Patent Docs

Successful Gene Therapy for Hemophilia B Reported

By Kevin E. Noonan --

One of the perennial promises of biotechnology is the possibility that genetic diseases can be cured by replacing a defective gene with a normal copy of it.  Gene therapy has been attempted on and off for about thirty years, although initial attempts were sporadic and in some cases of doubtful provenance.  And the field suffered a serious setback when a patient died undergoing clinical gene therapy trials.  Gene targets for therapeutic intervention have traditionally been related to diseases mediated by hematopoietic cells, since these are most easily manipulated ex vivo and returned to the body, but there have also been attempts to cure diseases of other somatic tissues.  One traditional problem has been the choice of vector:  since in only rare instances have attempts been made to target the replacement gene to the site of the genetic lesion, vectors for delivering exogenous genes have involved viral sequences.  But viruses (particularly efficiently integrating viruses like retroviruses) raise the specter of oncogenic transformation that has retarded their clinical development.  Alternatives, most commonly adenovirus or adeno-associated virus (AAV) (see graphic below), while having less oncogenic risk have been associated with immunological responses due to the prevalence of anti-adenovirus antibodies in humans as a result of naturally occurring infections.

All this may explain the excitement that has greeted the report by authors from University College London Cancer Institute, the Royal Free National Health Service Trust, Queen Mary School of Medicine, Basingstoke and North Hampshire NHS Foundation Trust, St. Jude's Research Hospital, the University of Chicago, Children's Hospital of Philadelphia, and the Howard Hughes Medical Institute.  The report, published in the New England Journal of Medicine this week, reports the results of clinical trials of gene therapy involving human blood clotting Factor IX (at right).  The disease, also called Hemophilia B, is like Hemophilia A an X-linked genetic disorder associated with uncontrolled bleeding, arthopathy and early death.  It is only controlled by frequent intravenous injection of Factor IX protein.  It suffers not only from expense and being palliative rather than providing a cure, but also because inhibitors can arise that reduce the effectiveness of the treatment.  Until now, clinical trials of gene therapy for Factor IX have shown only transient expression of the transgene but also cytotoxic T-cell response against the cells (hepatocytes) transduced with the transgene-encoding vector.

The new study, with a total of six patients, differed from earlier attempts in three ways.  First, the authors produced a "codon-optimized" expression cassette in which "complementary dimers" of the construct were packed in each virion.  These vectors were found to express the transgene "at substantially higher levels" than the previously used single-stranded AAV vectors.  Second, the virus capsids were "pseudotyped" with a capsid of serotype 8, which the authors report have a lower levels of native serum antibodies in the human population due to a lower prevalence of infection with the serotype 8 AAV (AAV8).  Finally, the virus was administered through a peripheral vein rather than into liver tissue directly, which provided a safer route for patients having compromised blood-clotting capacity.

The virus was administered in three concentration levels:  low (200 billion vector genomes/kg body weight); intermediate (600 billion vector genomes/kg body weight); and high (2 trillion billion vector genomes/kg body weight).  Patients were screened for the absence of neutralizing antibodies to AAV8.  All patients expressed less than 1% of normal amounts of Factor IX in the blood and all but one of them were receiving Factor IX protein therapy.  Only three adverse effects were reported, two of which involved anemia and the third being associated with an unrelated surgery.

All three treatment groups showed positive effects of gene transfer.  In the low dose group, one participant showed elevated (~2% of normal) Factor IX levels for 16 months after treatment and while prophylactic Factor IX treatment could be discontinued this patient required additional therapy associated with "accidental injury and elective surgery."  The second participant in the low dose trial showed less immediate effects of the transgene (~1% of normal Factor IX levels); these levels rose to about 2% of normal 23 weeks (~6 months) after therapeutic administration of the virus.  The intermediate dose group showed variable initial response (one patient showed less than 1% Factor IX while the other showed about 4% of normal Factor IX levels immediately after treatment), but over the course of the study these values stabilized to about 2-3% of normal Factor IX levels.  Finally, one member of the high dose group showed an initial large effect (Factor IX levels at about 7% of normal) but these levels dropped suddenly to about 3% in a manner consistent with hepatocyte injury due to an immunological reaction against the viral capsid.  The other member of the high-dose cohort showed persistent levels that were 8-12% of normal Factor IX values, although these levels were reduced after periods of intense physical activity.

Importantly, the study reports no humoral (antibody) immunological response to the Factor IX transgene product but did show a primary immune response against the AAV8 capsid.  Also significant was that no T-cell mediated immune response against the transgene were detected.  There was such a response, however, against the AAV8 viral vector, particularly in the higher dosages cohorts, although this resolved.

Skeptics will note that this report is based on a total of six patients, falling far beneath any success level that would be accepted by any regulatory agency for widespread use.  The authors recognize this, but also note that "this gene-therapy approach, even with the associated risk of transient hepatic dysfunction, has the potential to convert the severe bleeding phenotype into a mild form of the disease or to reverse it entirely."  That promise has driven gene therapy research for a generation and this success suggests that that promise may soon be fulfilled.

For additional information regarding other related topics, please see:

• "EMA Continues to Defer Approval of First Gene Therapy Application in Europe," July 26, 2011
• "Renova Therapeutics Begins Congestive Heart Failure Gene Therapy Trials," February 8, 2011
• "GSK Forms Alliance for Development of Gene Therapy Techniques for Rare Diseases," October 20, 2010
• "Gene Therapy Experiencing a Revival," May 3, 2010

Pfizer's Lipitor: A New Model for Delaying the Effects of Patent Expiration

By James DeGiulio --

Pfizer's exclusive right to sell atorvastatin, the active pharmaceutical ingredient in the blockbuster cholesterol drug Lipitor, ended yesterday, November 30, the day generic competitors are licensed to enter the market as agreed upon during settlement of past patent litigations.  It was a day the pharma giant has been dreading for quite some time.  This dread is well founded:  on average, once a drug goes off patent, the patent holder's market share typically falls by a staggering 89% in the first 6 months.  However, thanks to several innovative strategies, Pfizer's Lipitor, which has enjoyed a commanding 40% share in the cholesterol drug market, stands a good chance of being the exception to this trend, according to a recent article in The New York Times ("Facing Generic Lipitor Rivals, Pfizer Battles to Protect Its Cash Cow").  The sector outlook appears to be optimistic -- investor studies have upgraded Pfizer's rating, and expect the company to retain much of its market share even now that the patent has expired.  The strategies implemented by Pfizer, assuming they survive governmental scrutiny, may provide a model for brand companies facing blockbuster drugs going off-patent.

Pfizer has employed a multi-pronged approach to retain its position in the cholesterol market for these next critical 180 days.  First, Pfizer has several authorized generics deals in place.  For example, an authorized generic from Watson Pharmaceuticals went on sale yesterday.  However, Watson's drug is manufactured by Pfizer, and Watson has to give about 70 percent of its profits to Pfizer.

Perhaps more importantly, Pfizer has dropped the price of Lipitor considerably, and continues to aggressively discount the drug to match any price and maintain brand loyalty.  Pfizer's prices are currently undercutting most of the imminent generic competition on price.  Pfizer has also made it known that its new discounts can easily be adjusted to beat any responsive reduction in the expected generic pricing.  Pfizer has a huge margin because of the relatively low cost of materials for Lipitor.  And with their manufacturing and volume advantage over generic competitors who are just getting off the ground, Pfizer can afford to drop the price considerably and continue to profit off of Lipitor.

Pfizer is also providing incentives to customers to stay on the brand drug.  They have offered a reduced co-payment of $4 a month versus the $10 customers would pay for many generic prescriptions.  Pfizer's program, called "Lipitor for You," offers a $4 co-payment card and direct delivery of Lipitor.  The program is limited to privately insured customers.  However, the discounts can also be applied to many Medicare prescription drug plans, which have agreed to dispense Lipitor even if patients ask for generics.  Pharmacy benefit management company CVS/Caremark has notified pharmacies that the generic form of Lipitor would not be covered for 29 prescription drug plans it manages for Medicare Part D.  Instead, brand Lipitor will be filled, but only a generic co-pay will be applied.  Any prescription claims for generic atorvastatin will be rejected.  Pfizer, the benefit managers and some insurers insist all of the new discount will be passed along to consumers, companies and other payers.  While this remains to be seen, CVS/Caremark has already lowered its premiums for the government and Lipitor users.

Pfizer's tactics to protect its market share have naturally drawn scrutiny.  Many of these strategies may call into question the incentive system created to foster the development of generic drugs, as they arguably extend Pfizer's patent monopoly beyond its expiration.  The Federal Trade Commission and several Senators are investigating Pfizer's agreements with pharmaceutical benefit manager and generics companies.  Senators Max Baucus (D-MT), Chuck Grassley (R-IA) and Herb Kohl (D-WI) have written letters to Pfizer and those who have aligned with Pfizer, asking for information about agreements aimed at limiting the sale of generic atorvastatin.  According to these letters, the Senators believe that "just about everyone wins except consumers and taxpayers."

Not all companies have aligned with Pfizer -- some companies have rejected their advances.  Express Scripts and Medco Health Solutions, both large pharmacy benefit managers, are recommending that its clients not accept Pfizer's deals under the reasoning that it could cost them more in the long run.  However, these companies will still use Lipitor as a "house generic" because Pfizer has guaranteed to match the price and assured a supply.

Late yesterday, Ranbaxy Laboratories, the first filer against several patents covering Lipitor, was granted FDA approval for its avorstatin calcium, despite a federal investigation into falsifying records resulting in the production and sale of medications that failed to meet FDA standards.  Ranbaxy has a deal with Teva Pharmaceuticals, which already sells a generic Lipitor in Canada, to help supply the drug.  Once Ranbaxy's 180-day initial generic exclusivity has expired and all generics can produce avorstatin calcium, it may be inevitable that Pfizer finally loses its considerable market share.  Pfizer expects up to eight generics to compete for market share after the 180-day exclusivity period expires.

Rep. Burgess Introduces Genetic Diagnostic Testing Bill

By Kevin E. Noonan --

A decade after completion of the Human Genome Project, and after more than a decade of hyperbole regarding the promise and benefits of "personalized medicine," genetic diagnostic testing has come to the attention of Congress.  For example, Representative Debbie Wasserman Schultz (D-FL) introduced a provision of the Leahy-Smith America Invents Act (LSAIA) that would have "guaranteed" availability of "second opinion" testing for any patented genetic diagnostic test (see "Manager's Amendment (and Others) to H.R. 1249 -- Second Opinions in Genetic Diagnostic Testing").  She withdrew this amendment in the face of strong opposition from the American Civil Liberties Union and other groups, who pursue a complete ban on such testing as well as other aspects of biotechnology; she later introduced a standalone bill (H.R. 2276) that would "require the Director of the United States Patent and Trademark Office to conduct a study on effective ways to provide confirming genetic diagnostic test activity where gene patents and exclusive licensing exist" (see "Bio/Pharm Legislation Watch"); these provisions were added to the LSAIA enacted into law as a mandate that the U.S. Patent and Trademark Office perform a study directed to such a determination.  And Congressman Xavier Becerra continues to introduce a bill that would ban all gene patenting, at least prospectively (see "He's Baaack!").

