from 1.96 g/L in 2008. Although protein yields over 30 g/L are being reported by expression system developers and early adopters, these yields are the exception, and yields for commercial manufacture in the 5–10g/L range are more likely in coming years (1).  

 Better assay methods to permit process monitoring and product characterization will enable more biosimilar approvals. FDA and other regulatory agencies will largely rely on analytical data to support conclusions that biosimilar candidates are sufficiently similar to their marketed reference products to allow generic-like approvals. As such, regulators are likely to look for better analytic characterization through more combinations of attributes at greater sensitivities with multiple complementary methods. For drug developers, analytical method development and testing will be less expensive and quicker compared to reliance on clinical trials to support approvals. 

Figure 2: Select new product-development areas of interest (1).  

Progress in the development of bioprocessing-related assays and analytical equipment, however, has not kept up with industry demands. Better analytical technologies are being sought by the industry for improving productivity, process monitoring, real-time product quality control, process optimization, and analytical characterization for biosimilars. These trends are reflected in a recent BioPlan Associates survey, where more than 32% of biopharmaceutical manufactures and 21% of CMOs expressed demands for improved analytical assays (see Figure 2). The survey showed that, after single-use/disposable bioprocessing equipment, more relevant and cost-effective assays and analytical equipment is a strong need. Areas of interest include better probes and sensors, in-house real-time analyses of process streams, use of biological assays to determine active agent-related quality (e.g., glycosylation variants) and outsourcing of specialized chemical analysis and biological assays.  

Figure 3: Percentage of all biopharmaceutical Industry vendors actively funding assay-related R&D (1).  

More than one quarter (26.2%) of respondents cited analytical testing and drug-product releases as major factors likely to constrain their organization's production capacity during the next five years. Respondents identified 26 areas where new and improved testing technologies are required. More than 40%, cited glycosylation and comparability testing (primarily for demonstration of comparability between lots/batches of the "same" product, but also to show similarity for biosimilar products). Also, early 40% of all respondents cited the need for better host-cell protein assays, biophysical characterization during process development, and in-process testing and aggregation assays. Figure 3 shows the percentage of vendors funding assay-related R&D.  

 is president of BioPlan Associates, tel. 301.921.5979, 

 1.  BioPlan Associates, "8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production: Survey of Biotherapeutic Developers and Contract Manufacturing Organizations" (Rockville, MD, April 2011).   

 2.  BioPlan Associates, "Biopharmaceutical Expression Systems and Genetic Engineering Technology: Current and Future Manufacturing Platforms" (Rockville, MD, 2008).  

Outsourcing

Biosimilar manufacturers need better expression systems and analytical tools to compete.

PTSM: Pharmaceutical Technology Sourcing and Management-12-07-2011

World Health Organization Issues Progress Report on Combating HIV/AIDS

CSR and Sustainability in the News

Pharmaceutical Companies Target Green Manufacturing

Technical Perspectives: Antibody Drug Conjugates

Patent Reform and the Pharmaceutical Industry: From First-To-File To Post-Grant Review And Beyond

Biosimilars' Technology Needs