The latest Congressional foray into genetic diagnostic testing comes from Rep. Michael Burgess (R-TX) (at left), who introduced legislation that would prohibit the Food and Drug Administration from regulating genetic diagnostic testing, based on the apprehension that such regulation would cripple innovation and that such testing would be "subsumed" by the bureaucracy.  Such testing is already regulated (as is all other laboratory testing) by the Centers for Medicare and Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments (CLIA).  Rep. Burgess discussed his bill on November 17th at a "bi-partisan policy forum" sponsored by The Hill and the American Clinical Laboratory Association.  The bill was prompted, in part, by FDA announcements that it intends to regulate "direct-to-consumer" genetic diagnostic tests.  Rather than cast the legislation as a ban, his bill (the "Modernizing Laboratory Test Standards for Patients Act of 2011," H.R. 3207) provides for regulation of such genetic diagnostic tests under the current CLIA regime, but with new guidelines and regulations directed towards greater clinical validity of such tests.  The bill also provides for the establishment of a Laboratory Developed Test (LDT) Test Registry Data Bank (for promoting "transparency") and a reporting requirement for clinical laboratories regarding death or serious injury that occurred as the result of a LDT.

In this regard, the bill requires disclosure for LDTs of the following information to the Data Bank:

• The location of the laboratory.
• The certification and licensure information of the laboratory.
• The purpose of the test.
• The claimed use or uses of the test.
• A description of the test methodology.
• Information regarding the analytical validity of the test.
• Information regarding the clinical validity of the test for each of its claimed uses.
• Information describing the status of the test as an existing test (as described under paragraph (4)), a new test pending review (under subsection (c)), or an authorized new test (under subsection (c)(4)(B)).

For so-called "direct-to-consumer" (DTC) DNA testing, the information required to be submitted includes all the aforementioned and in addition:

(i)  The identity, location, and registration information of the test-offering entity.
(ii)  The identity of the certified laboratory that will perform the test, and the certification and licensure information for such laboratory.
(iii)  information to demonstrate that the consumer will be provided with access to pre-test and post-test counseling by a physician or qualified genetic counselor.

Rep. Burgess has garnered the support of 4 co-sponsors (Rep. Marsha Blackburn, R-TN; Rep. Howard Coble, R-NC; Rep. Robert Latta, R-OH, and Rep. Erik Paulsen, R-MN).  The bill was referred to the House Committee on Energy and Commerce, and specifically the Subcommittee on Health, on October 14, 2011.

Geron Discontinues hESC Programs

By Donald Zuhn --

On Monday, Geron Corporation announced that it was discontinuing further development of its human embryonic stem cell (hESC) programs and would be seeking partners for each of the programs, which include oligodendrocyte progenitor cells (GRNOPC1) for central nervous system disorders, cardiomyocytes (GRNCM1) for heart disease, pancreatic islet cells (GRNIC1) for diabetes, dendritic cells (GRNVAC2) as an immunotherapy vehicle, and chondrocytes (GRNCHND1) for cartilage repair.  In place of the hESC programs, the biopharmaceutical company noted that it would be focusing on its oncology programs.

According to Dr. John Scarlett, Geron's CEO, the company's decision to discontinue its hESC programs was necessitated by "the current environment of capital scarcity and uncertain economic conditions."  By narrowing the company's focus to the oncology therapeutic area, Dr. Scarlett explained that Geron would have sufficient financial resources to reach important clinical milestones over the next 20 months for its oncology drug candidates imetelstat and GRN1005.  He added that "[t]his would not be possible if we continue to fund the stem cell programs at the current levels."

Geron noted that the decision to narrow the company's focus was made after "a strategic review of the costs, value inflection timelines and clinical, manufacturing and regulatory complexities associated with the Company's research and clinical-stage assets."  As a result of the decision, Geron will be eliminating 66 positions, representing 38% of the company's workforce.  The company will also be closing its GRNOPC1 trial for spinal cord injury -- the first hESC trial approved in the U.S. -- to further enrollment, but would continue to follow currently enrolled patients, accrue data, and update the FDA and medical community on the trial's progress.  The trial, which was initiated last April, has shown GRNOPC1 to be well tolerated with no serious adverse events.

For additional information regarding this and other related topics, please see:

• "Geron Initiates Human ES Cell Clinical Trial," October 18, 2010
• "Geron Gets Approval for First Human Clinical Trial Using Embryonic Stem Cells," January 25, 2009

Maybe (Just Maybe) President Obama Is Beginning to Get It Regarding Technology Policy

By Kevin E. Noonan --

Despite achieving a legislative accomplishment that had been frustrated for over a generation (i.e., healthcare reform), the Obama Administration's technology policies have left even the President's supporters perplexed by a fundamental paradox.  Specifically, how could the President (an intelligent man) and his advisors (comprising this generation's "best and brightest") be so seemingly clueless about technology policy?  From promoting the Leahy-Smith America Invents Act as a way to stimulate the economy and create jobs (see "Commerce Secretary Provides Administration's Views on America Invents Act" and "Obama Administration Supports S. 23"), to supporting the Federal Trade Commission's single-minded pursuit of an end to reverse payment agreements between innovator and generic drug companies (despite copious evidence that such agreements actually promote generic drugs to market), to his dogged persistence on trying to limit the data exclusivity provisions of the follow-on biologics portion of the healthcare reform bill from 12 to 7 years (see "President's Deficit Reduction Plan Seeks to Reduce Exclusivity Period for Biologics and Prohibit Pay-for-Delay Deals"), to the spectacularly "simple-minded" nonsense of the "magic microscope" standard for patent eligibility of DNA claims in the Myriad case (see "AMP v. USPTO: Oral Argument at the Federal Circuit"), the President's policies seem disconnected from the reality of promoting innovation in America (and the resulting economic benefits thereof).

Thus, it may be a sign that the clouds of confusion are clearing in Washington that the President issued the following Memorandum for the heads of all Executive departments and agencies in Friday, October 28th:

THE WHITE HOUSE

Office of the Press Secretary

For Immediate Release October 28, 2011

October 28, 2011

MEMORANDUM FOR THE HEADS OF EXECUTIVE DEPARTMENTS AND AGENCIES

SUBJECT: Accelerating Technology Transfer and Commercialization of Federal Research in Support of High-Growth Businesses

Section 1. Policy. Innovation fuels economic growth, the creation of new industries, companies, jobs, products and services, and the global competitiveness of U.S. industries. One driver of successful innovation is technology transfer, in which the private sector adapts Federal research for use in the marketplace. One of the goals of my Administration's "Startup America" initiative, which supports high-growth entrepreneurship, is to foster innovation by increasing the rate of technology transfer and the economic and societal impact from Federal research and development (R&D) investments. This will be accomplished by committing each executive department and agency (agency) that conducts R&D to improve the results from its technology transfer and commercialization activities. The aim is to increase the successful outcomes of these activities significantly over the next 5 years, while simultaneously achieving excellence in our basic and mission-focused research activities.

I direct that the following actions be taken to establish goals and measure performance, streamline administrative processes, and facilitate local and regional partnerships in order to accelerate technology transfer and support private sector commercialization.

Sec. 2. Establish Goals and Measure Progress. Establishing performance goals, metrics, and evaluation methods, as well as implementing and tracking progress relative to those goals, is critical to improving the returns from Federal R&D investments. Therefore, I direct that:

(a) Agencies with Federal laboratories shall develop plans that establish performance goals to increase the number and pace of effective technology transfer and commercialization activities in partnership with non-federal entities, including private firms, research organizations, and non-profit entities. These plans shall cover the 5-year period from 2013 through 2017 and shall contain goals, metrics, and methods to evaluate progress relative to the performance goals. These goals, metrics, and evaluation methods may vary by agency as appropriate to that agency's mission and types of research activities, and may include the number and quality of, among other things, invention disclosures, licenses issued on existing patents, Cooperative Research and Development Agreements (CRADAs), industry partnerships, new products, and successful self-sustaining spinoff companies created for such products. Within 180 days of the date of this memorandum, these plans shall be submitted to the Office of Management and Budget (OMB) which, in consultation with the Office of Science and Technology Policy (OSTP) and the Department of Commerce, shall review and monitor implementation of the plans.

(b) The Interagency Workgroup on Technology Transfer, established pursuant to Executive Order 12591 of April 10, 1987, shall recommend to the Department of Commerce opportunities for improving technology transfer from Federal laboratories, including: (i) current technology transfer programs and standards for assessing the effectiveness of these programs; (ii) new or creative approaches to technology transfer that might serve as model programs for Federal laboratories; (iii) criteria to assess the effectiveness and impact on the Nation's economy of planned or future technology transfer efforts; and (iv) an assessment of cooperative research and development venture programs.

(c) The Secretary of Commerce, in consultation with other agencies, including the National Center for Science and Engineering Statistics, shall improve and expand, where appropriate, its collection of metrics in the Department of Commerce's annual technology transfer summary report, submitted pursuant to 15 U.S.C. 3710(g)(2).

(d) The heads of agencies with Federal laboratories are encouraged to include technology transfer efforts in overall laboratory evaluation.

Sec. 3. Streamline the Federal Government's Technology Transfer and Commercialization Process. Streamlining licensing procedures, improving public availability of federally owned inventions from across the Federal Government, and improving the executive branch's Small Business Innovation Research (SBIR) and Small Business Technology Transfer (SBTT) programs based on best practices will accelerate technology transfer from Federal laboratories and other facilities and spur entrepreneurship. Some agencies have already implemented administrative changes to their SBIR and SBTT programs on a pilot basis and achieved significant results, such as reducing award times by 50 percent or more. Over the past year, some agencies have also initiated pilot programs to streamline the SBIR award timeline and licensing process for small businesses. In addition, some agencies have developed new short-term exclusive license agreements for startups to facilitate licensing of inventions to small companies. Therefore:

(a) Agencies with Federal laboratories shall review their licensing procedures and practices for establishing CRADAs with the goal of reducing the time required to license their technologies and establish CRADAs to the maximum practicable extent.

(b) The Federal Chief Information Officer and the Assistant to the President and Chief Technology Officer shall, in coordination with other agencies: (i) list all publicly available federally owned inventions and, when available, licensing agreements on a public Government database; (ii) develop strategies to increase the usefulness and accessibility of this data, such as competitions, awards or prizes; and (iii) report their initial progress to OMB and OSTP within 180 days of the date of this memorandum.

(c) The heads of agencies participating in the SBIR and SBTT programs shall implement administrative practices that reduce the time from grant application to award by the maximum practicable extent; publish performance timelines to increase transparency and accountability; explore award flexibility to encourage high quality submissions; engage private sector scientists and engineers in reviewing grant proposals; encourage private sector co-investment in SBIR grantees; partner with external organizations such as mentoring programs, university proof of concept centers, and regional innovation clusters; and track scientific and economic outcomes. The OMB, OSTP, and the Small Business Administration shall work with agencies to facilitate, to the extent practicable, a common reporting of these performance measures.

Sec. 4. Facilitate Commercialization through Local and Regional Partnerships. Agencies must take steps to enhance successful technology-innovation networks by fostering increased Federal laboratory engagement with external partners, including universities, industry consortia, economic development entities, and State and local governments. Accordingly:

(a) I encourage agencies with Federal laboratories to collaborate, consistent with their missions and authorities, with external partners to share the expertise of Federal laboratories with businesses and to participate in regional technology innovation clusters that are in place across the country.

(b) I encourage agencies, where appropriate and in accordance with OMB Circular A-11, to use existing authorities, such as Enhanced Use Leasing or Facility Use Agreements, to locate applied research and business support programs, such as incubators and research parks, on or near Federal laboratories and other research facilities to further technology transfer and commercialization.

(c) I encourage agencies with Federal laboratories and other research facilities to engage in public-private partnerships in those technical areas of importance to the agency's mission with external partners to strengthen the commercialization activities in their local region.

Sec. 5. General Provisions. (a) For purposes of this memorandum, the term "Federal laboratories" shall have the meaning set forth for that term in 15 U.S.C. 3703(4).

(b) This memorandum shall be implemented consistent with applicable law and subject to the availability of appropriations.

(c) Nothing in this memorandum shall be construed to impair or otherwise affect the functions of the Director of OMB relating to budgetary, administrative, and legislative proposals.

(d) Independent agencies are strongly encouraged to comply with this memorandum.

(e) This memorandum is not intended to, and does not, create any right or benefit, substantive or procedural, enforceable at law or in equity by any party against the United States, its departments, agencies, or entities, its officers, employees, or agents, or any other person.

BARACK OBAMA

It must be acknowledged that this is merely a statement of intentions and policy goals, and that the extent to which it influences or changes the pace and scope of technology transfer from Federal laboratories is uncertain (and perhaps more dependent on the personalities in charge of those laboratories, both administration and scientific).  However, it is refreshing to see the Administration take this tack on innovation policy, particularly in view of the contrary (and contradictory) signals that has characterized the past few years.

GOP Candidates Unified in Opposition to Embryonic Stem Cell Research

By Donald Zuhn --

On Saturday, the GOP kicked off the 2012 presidential election cycle with Iowa Republicans gathering in Ames, Iowa to participate in the Ames Straw Poll.  Minnesota Rep. Michele Bachmann picked up 4,823 votes (28.6%) of the 16,892 votes cast in the straw poll to edge out Texas Rep. Ron Paul, who received 4,671 votes (27.7%).  Texas Gov. Rick Perry collected 718 write-in votes after announcing his candidacy in South Carolina on the day of the Ames Straw Poll, and former Massachusetts governor Mitt Romney picked up 567 votes after deciding to skip the straw poll in June.

In an article published in The Boston Globe prior to the Ames Straw Poll, the positions of the Republican presidential candidates on embryonic stem (ES) cells was examined ("Most in GOP field would scale back stem cell funding").  The Globe reported that "[n]early all of the Republican presidential candidates would put the brakes on President Obama's efforts to broaden federal spending on embryonic stem cell research."  In March 2009, President Obama issued Executive Order 13505, entitled "Removing Barriers to Responsible Scientific Research Involving Human Stem Cells," which reversed limits imposed by the Bush administration on taxpayer support of ES cell research (see "President Obama to Lift Stem Cell Limits on Monday" and "President Obama Reaffirms Faith in Science").

The Globe noted that most of the candidates responded to the newspaper's survey of their positions on federal funding of ES cell research "with vague statements and dodged questions about whether they would endorse Bush's position of allowing funding for research on a limited number of existing stem cell lines to continue."  However, the article points out that the socially conservative Susan B. Anthony (SBA) List has suggested that Rep. Bachmann, Rep. Paul, former senator Rick Santorum, former House speaker Newt Gingrich, and Rep. Thaddeus McCotter (MI) would oppose further expansion of federal funding of ES cell research.  (The SBA List also indicated that former Minnesota governor Tim Pawlenty would also oppose further expansion of federal funding of ES cell research, but after his third-place finish on Saturday, Mr. Pawlenty withdrew from the Republican presidential race on Sunday.)  Mr. Romney told the Globe that he would not allow federal funding of ES cell research, but "would make an examination of the science and speak with experts in the field" before deciding whether to follow the Bush administration's example by permitting research to be conducted on existing ES cell lines.

According to a report in Salon, Gov. Perry (at left), who had not officially entered the race when the Globe article was published, would appear to side with the other Republican candidates, having declared that stem cell research has "turn[ed] the remains of unborn children into nothing more than raw material" ("Gov. Rick Perry underwent stem cell therapy").  While not inconsistent with Gov. Perry's position on ES cell research, the Salon article noted (with some surprise) that the Texas governor underwent an experimental spinal fusion procedure last month in which he was injected with adult stem cells to treat a back injury.  As a result of the procedure, which the Perry campaign called a success, the Texas governor is a strong proponent of adult stem cell research ("Perry's Surgery Included Experimental Stem Cell Therapy").

Interestingly, in opposing ES cell research and federal funding of such research, the Republican presidential candidates side with a minority of Americans -- a Gallup 2011 poll indicated that 62% of Americans believe ES cell research is morally acceptable, and a Pew Research Center poll showed that 58% of Americans support federal funding of ES cell research.

EMA Continues to Defer Approval of First Gene Therapy Application in Europe

By James DeGiulio --

Last year we reported that gene therapy was experiencing a revival of sorts, now that many of the safety concerns raised from early clinical trials have been resolved (see "Gene Therapy Experiencing a Revival").  However, this revival has not yet produced marketable therapeutics, as the FDA has yet to approve a gene therapy therapeutic in the U.S., and in March 2010, the European Medicines Agency (EMA) rejected Europe's first filed gene therapy application.  Expectations in the field were that Amsterdam Molecular Therapeutics' (AMT) new Glybera therapy could very well be the first for approval -- but on June 24, AMT announced that the EMA had rejected its application for a gene therapy therapeutic for lipoprotein lipase deficiency (LPLD).  AMT moved quickly and has already filed an application for re-examination.  However, the reward for the first approved gene therapy therapeutic in a registered market remains unclaimed.

Glybera (alipogene tiparvovec) was developed as a treatment for the rare genetic disorder LPLD.  Because of a defective gene, LPLD patients do not produce an enzyme that normally breaks down a certain type of fat carrying particles in the blood.  Glybera uses an adeno-associated virus (AAV) vector that carries a gene for lipoprotein lipase, which restores the enzyme's activity required to process the fat carrying particles.  LPLD patients have extremely high fat levels in their blood, resulting in recurrent and potentially lethal pancreatitis as well as an increased risk of cardiovascular complications and diabetes.  Currently, there exists no effective treatment or cure for the serious disease.

The EMA told AMT that it has not provided enough evidence of the long-term efficacy of the product.  LPLD is an extremely rare condition, and the clinical trial data submitted to EMA for approval included only 27 patients.  The EMA said at present there are too few patients for whom sufficiently long-term data were available, and as a result, there was insufficient evidence of a reduction in the rate of pancreatitis.  Importantly, the EMA did not have any concerns about the safety of Glybera, which supports an emerging inclination that the safety of gene therapy is no longer the roadblock to regulatory approval as it has been in the past.  Indeed, the first gene therapy product ever to be filed for approval with EMA was Cerepro, a gene therapy for treating brain cancer, which also presented no concerns about the safety of the product.  The EMA refused approval of Cerepro because there was not enough evidence that Cerepro was effective.

AMT believes it can avoid the pitfalls of Cerepro, and has already filed for re-examination of its application.  AMT must now collect more data to show that there is a long-term reduction in the incidence of pancreatitis in treated patients.  AMT said it will be possible to generate the additional data required from the existing treated patients, and the data will come from a trial which the company had already planned to do as a postmarketing study.  AMT hopes to garner the additional data and resubmit the Glybera file by the end of 2011.  In addition to its pursuit of Glybera, AMT will also continue development of other gene therapy products in the company's pipeline, such as therapeutics for Parkinson's disease and Huntington's disease.  AMT is also preparing to apply for market approval of Glybera in Canada and the U.S.

Increase in Drug-Resistant Bacteria Creating Need for New Antibiotics

By James DeGiulio --

Over the past five years, the pharmaceutical industry seems to have had little interest in developing new antibiotics despite drug-resistant bacteria representing a serious public health issue.  Since the appearance of the first antibiotic-resistant bacterial strains in the 1940's, at least thirteen strains that are impervious to many antibiotics have been discovered.  According to the Infectious Disease Society of America, bacteria that are resistant to one or more drugs are responsible for some 100,000 U.S. hospital deaths a year, and cost the health care system more than $34 billion.  According to a recent Bloomberg report, however, smaller biotech firms may be assuming the role normally occupied by large pharmaceutical companies, and stepping up to develop new classes of antibiotics.

Due to lack of expected revenue opportunity, the pharmaceutical industry has all but abandoned the development of new antibiotics.  While important for quality medical care, antibiotics rarely provide blockbuster potential to a pharmaceutical company.  Because antibiotics are used for only weeks at a time, as compared with years for drugs that treat chronic diseases, the revenue stream for antibiotics is not long-term.  Furthermore, physicians are advised to limit antibiotic treatment because of concerns that overuse can spur resistance, which can have a negative effect on sales.  This removes incentives to spend funds on research and regulatory approval for new antibiotics.  Indeed, since 2006, only three of 111 drugs approved by the FDA were antibiotics, and only two of the top six drugmakers are currently developing antibiotics.  The top five antibiotics earned a relatively modest combined $6 billion in 2010 in the U.S.

Despite this antibiotic apathy among big industry players, there is certainly a public health need for developing new antibiotics.  For patients hospitalized with skin infections, for example, it is reported that about 20 percent will not respond to first-choice treatment with clindamycin or Bactrim.  For these patients, the hospital has two options, both of which are much more expensive than clindamycin or Bactrim treatment:  a 10-day course of Pfizer's Zyvox, which costs about $1,000, or alternatively, an intravenous drug like vancomycin can be used, which requires a hospital stay.

Smaller biotech companies are beginning to fill the void left by the lack of interest in new antibiotics by big pharma.  Smaller companies do not necessarily need a blockbuster drug to flourish, and antibiotics present a manageable product.  Some of the early entrants are already projecting solid returns on their efforts.  Optimer, a San Diego-based company, is nearing approval for Dificid, a drug that fights stomach infections, which is expected to generate $500 million a year in sales.  The Medicines Co., of Parsippany, New Jersey, is developing oritavancin, a skin infection antibiotic which is expected to generate as much as $300 million.  Other companies in final testing of drugs that may gain U.S. marketing approval by 2014 include Paratek Pharmaceuticals Inc. (omadacycline, an injectable derivative of tetracycline), Cubist Pharmaceuticals Inc. (drug targeting pneumonia, abdominal and urinary tract infections caused by gram-negative bacteria), and Durata Therapeutics (dalbavancin, a lipoglycopeptide that breaks down the cell walls and membranes of bacteria).

The Hinxton Group Foresees Stem Cell Issues and Proposes Solutions

By Kevin E. Noonan --

Think tanks, consortia, foundations, subcommittees, and "working groups" frequently assay an area with some social, economic, or technological significance to determine whether issues exist or can be anticipated that deserve to be studied to minimize harm or maximize opportunity.  These groups can be helpful in focusing attention of what may be "over the horizon," although it is hard to remember any examples of a report from such groups that actually helped avoid the unforeseen problem.  What must be remembered in reviewing the recommendations of such groups (or government agencies like the Federal Trade Commission) is the political aspect:  none of these reports ever concludes that "everything is fine, there is nothing to worry about."  Dr. Pangloss cannot be found in the roster of luminaries populating such bodies.

All this comes to mind when assessing the recommendations of The Hinxton Group on stem cell policy.  The Group's Report, entitled "Statement on Policies and Practices Governing Data and Materials Sharing and Intellectual Property in Stem Cell Science," which issued in February, contains several fairly commonsensical recommendations; that some of them are accompanied by admonitions that they should be adopted through coercion merely reflects the tendency for intelligent and well-minded people not to understand and to be offended by anyone who disagrees with them.  More troubling than the recommendations are the justifications for them contained in the preamble of the Report, about which it can only kindly be said suffers from the rhetorical error of assuming the conclusion of the argument it tries to raise.

But first to the recommendations, which number five:

1a:  Establish a central hub for accessing global stem cell registry information

The basis for this recommendation is purportedly a lack of data sharing due to a failure to publish or otherwise disclose.  The proposed solution is to provide an "information portal" to be established as a resource, taking as examples existing resources such as the National Institutes of Health, the EU and International Stem Cell Registries, to be modeled after NCBI, GenBank, and EMBL Bank.  The Report also recommends that the data to be shared be contained in multiple sites (as is genetic information), which is advocated to distribute "funding, physical security, transparent operation and collective ownership."

The Report cites as advantages of such repositories collaboration, incentives for participation, and open access, as well as promoting cooperation and coordination across organizations, standardized formats, information about cells, mutations, characteristic features, publication details, and other aspects of information distribution.  It also recommends that participation be coerced, for example by requiring participation as a condition for obtaining grants or access to publication in major journals (or alternatively that participation be left voluntary).  It seems that the recommendation that such behavior be compelled rather than voluntary could undermine the purported advantages of this recommendation, by reducing the incentives for disclosure and making more attractive private rather than public funding sources.

1b:  Establish a central hub for accessing information about stem cell patents

The Report cites "scholars" as contending that:  1) public databases of patent information "are often difficult to search"; 2) outcomes of patent examination differ in different jurisdictions (which is certainly true); 3) intellectual property rights (IPR) are "copious and atomized into a profusion of patents with overlapping claims"; and 4) "no one is curating the global body of patent data."  This results in "considerable uncertainty and enormous costs" in trying to survey the IPR landscape.  Evocatively, the Report states that "[e]veryone suffers when there is no map for a new research area, and individual explorers are in no position to do the mapping and have no incentive to satisfy the needs of other stakeholders."

Distinct from the stem cell hub proposed in Recommendation 1a, this recommendation envisions an "information resource" for IPR (called the IPR Resource), and suggests primary (patent) and secondary (scientific journals, etc.) databases and linkages between them.  Underlying this proposal is the benefits of coordination and cooperation, including information on patent licensing and assignment information from public sources (such as the trade press) and even a stem cell patent "wiki."  While this recommendation undoubtedly could help academic and legal research and researchers, it is unlikely that anyone seeking this information for commercial purposes would neglect to consult a patent attorney, for whom many of these impediments would not be as daunting.

Recommendation 2:  Encourage, support and coordinate international human stem cell banks and human tissue and cell repositories

This recommendation is aimed at material transfer agreements and "impediments" to stem cell "sharing" between laboratories (presumably, academic laboratories).  Also addressed is the possibility that "[w]e may need new, internationally coordinated mechanisms to deal with emerging issues related to informed consent and privacy."  The Report recommends that existing stem cell banks (e.g., UK Stem Cell Bank) be "supported" and that existing stem cell banks and repositories coordinate with one another regarding "standards," proposing "a well‐networked international set of cell banks and repositories could quickly and efficiently distribute existing and newly generated human stem cell lines of common interest."

The Report also advocates that provenance information be coordinated between banks (which, while admirable and useful may conflict with "standards" for protecting privacy), and addresses emerging areas like induced pluripotent stem cell (iPSC) characterization, and standards for inclusion based on academic "popularity," potential for use in "particular therapeutic efforts" and the "level of constraint" there may be on the use of certain stem cells, such as from IPR.

Recommendation 3:  Develop and institute incentives for data and materials sharing through publication, participation in information hubs, and other mechanisms

This recommendation is related to the earlier-noted problem of data accession and efficiencies for sharing materials.  The Report cites disincentives to "early publication and distribution, especially in industry" and lack of avenues for publishing negative data.  The recommendation argues that databases be established, to be populated by the "insist[ance] on the deposition of data, with release on  . . . publication."  Examples (or perhaps justification) for such restrictions cited in the Report are standards for publishing results of clinical trials from the NIH in collaboration with "the top 20 clinical journals," and microarray standards (MIAME) to which 50 journals ascribe.

The Report also recommends that funding agencies require minimum information on methods etc. regarding a publication, with mechanisms to supplement if information is found to be inadequate.  Such efforts should be part of consistent policies between "[r]egulatory bodies, research institutions funding bodies, companies and journals" for data and material sharing, again using a coercive rather than voluntary or cooperative paradigm.  The Report also advocates estabilishing bases for promoting release of negative data, for example by entry into a database, and that all publications should conform to guidelines for "appropriate standards for data completeness and norms of behavior."

Recommendation 4:  Explore options for formal collaborative networks, patent brokering, and formation of patent pools when those mechanisms for collective management of intellectual property can move the field forward

Turning again to IPR, the Report advances the idea that there is "[c]opious IP" that requires "[c]ollective action . . . to reduce transaction costs and bureaucratic friction that can intrude on market mechanisms to advance stem cell R&D."  The Report claims that individual research institutions are "hedging their bets" and "seeking patent rights as a matter of course, in the unlikely event that one of these patents will result in a large financial payoff."  This "creat[es] a culture of pervasive patent infringement married to a potential option for prosecuting selected infringement later," creating a "broad shadow of uncertainty about freedom to do research and pursue applications."

This portion of the recommendations highlights a pervasive concern among academic researchers:  the unlikely event that mere scientific research will incur patent infringement liability.  This fear informs the Report's assertions that IPR promotes "under-investment in new firms, high barriers to entry for new innovators, and slower progress in the field" than would be the case "if individual research institutions were more constrained and targeting in their seeking of patent rights."  The "problem" posits a fear of later patent lawsuits from "research institutions with public missions."  Of course, the other way to view the current situation is that without IPR, universities would see their publicly funded research pirated by corporations, foreign and domestic.

The Report recommends that the law recognize distinctions between stem cell IPR and other technologies, without any express statement of what those distinctions are.  For example:

Intellectual property relevant to stem cell research has several features in common with other technologies, but some features that are distinctive.  Many patents have been granted in different countries and multinational patent jurisdictions (such as the European Patent Office).  The accumulation of IPR is common for an emerging technology, and since 1998, this has been occurring in human pluripotent stem cell research and its applications.

The Report asserts (without reciting evidence in support of its assertions) that the number and frequency with which researchers are encountering "delays and blockages" may be sufficient to produce a consensus that there is an IPR problem that needs to be addressed, particularly with regard to iPSCs.  "The time may be ripe for collective action to ensure that R&D proceeds apace, and with less congestion or friction than is likely to be possible without such coordinated action," according to the Report's authors.  Proposals for "disposing of the accumulated IPR in a way that benefits all parties" include:

Patent Pools.  Formal patent pools are one possible solution to reducing transaction costs around particular applications or standards (this may include iPSCs).  Patent pools require a collection of issued patents that patent holders agree to "pool," meaning that they have a formal contractual agreement to not enforce the patents against one another or against others licensed by the pool.  A pool requires valid patents, a gatekeeping function to determine what belongs or does not belong in the pool, a way to value and return revenues for patents in the pool, and sufficient common interests among the patent‐holders to be sustained.

Usenow paylater semicommons.  Another model for collective management of IPR involves a set of rules designed and enforced by stakeholders, through a network of agreements.  Some agreements may be informal, but a subset of rules and practices needs to be written and formal.  The formation of norms and practices around IPR is easier when there is a small number of research funders, but in stem cell research, the emergence of the field from small companies, individual universities and funding by state governments within the US, and many regional and national governments internationally, but without a dominant funding organization, has led to an unusually intense problem of research coordination, coupled to a profusion of IPR held by disparate actors with divergent interests.  The development of a semicommons may be a way to address this.

Patent brokers.  Short of a formal patent pool, if patent‐holders have generally similar licensing strategies, collections of patents managed by a neutral arbiter could emerge.  A "patent supermarket" does not require a strong gatekeeper to vet the patents entering a formal pool, but only a broker to collect patents available to potential licensees to be made available on standard terms.  A "royalty clearinghouse" can consolidate and simplify the transactions of incremental royalty payments for such standard term licenses.

Collaborative networks.  One promising strategy is to reduce transaction costs by eliminating patents that are never enforced, licensing existing patents on nonexclusive terms except when exclusivity is needed to induce investment in product development, and generally clearing out the accumulated underbrush of IPR detritus.  These actions require changes in policy among individual stakeholders in the field, and are likely to emerge only if there are explicit norms articulated by those engaged in stem cell research.

The deficiencies in these specific recommendations is that there is little evidence in the Report to support imposing any of these "controls" on how the various stakeholders are managing their IPR, or that such arrangements are impossible without being imposed by government, funding agencies or other outside forces (in contrast to the experience of the computer industry, for example, where standards-setting and cooperative patent licensing has evolved without such externally imposed conditions).

Recommendation 5:  Adopt licensing practices and patent policies that promote fair, reasonable, and nondiscriminatory (equitable) access to knowledge and health care applications

The Report proposes that licensing "should reflect the goal of global justice, borne out of a human dignity common to all and a universal commitment to reduce suffering"; while a laudatory statement of moral behavior, licensing as it is understood in the marketplace is not a flexible means for promoting social goals.  These statements are reminiscent of the idea that "a patent is affected with a public interest," and here the interest relates to using the "power of the state" to enforce IPR, which must be done with an "awareness of its social context and utility," requiring "reasonable limits on its use in the form of obligations towards others."  The Report also cites as justification the altruism of donors (which is both an assumption and certainly not always a factor in making such a donation, any more that altruism explains all blood donations) and "commitments made to ethics review bodies."

This portion of the Report contains specific recommendations, in contrast to other portions of the Report.  Citing to "statements of principle" such as the "Nine Points" adopted by the Association of University Technology Managers (AUTM) and others, they propose:

First, that [a]ny licensing on government‐funded stem cell inventions must:

• Reserve research rights for non‐profit institutions;
• Promote R&D on and access to technologies that can help meet critical health needs in both developing and developed nations.  This can be facilitated through the use of, wherever possible, negotiated global access terms and jurisdictional and field‐of‐use limitations;
• Use non‐exclusive licensing of platform technologies and technologies of broad ancillary utility that are instrumental to the development of the field; and,
• Ensure that data and materials are available to government and academic researchers with a minimum of delay.

Second, that "[t]echnology transfer offices in government‐funded research institutions should make public their stem cell IPR, including their geographic scope and licensing history (including where rights have been reserved or non‐assert clauses have been used), in order to promote transparency and greater use of stem cell technologies.

Third, "[p]atent offices and key policymakers should reassess whether the current standards for granting stem cell patents are appropriate, given both the power of broad platform patents to block R&D, and the proliferation of patents that can create uncertainty and fragmentation in the patent landscape.

While reasonable people may differ regarding specific recommendations and the need for the recommendations in the Report in general, in some ways the most interesting aspect of the Report is the Preamble.  This section contains the general justification for the recommendations and definition of the problem.  Unfortunately, this is also the section that contains the least evidentiary support, and indeed has a tone and tenor that the problems are self-evident.  For example:

Tension is increasing between fairly new and pervasive policies and practices governing data and materials sharing and intellectual property in science ('proprietary structures'), and norms of openness and free exchange.  While intellectual property rights (IPR) can bring private investment into areas underfunded by governments and help bridge gaps between scientific invention or discovery and useful technologies, some new and emerging policies and practices risk slowing innovation in research and development (R&D) and skewing attention toward large markets, to the disadvantage of small markets, such as those for rare diseases and in some emerging economies.  This is of concern, as one central goal of the life sciences is to improve global health: our shared humanity and the potential for biological knowledge to benefit all people create this obligation. Further, the self‐ regulatory structures within scientific communities, as much as the legal institutions we consciously erect for science, should be responsive to this goal.

While the proprietary dilemmas currently faced in stem cell science confound many if not all areas of cutting edge life science, they are especially pronounced in the field of stem cell research.  First, the tree‐like shape of cellular differentiation makes the field especially prone to IPR holdings that can function as tollbooths to broad areas of work, creating a drag on investment and slowing down basic research.  Second, the consequences of such slowing are especially severe in the stem cell field, where novel cell lines, reagents and related technologies function as platforms for broad areas of follow‐on work.  Third, the competition to stake out aggressive patent positions is accentuated in the current context of competitive national innovation policies featuring stem cell science.

None of these assertions is supported by evidence, and in fact there is significant evidence to the contrary.  Examples include the expiry of foundational stem cell patents, which will occur within the next 7-10 years; patent challenges to such patents in the U.S. and abroad; and the likelihood that successful commercialization of stem cell science will take much longer than the term of even the most recent patents, and that the growing body of expired patent disclosure will promote the same goals the Report now advocates.  The difference, of course, is patent rights prior to expiry will foster investment when it is most critical, at the beginning of the development cycle, nurturing translation of basic research to useful medical technologies.  Openness is in fact promoted by the patent system, which requires not only a written description and enabling disclosure but also (at least for now) disclosure of the best mode for practicing the invention.  None of these requirements exist with regard to scientific journal articles or public grant proposals, and indeed there are significant incentives against such full disclosure in those documents.  While the potential for harm recited in the Report may in fact exist, neither the preamble nor the body of the recommendations establish (or even provide evidence for) the assertion that the Report's recommendations be adopted to avoid such harm, or that the consequences of adopting the Report's recommendations would not cause other, different harms.  One of those possible harms is likely to be reducing or limiting full, frank and enabling disclosure of stem cell technology as it develops over the next decades.  Such a cure would be worse that the disease.

The Hinxton Group consists of:

Steering Committee:

Sarah Chan, BSc(Hons), LLB, MA (Health  Care Ethics and Law)
Deputy Director & Research Fellow in Bioethics and Law
Institute for Science, Ethics and Innovation
School of Law, University of Manchester

Peter J Donovan, PhD
Professor, Departments of Biological Chemistry and Developmental & Cell Biology
Co‐Director, Sue & Bill Gross Stem Cell Center
University of California – Irvine

Ruth Faden, PhD, MPH
Philip Franklin Wagley Professor of Biomedical Ethics
Executive Director, Johns Hopkins Berman Institute of Bioethics
Professor, Department of Health Policy & Management, School of Public Health
Professor, Department of Medicine
The Johns Hopkins University

John Harris, FMedSci, BA, DPhil
Lord Alliance Professor of Bioethics Director, Institute for Science, Ethics and Innovation
School of Law
University of Manchester

Robin Lovell­Badge, PhD, FMedSci, FRS
Head, Division of Developmental Genetics,
MRC National Institute for Medical Research
Division of Developmental Genetics
MRC National Institute for Medical Research

Debra JH Mathews, PhD, MA
Assistant Director for Science Programs,
Johns Hopkins Berman Institute of Bioethics
Assistant Professor, Department of Pediatrics
The Johns Hopkins University

Alan Regenberg, MBe
Bioethics Research Manager, Johns Hopkins
Berman Institute of Bioethics
The Johns Hopkins University

Julian Savulescu, BMedSci, MB, BS, MA, PhD
Uehiro Chair in Practical Ethics
Director, Oxford Uehiro Centre for Practical Ethics
University of Oxford

David Winickoff, JD
Co‐Director, Science, Technology, and Society Center, University of California – Berkeley
Associate Professor of Bioethics and Society University of California – Berkeley

Executive Committee:

Robert Cook­Deegan, MD
Director, IGSP Center for Genome Ethics, Law & Policy
Duke University

Gregory Graff, PhD
Assistant Professor, Department of Agricultural and Resource Economics
Colorado State University

Aurora Plomer, BA, MA, LLB, PhD
Chair in Law and Bioethics, Director of SIBLE, School of Law, University of Sheffield
Director, Sheffield Institute of Biotechnology Law and Ethics
University of Sheffield

Kris Saha, PhD
Postdoctoral Fellow, Whitehead Institute for Biomedical Research, MIT
Science Technology and Society Fellow, Kennedy School of Government
Harvard University

Christopher Scott
Director, Program on Stem Cells in Society, Center for Biomedical Ethics, Stanford University
President/CEO, The Stem Cell Advisors

John Sulston, PhD
Chair, Institute of Science, Ethics, and Innovation
University of Manchester School of Law
University of Manchester

Patrick Taylor, JD
Fellow, Petrie‐Flom Center for Health Law Policy, Biotechnology and Bioethics, Harvard Law School
Assistant Clinical Professor, Harvard Medical School
Staff Scientist, Children’s Hospital, Boston, MA

Hinxton Group Members:

Elona Baum, JD (Observer*)
General Counsel, California Institute of Regenerative Medicine

Laura Biron, PhD
Greenwall Fellow in Bioethics and Health Policy, Johns Hopkins Berman Institute of Bioethics, The Johns Hopkins University

Tania Bubela, PhD
Assistant Professor, School of Public Health, University of Alberta, Canada

Francesca Cesari, PhD (Observer*)
Senior Editor, Nature

Haidan Chen, PhD
Post Doctoral Research Fellow, Center for STS, Zhejiang University, China

Jorge Contreras, JD
Director, Intellectual Property Program, School of Law
Washington University in St. Louis

Ishan Dasgupta
Research Program Coordinator, Johns Hopkins Berman Institute of Bioethics
The Johns Hopkins University

Matthew DeCamp, MD, PhD
Greenwall Fellow in Bioethics and Health Policy, Johns Hopkins Berman Institute of Bioethics, Fellow in General Internal Medicine
The Johns Hopkins University

Richard Gold, SJD
Professor, McGill University Faculty of Law
President, Innovation Partnership

Søren Holm, BA, MA, MD, PhD, DrMedSci
Chair, Center for Social Ethics and Policy, University of Manchester
Professor of Medical Ethics, University of Oslo

Jim Houlihan, PhD (Observer*)
Head of Innovation Policy
UK Intellectual Property Office

Ryuichi Ida, LLB, LLM
Professor of International Law, Kyoto University Graduate School of Law
Member, Expert Panel on Bioethics, Council for Science and Technology Policy,
Japan Member, Bioethics & Biosafety Committee, Ministry of Education, Culture, Sport, Science & Technology, Japan

Kazuto Kato, PhD
Associate Professor of Science Communication and Bioethics, Institute of Research in Humanities, Graduate School of Biostudies
Kyoto University

Annabelle Lever, PhD
Wellcome Interdisciplinary Research Fellow, Institute of Science, Ethics, and Innovation
University of Manchester

Jacob Leveridge (Observer*)
Biomedical Ethics & Medical Humanities Adviser
Wellcome Trust

Reinhard Merkel, Prof, Dr
Institut für Kriminalwissenschaften
Universität Hamburg

Dianne Nicol, LLM, PhD
Professor
University of Tasmania, Australia

Amanda OdellWest, PhD
Lecturer in Law, School of Law
University of Manchester

Beverly A Purnell, PhD
Senior Editor, Science Magazine

Mahendra Rao, MD, PhD
Vice President, Stem Cells at Invitrogen
Adjunct Professor, Buck Institute of Age Research
Vice President, Medicine at Life Technologies

Brock Reeve, MPhil, MBA
Executive Director, Harvard Stem Cell Institute
Harvard University

Mark Rohrbaugh, PhD, JD (Observer*)
Director, Office of Technology Transfer
National Institutes of Health

Mark Sheehan, PhD, MA
BRC Ethics Fellow, The Ethox Centre
James Martin Research Fellow in the Program on the Ethics of the New Biosciences
Oxford University

Glyn Stacey, PhD
Head of Division of Cell Biology and Imaging, National Institute for Biological Standards and Control, Director, The UK Stem Cell Bank

Jeremy Sugarman, MD, MPH, MA
Harvey M Meyerhoff Professor of Bioethics and Medicine
Deputy Director for Medicine, Johns Hopkins Berman Institute of Bioethics
The Johns Hopkins University

Dieter Treichel, PhD
Patent and Start‐up Manager
Max Planck Innovation

Fanyi Zeng, MD, PhD
Professor, Associate Director, Shanghai Institute of Medical Genetics, Shanghai Stem Cell Institute, Shanghai Jiao Tong University, China

Biotech Industry Losing Interest in the Therapeutic Potential of RNAi

By James DeGiulio --

When Andrew Fire and Craig Mello (at right) unraveled the mechanism of RNA interference (RNAi) and were awarded the Nobel Prize in 2006 for their efforts, RNAi was predicted to become the next great source of new therapeutics.  Pharmaceutical companies moved quickly to devote research funding and personnel to developing what appeared to be a novel way to target nearly any protein involved in nearly any disease.  However, five years -- and billions of dollars in research and development -- later, it appears that RNAi is falling out of favor in the industry, which is moving away from investing in potential RNAi therapeutics, according to a recent New York Times article ("Drugmakers’ Fever for the Power of RNA Interference Has Cooled").  Despite the nearly universal belief that at a certain point RNAi will make it to the market, the efficiency of RNAi delivery has thus far limited its therapeutic potential.  Industry executives claim that alternatives to RNAi that are closer to producing marketable drugs have taken priority, including conventional drugs, monoclonal antibodies, and even older antisense gene silencing technology.

RNAi was first discovered in 1998 in the nematode worm Caenorhabditis elegans and later found in a wide variety of organisms, including mammals.  Research development moved quickly, and by 2005, three drugs were ready for clinical trials.  Since then, however, two of the three trials have already been dropped due to inefficient delivery.  The third, targeting respiratory infection, has shown some signs of effectiveness, but conclusive trials are only now under way.  Achieving efficient delivery of RNAi molecules has been the largest obstacle to realizing the therapeutic potential of RNAi, an obstacle that has also limited gene therapy applications.  Drugs working through the RNAi mechanism have been shown to successfully silence genes, but it has been difficult to deliver these drugs to the cells where they are needed.  One major problem is that RNA is quickly degraded in the bloodstream, and even if the RNA can reach the target cells in the body, it has trouble entering the cells.  Yet another obstacle is the immune response that double-stranded RNA particles can provoke.  To address these issues, scientists have developed RNA chemical modifications which prevent degradation in the bloodstream and avoid immune responses, but achieving efficient and reliable delivery of RNAi remains elusive.

Within the past year, some big players in the biotech industry have pulled the plug on development of RNAi therapeutics.  In November 2010, Roche announced the end of its efforts to develop drugs using RNAi, after it had invested half a billion dollars in the field over four years.  In January 2011, Pfizer decided to shut down its 100-person unit working on RNAi and related technologies.  Abbott Laboratories has also ended its RNAi drug development work.  Partnerships have also decreased, as big pharma companies have been increasingly hesitant to invest capital in smaller companies that specialize in RNAi.  Alnylam Pharmaceuticals, widely considered the leader among these companies, cut a quarter of its work force late last year after Novartis decided against partnership.

History may indicate that the RNAi hype is just dying down, and more realistic expectations are now taking hold.  It is not unusual for the initial enthusiasm for a new technology to wane as the technology slowly is perfected.  A prime example is monoclonal antibodies, which took twenty years to translate into blockbuster drugs like Avastin and Humira.  Indeed, regardless of the decisions of big pharma, interest in RNAi technology still remains.  In early February, two midsize European drug companies signed small deals to explore development of RNAi drugs.  Also, despite no clear proof that a drug using RNAi can effectively treat a human disease, about a dozen RNAi drugs in clinical trials are currently pending, which is more than ever before.

Renova Therapeutics Begins Congestive Heart Failure Gene Therapy Trials

By James DeGiulio --

Last year, we reported on the revival of the therapeutic potential of gene therapy, after the technique hibernated for years due to questions of safety and inefficient gene delivery (see "Gene Therapy Experiencing a Revival").  The revival continues with the announcement of a new gene therapy clinical trial initiated by San Diego startup Renova Therapeutics.  Renova announced that researchers at the VA San Diego Healthcare System are entering Phase II testing of a very promising adenovirus-based gene replacement therapy for patients with Congestive Heart Failure (CHF).  If the human trials follow the animal data, Renova's therapy could substantially extend the lifespan of humans suffering from CHF.  The NIH has shown great faith in the gene therapy project, contributing $23 million so far.  However, if Phase II proves successful, Renova would likely look to partner up with a larger company to move into Phase III trials.  The Phase II data is expected sometime in 2012.

CHF is a condition where the heart is unable to pump sufficiently to provide the body with enough blood flow to match its needs, since the hearts of CHF patients contain low levels of cAMP.  The prognosis for CHF is dismal -- 50% of those diagnosed die within 4-5 years.  CHF afflicts more than 5 million Americans.  The project began when Dr. Kirk Hammond (at left), Renova founder and a cardiologist at the VA San Diego Healthcare System and Professor of Medicine at the University of California, San Diego, discovered that the adenylyl cyclase type 6 (AC6) gene was downregulated in CHF patients.  Dr. Hammond later discovered that increasing the heart's content of AC6 improves heart function.  Dr. Hammond and his group sequenced and patented the human AC6 gene.

The gene therapy technique uses the same adenovirus vector (Ad5.hAC6) as previous gene therapy candidate Generx, which reached Phase IIb/III studies before Schering determined that the protocol could not deliver enough gene product after 400 patients were screened.  However, Renova's technique improves expression of AC6 gene product by delivering the adenovirus via a coronary catheter to the arteries of the heart, similar to angiography, which is preferable because the technique does not require surgery.  This gene delivery technique is covered by U.S. Patent No. 5,792,453.  The results from the preclinical animal studies were excellent, the data showing that mice with cardiomyopathy (a type of CHF) who received the AC6 gene therapy lived as long as normal, healthy mice.  Whether human CHF patients experience an extension in lifespan remains to be seen.

The first trial site invites active and retired military personnel to volunteer in the clinical trial.  They must be between 18 and 80 years old, and diagnosed with CHF.  A second clinical trial site has recently opened at the William Beaumont Hospital in Royal Oak, Michigan, which is open to all subjects and is not limited to military.  More information on the gene therapy clinical trial can be found on the AC6 Gene Transfer page at the ClincalTrials.gov site as well as on Renova's website.

President Obama Proposes, BIO Agrees

By Kevin E. Noonan --

In his State of the Union address to Congress and the nation, President Obama emphasized the need for America to return to its innovator and entrepreneurial roots, and harness the ingenuity and commercial vigor long associated with this country to effectively compete in the global economy.

The Biotechnology Industry Organization (BIO) agrees.  On Wednesday, BIO President and CEO Jim Greenwood issued the following statement:

We commend President Obama for highlighting the need to increase our nation's global competitiveness and job creation by stimulating investment and research in innovation.  As the President said, "The first step in winning the future is encouraging American innovation."

There is no industry better poised to meet this challenge than biotechnology.  With a strong and predictable patent system, science-based regulatory systems, and appropriate tax policy and incentives, America's biotechnology sector can help drive substantial job growth in the United States and advance our nation's competitiveness over the long term, while providing cutting-edge technologies to address pressing concerns in health care, energy independence and agricultural sustainability.  Innovation is how we make our living.  We are just what the doctor -- and the President -- ordered.

• Therapeutic Discovery Project (TDP) -- We continue to advocate for the extension and expansion of the Therapeutic Discovery Project (TDP) program, which awarded tax credits to small cutting-edge biotech companies to support research and development efforts to cure diseases such as cancer, Parkinson's and Multiple Sclerosis.  Targeted programs like the TDP can help spur continued medical innovation, create and preserve American jobs, and position our nation for continued leadership in the global marketplace.

• Alternative Energy Sources -- The President also renewed his call for the development of clean energy during tonight's speech.  The biotechnology industry, which provides the key technology for producing advanced biofuels and biobased products from renewable biomass, stands ready to provide new green jobs in the United States by developing secure and sustainable sources of domestic energy.

• Regulations for Agricultural Biotechnology Products -- We welcome the President's call to support technology and to review regulations that are barriers to growth.  Agricultural biotechnology provides innovative solutions to help feed and clothe the world, support energy security, and reduce the impact of agriculture on the environment.  The U.S. government's regulatory review on the safety of these products needs to be far more efficient in order to sustain and grown jobs in the industry and bring innovation to market.

America is the world leader in biotechnology.  Our nation's biotechnology industry is comprised of scientists, entrepreneurs, and large and small companies in all 50 states engaged in translating the latest scientific discoveries into innovative new medical therapies and environmental products, increased agricultural production and farm incomes, and greener bio-based products and biofuels.  Nationwide, our industry directly employs more than 1.4 million people and indirectly generates jobs for an additional 6.6 million people.  These are high-quality jobs, paying substantially more than the average U.S. wage.

We look forward to working with President Obama, members of his Administration and the Congress in support of public policies that encourage investment in biotechnology innovation.  The right policies will help create jobs, propel continued innovation, and increase our nation's competitiveness, and security, in the global marketplace for years to come.

The history of the last generation can be interpreted as American ingenuity -- as represented by the biotechnology and computer industries -- lifting the U.S. from its mid-1980's doldrums to the economic prosperity that characterized the years between 1992-2000.  The success of that ingenuity can be exemplified by a simple image:  in 1998 everyone had a Sony Walkman®, and in 2008 everyone had an Apple iPod.  That type of innovation may be less visible in biotechnology, but the pre-eminent biotechnology companies -- Amgen, Genentech, Biogen, Genzyme, and dozens of others -- were American companies.  Mr. Greenwood reminds us that the qualities the President extolled about our country and culture -- risk-taking spirit, availability of venture capital, and acceptance of failure, to name a few -- are just those qualities that support small startup companies, the hallmark of the biotechnology industry.  And his statement brings to mind an apt aphorism by the anthropologist, Margaret Mead:

Never doubt that a small group of thoughtful, committed people can change the world.  Indeed, it is the only thing that ever has.

BIO Survey Shows Support for DNA-Based Patents Despite Some Reservations

By Donald Zuhn --

A survey commissioned by the Biotechnology Industry Organization (BIO) shows that 89% of respondents believe patents provide the protection, time, and funding researchers to work on major technological discoveries, and therefore, are a "good thing."  The survey also showed that while 51% respondents had reservations about DNA-based patents, those respondents could support them because such patents allow biotech companies to work on treatments and cures for deadly diseases.

The results of the survey were summarized in the December issue of BIO's e-newsletter BIOtech NOW.  The survey, which was conducted by Public Opinion Strategies, assessed the views of 400 "elite" voters, which were defined as voters having a college degree, a household income of more than $75,000, and who closely follow current events.

According to the article in BIOtech NOW, the survey highlighted the need for DNA patent proponents to explain to the public that:

• further research can still take place during the life of the patent;
• when the patent expires, it's freely available to the public;
• the opposition has already inserted "gene patents" and "human gene patents" into the vernacular of this debate, terms that produce the negative reactions;
• it would be helpful to adopt alternative terms, such as "genome sequence patents," "DNA-based patents" or "DNA patents."

GSK Forms Alliance for Development of Gene Therapy Techniques for Rare Diseases

By James DeGiulio --

Earlier this year, we reported on the therapeutic potential of gene therapy experiencing a revival of sorts after falling out of favor for over 10 years (see "Gene Therapy Experiencing a Revival").  That revival continues, as evidenced by a press release issued by GlaxoSmithKline on Monday, in which the pharmaceutical company reports that it has licensed a gene therapy treatment for a rare disease that afflicts just 350 children worldwide.  Following its recent formation of a rare disease unit, GSK has allied with two Italian groups, Fondazione Telethon and Fondazione San Raffaele, and has obtained an exclusive license to develop an experimental gene therapy for a disease called ADA severe combined immune deficiency (ADA-SCID).

The ADA-SCID gene therapy news may remind some of the infamous 1999 attempt to cure the related disease severe combined immune deficiency using gene therapy.  Unfortunately, due to carcinogenic viral integration, the therapy caused leukemia in some of the patients.  While ADA-SCID is similar to severe combined immune deficiency, the techniques used in this gene therapy treatment are different, and the Italian group has provided very promising results.  In this ex vivo stem cell therapy, the patient's hematopoietic stem cells are harvested from the body, functional copies of the gene are inserted into the stem cells using a modified viral vector, and the cells are re-introduced to the patient.  Because the technique uses the patient's own cells, there is much less risk of immune rejection compared to a bone marrow transplant, which is currently the best treatment option available.  Most importantly, the ex vivo technique appears to be extremely safe.  On July 22, 2010, the San Raffaele Telethon Institute group published an article in the New England Journal of Medicine showing successful treatment in 8 of 10 children without substantial side effects, including no leukemia cases observed after four years.

GSK also plans to work with the Italian researchers to develop ex vivo stem cell therapy for six other rare diseases, with the potential to treat a range of rare disorders.  The first two disorders will be metachromatic leukodystrophy and Wiskott-Aldrich Syndrome -- clinical trials for both of these disorders were initiated last spring.  Others include beta-thalassemia, mucopolysaccharoidosis type I (MPS), globoid leukodystrophy (GLD), and chronic granulomatous disorder (CGD).  All of these disorders have molecular mechanisms that are well understood and all are caused by faults in a single gene.  GSK's rare disease unit will look at roughly 200 of the 6,000 rare diseases.  The unit will not be conducting its own research, but will instead further develop approaches discovered in academia or within other GSK units.

James DeGiulio has a doctorate in molecular biology and genetics from Northwestern University and is a graduate of Northwestern University School of Law.  Dr. DeGiulio is a member of MBHB's 2010 associate class and he can be contacted at degiulio@mbhb.com.

Geron Initiates Human ES Cell Clinical Trial

By Donald Zuhn --

Last week, Geron Corp. announced that it had enrolled the first patient in the company's clinical trial of GRNOPC, a human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cell line.  The trial's first patient, who has asked to remain anonymous, was enrolled at Shepherd Center in Atlanta, GA, one of seven U.S. sites that may enroll patients in the trial.  Geron's release noted that Northwestern Medicine in Chicago, IL was also open for patient enrollment.  The company said it will announce the remaining locations as they are ready to enroll patients.

According to a press release issued by Geron, the Phase I clinical trial will assess the safety and tolerability of GRNOPC1 in patients with complete American Spinal Injury Association (ASIA) Impairment Scale grade A thoracic spinal cord injuries.  The release notes that participants in the trial must be newly injured (i.e., receive GRNOPC1 within 14 days of the injury), and have suffered a crushed but not severed spinal injury.  Only eight patients will participate in the study.

Geron president and CEO Dr. Thomas Okarma called the trial "a milestone for the field of human embryonic stem cell-based therapies," and noted that the trial was the culmination of work on hESCs that the company began in 1999.  Dr. David Apple, Shepherd Center's medical director emeritus and principal investigator of the Shepherd Center trial, said the trial represented another step forward "in an attempt to find a cure for paralysis in people with spinal cord injury."

Additional information regarding the trial and enrollment of the first patient can be found in reports by ABC News, Forbes, and Reuters.

"At-Home" Testing for BRCA Gene Mutations

By Kevin E. Noonan --

With great fanfare (if not braggadocio), researchers at the University of Maryland, College Park have published a paper in Genome Biology that purports to provide the means for individuals to assess their risk for breast or ovarian cancer despite patenting of isolated human BRCA1 and BRCA 2 genes by the University of Utah (licensed to Myriad Genetics).

As disclosed here, Professor Steven L. Salzberg and Mihaela Pertea from the Center for Bioinformatics and Computational Biology report "a computational screening method that test[s] an individual's genome for mutations in the BRCA genes, despite the fact that both are currently protected by patents."  The method utilizes "open source" software (found here) for "do-it-yourself home testing . . . for interrogating a genome for the presence of mutations in the BRCA genes."  The methods are set forth broadly as follows

We used the Bowtie short-read alignment program (Langmead et al., 2009, Genome Biol. 10: R25) to screen all sequence reads against the BRCA1 and BRCA2 regions (located on chromosomes 17 and 13, respectively) and against a set of 68 known mutations from the Online Mendelian Inheritance in Man (OMIM) database (see Methods).  The size of the datasets ranged from 2.8 to 4.1 billion reads for each genome, with most reads being 35-36 bp.  The BRCA genomic regions are each about 80-90 kb; with these small target sequences Bowtie is extremely fast.  Using only a single 2.4 GHz processor, Bowtie aligned reads at 127 million reads per hour, and alignment of the largest of our datasets took about 8 hours.  Thus despite the enormous number of reads for each genome, screening was relatively fast.

Using these methods, the researchers interrogated publically available whole genome sequence information from Asian and African males and a Caucasian female.  A single mutation was found at one site in the genomic BRCA2 gene in the female, known to be associated with a 30-40% increased risk of breast cancer, according to the paper.

The researchers tout the benefits of their method:

If free software can be used to diagnose human genetic mutations, then individuals will be able to run their own tests in the privacy of their own homes.  Fundamentally, this seems no different from measuring one's temperature or blood pressure, but because of gene patents, the act of reading one's own genome may require the permission of a private company.  It is hard to envision how the patent holders can enforce their claims in this scenario.  Our contention is that these patents never should have been awarded, and that no private entity should have rights to the naturally occurring gene sequences in every human individual.

While consistent with the uninformed lay opinion that "private companies . . . own" human genes, the adage that "the name of the game is the claim" has not been abrogated for gene patents, and the limits of a patentee's right to exclude conduct by others is limited by the terms of their claims.  For the BRCA patents, it is informative to review the fifteen claims of the seven patents involved in (and invalidated by) the ACLU's lawsuit (AMP v. U.S. PTO).  Specifically, the following U.S. patents were set forth in the complaint:  U.S. Patent Nos. 5,747,282; 5,837,492; 5,693,473; 5,709,999; 5,710,001; 5,753,441; and 6,033,857.  Not all claims of these patents were challenged (see Patent Docs post).  Of these claims, none of the claims challenged by AMP and its co-plaintiffs for the '282, '492, or '473 patents would be infringed by Dr. Salzberg's disclosed method, because inter alia they require isolation of DNA encoding the BRCA1 or BRCA2 proteins that is not required for the practice of his method.

For the remaining patents, the following claims could be implicated:

For the '999 patent:

1.  A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1.

For the '441 patent:

1.  A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject.

(Infringement of these claims would require the sequence to be the germline sequence and that it be obtained from a tissue sample.)

For the '857 patent:

1.  A method for identifying a mutant BRCA2 nucleotide sequence in a suspected mutant BRCA2 allele which comprises comparing the nucleotide sequence of the suspected mutant BRCA2 allele with the wild-type BRCA2 nucleotide sequence, wherein a difference between the suspected mutant and the wild-type sequences identifies a mutant BRCA2 nucleotide sequence.

2.  A method for diagnosing a predisposition for breast cancer in a human subject which comprises comparing the germline sequence of the BRCA2 gene or the sequence of its mRNA in a tissue sample from said subject with the germline sequence of the wild-type BRCA2 gene or the sequence of its mRNA, wherein an alteration in the germline sequence of the BRCA2 gene or the sequence of its mRNA of the subject indicates a predisposition to said cancer.

The challenged method claims of the remaining patent, No. 5,720,001 would not be infringed using Dr. Salzberg's method, since it requires that a tumor sample is analyzed, something even the most ambitious at-home diagnostic test is unlikely to perform.

As described by Dr. Salzberg's paper, it is necessary to determine a human's genomic DNA sequence and then use the software to compare the sequence with known mutations in BRCA1 or BRCA2 associated with disease.  (The paper notes that the method could readily be adapted for other genes and other mutations for other diseases.)  This is something that is undoubtedly outside the scope of any at-home test, and presumably would require an outside vendor to make the genomic sequence determination and provide the individual's genomic sequence using conventional (and ever more rapidly-provided) methods.  The individual would then perform the method that the paper asserts would be infringing ("because even a noncommercial use -- such as examining one's own genome -- is considered to be patent infringement," ironically citing the ACLU's website about its "free speech" challenge to gene patents).  While technically correct, there is no movement or groundswell for patentees to sue individual users (in contrast to record companies suing copyright infringers, for example).  Rather, it is more likely that any commercial entity providing whole genome sequences for use with Dr. Salzberg's method might be liable for inducing infringement (although the evidentiary burden for establishing liability may be high).  It is also possible that Dr. Salzberg could be adjudged liable as well, depending on whether this paper is the extent of his involvement or if he is actively involved in promoting commercial exploitation of the method.

Acknowledged in Dr. Salzberg's paper is a consequence that is much more serious than whether his method could be used to circumvent Myriad's patent rights.  This is that "at-home" methods are devoid of the support systems (physicians and genetic counselors) that are provided by commercially available test providers (as well as with testing provided by clinical genetics labs).  The same emotional aspects of human genes that seemingly motivates much of the animus against human gene patents is attendant on any genetic diagnosis, and while the consequences of bearing certain BRCA mutations are a high likelihood of developing breast or ovarian cancer, other mutations are not as predictive.  It is difficult to envision how an at-home test could provide sufficient information for an individual to properly assess the difference.  As a consequence, in addition to providing "free" access to an individual's genetic complement, such at-home tests would provide unnecessary pain, suffering, and anxiety for an individual and her family.  These costs should not be ignored in the overall calculus of the value of thwarting private companies from providing (and profiting from) genetic testing.

Nobel Prize in Physiology and Medicine Awarded to Robert G. Edwards

By Kevin E. Noonan --

The Karolinska Institute announced today that the Nobel Prize in Physiology and Medicine was awarded to Robert G. Edwards for his work in developing in vitro fertilization (IVF) in humans.

The Institute's press release announcing the prize noted that this work began in the 1950's, finally reaching success on July 25, 1978 when the first human child was born as a result of his methods.  Since then, it is estimated that approximately four million "test tube babies" have been born worldwide as the result of IVF.  The method has helped the estimated 10% of couples who are infertile, and started a "new field of medicine," according to the Karoliniska.

Dr. Edwards's (at left) IVF work was not a simple application of principles that had worked with animal embryos, however.  As the explanation of his work explains, Dr. Edwards "made a number of fundamental discoveries" on human egg cell development and how it differs from animal (rabbit) eggs that had been previously fertilized in vitro, including hormonal influences and the conditions and timing for both sperm and egg to facilitate fertilization.  Significantly for the development of the method, Dr. Edwards found that eggs that had matured in vivo were required for the in vitro fertilized egg to develop past the zygote stage.

While not naming him as a co-recipient, the Institute recognized Dr. Patrick Steptoe, a gynecologist whose contributions helped Dr. Edwards to develop IVF "from experiment to practical medicine."  This involved application to Steptoe's skills in laparoscopy, which was a new technique at the time, to harvest eggs from ovaries in vivo that Edwards then used for IVF.  This was the work that led to the birth of Louise Brown (at right), the first test tube baby in 1978.

The references cited by the Nobel Committee for this work are:

• Edwards RG, "Maturation in vitro of human ovarian oocytes," Lancet 2: 926-29 (1965).
• Edwards RG, Bavister BD, Steptoe PC, "Early stages of fertilization in vitro of human oocytes matured in vitro," Nature 221: 632-35 (1969).
• Edwards RG, Steptoe PC, Purdy JM, "Fertilization and cleavage in vitro of human oocytes matured in vivo," Nature 227: 1307-09 (1970).
• Steptoe PC, Edwards RG, "Birth after the reimplantation of a human embryo," Lancet 2: 366 (1978).
• Edwards RG, "The bumpy road to human in vitro fertilization," Nature Med. 7: 1091-94 (2001).

This work was not patented, and in view of the times, the use of human embryos, and the uncertainties of the procedures this is perhaps not surprising.  This technology is one amenable to other means of intellectual property protection, and at least initially it was difficult if not impossible for others to practice this technology merely by reading research articles -- it required the expertise and experience Drs. Edwards and Steptoe had developed to reliably use a test tube to make a baby.  Their experience, even if exercised merely to ensure that the technology was properly used may be instructive for other areas (like genetic diagnostics) that may need alternatives to patent protection as the science and law evolve over the next several years.

Photos of Dr. Edwards and Louise Brown from "Robert G. Edwards - Photo Gallery," Nobelprize.org, 5 Oct. 2010 <http://nobelprize.org/nobel_prizes/medicine/laureates/2010/edwards-photo.html>.

Special Edition of Scientific American Offers Global Biotechnology Perspective

By Donald Zuhn --

Scientific American has released its second annual examination of the ways in which governments, scientists, industry players, and life science stakeholders are advancing biotechnology innovation around the globe.  The special edition of the consumer science magazine, entitled "Worldview: A Global Biotechnology Perspective," explores biotech's most compelling trends and developments worldwide.

The issue, which was prepared in collaboration with the Biotechnology Industry Organization (BIO), includes the Worldview Scorecard, a list of innovation-capacity scores for 39 countries.  Also included in the issue are a number of articles, such as "Back From The Brink," which looks at economic signs around the world that indicate an improving environment for biotechnology, and a series of articles examining biotechnology in China.

The Worldview Scorecard ranks countries according to their capacities to develop biotechnology, and presents data on a wide range of other topics, including the impact of public policies on biotechnology.  Overall innovation-capacity scores were computed by assessing each country's performance in several individual metrics (e.g., intellectual property protection) on a scale from 0 to 10, with the lowest-ranked country scored as 0 and the highest-ranked country scored as 10 (an explanation regarding the methodology employed by the editors can be found here).  The top dozen countries on this year's scorecard (with final scores) were:

1. United States - 37
2. Singapore - 31
3. Canada - 29
4. Sweden - 28
5. Denmark - 27
5. Finland - 27
5. Israel -27
8. France - 26
8. Iceland - 26
8. Japan - 26
8. Netherlands - 26
8. Switzerland - 26

With regard to IP scores, the United States received the top score (10.00) and Belgium, Canada, Denmark, Finland, France, Ireland, Italy, Japan, and the Netherlands all received scores of 9.05.  The lowest IP scores were given to Iceland (3.82), Brazil (4.18), Russia (4.59), India (4.95), and Mexico (5.49).  A full list of scores can be viewed here.

Rep. Kucinich Introduces Legislation Related to Genetically Engineered Organisms

    By Donald Zuhn --

Last week, Representative Dennis Kucinich (D-OH) (at right) introduced three bills in the House related to the labeling of food containing genetically engineered material, the cultivation and handling of genetically engineered crops, and the establishment of a set of farmer rights regarding genetically engineered animals, plants, and seeds:

• The "Genetically Engineered Food Right to Know Act" (H.R. 5577) would amend the Federal Food, Drug, and Cosmetic Act, the Federal Meat Inspection Act, and the Poultry Products Inspection Act to require that food that contains a genetically engineered material, or that is produced with a genetically engineered material, be labeled accordingly.  The bill states that "[t]he process of genetically engineering foods results in the material change of such foods," and asserts that "Federal agencies have failed to uphold Congressional intent by allowing genetically engineered foods to be marketed, sold and otherwise used without labeling that reveals material facts to the public."  The bill, which has been referred to the House Committees on Agriculture and Energy and Commerce, was co-sponsored by Rep. Peter DeFazio (D-OR), Barney Frank (D-MA), Raul Grijalva (D-AZ), Barbara Lee (D-CA), Jim McDermott (D-WA), Pete Stark (D-CA), and Lynn Woolsey (D-CA).

• The "Genetically Engineered Safety Act" (H.R. 5578) would "prohibit the open-air cultivation of genetically engineered pharmaceutical and industrial crops, . . . prohibit the use of common human food or animal feed as the host plant for a genetically engineered pharmaceutical or industrial chemical, . . . establish a tracking system to regulate the growing, handling, transportation, and disposal of pharmaceutical and industrial crops and their byproducts to prevent human, animal, and general environmental exposure to genetically engineered pharmaceutical and industrial crops and their byproducts, [and] amend the Federal Food, Drug, and Cosmetic Act with respect to the safety of genetically engineered foods."  Noting that "[m]any of the novel substances produced in pharmaceutical crops and industrial crops exhibit high levels of biological activity and are intended to be used for particular medical or industrial purposes, under very controlled circumstances," and that "[n]one of these substances is intended to be incorporated in food or to be spread into the environment," the bill declares that the risks of contamination "necessitate a zero tolerance standard for the presence of pharmaceutical crops and industrial crops and their byproducts in crops used to produce human food or animal feed."  The bill, which has been referred to the House Committees on Agriculture and Energy and Commerce, was co-sponsored by Rep. Peter DeFazio (D-OR), Barney Frank (D-MA), Raul Grijalva (D-AZ), Barbara Lee (D-CA), Pete Stark (D-CA), and Lynn Woolsey (D-CA).

• The "Genetically Engineered Technology Farmer Protection Act" (H.R. 5579) would "provide additional protections for farmers and ranchers that may be harmed economically by genetically engineered seeds, plants, or animals, . . . ensure fairness for farmers and ranchers in their dealings with biotech companies that sell genetically engineered seeds, plants, or animals, [and] assign liability for injury caused by genetically engineered organisms."  The bill states that "[p]olicies promoted by biotech corporations, such as patenting of seeds, depriving farmers the right to save seed, unreasonable seed contracts, and intrusion into everyday farm operations, have systematically acted to remove basic farmer rights enjoyed since the beginning of agriculture and essential for agricultural sustainability and the survival of family farms," and asserts that "[t]he introduction of genetically engineered crops has also created obstacles for farmers, including the loss of markets and increased liability concerns."  The purpose of H.R. 5579 is "[t]o mitigate the abuses upon farmers, a clear set of farmer rights must be established."  Among the rights that would be created by the bill are (1) a requirement for biotech companies to fully disclose the risks of using genetically engineered animals, plants, or seeds, and (2) the prohibition of certain terms and limitations in contracts for the sale of genetically engineered animals, plants, or seeds, including a provision that would "prohibit[] the purchaser from retaining a portion of the harvested crop for future crop planting by the purchaser or that charge[] a fee to retain a portion of the harvested crop for future crop planting."  H.R. 5579 would allow for a maximum $100,000 penalty to be assessed for violations of the Act.  The bill, which has been referred to the House Agriculture, Energy and Commerce, and Judiciary Committees, was co-sponsored by Rep. Peter DeFazio (D-OR), Barney Frank (D-MA), Raul Grijalva (D-AZ), Barbara Lee (D-CA), Pete Stark (D-CA), and Lynn Woolsey (D-CA).

In a press release posted on Rep. Kucinich's website, the Congressman stated that:

To ensure we can maximize benefits and minimize hazards, Congress must provide a comprehensive regulatory framework for all Genetically Engineered products.  Structured as a common-sense precaution to ensure [Genetically Engineered] foods do no harm, these bills will ensure that consumers are protected, food safety measures are strengthened, farmers’ rights are better protected and biotech companies are responsible for their products.

The release noted that Rep. Kucinich had introduced similar bills in previous sessions of Congress.

Not Quite Artificial Life, But We're Getting Closer: Reactions to Venter's Synthetic Cell

    By James DeGiulio --

Recently, we reported that a research team led by Dr. Craig Venter had developed a "synthetic cell" controlled by purely synthetic DNA (see "Dr. Craig Venter Creates First Cell Controlled Entirely by Synthetic DNA").  To evaluate the significance of the discovery, the journal Nature asked eight synthetic-biology experts about the implications for science and society of the "synthetic cell" made by the Dr. Venter's research team ("Life after the synthetic cell").  Generally, most commentators downplayed the gravity of Dr. Venter's discovery, most finding the synthetic cell as falling short of "artificial life."  The following is a summary of each expert's commentary, to illustrate the variety of reactions to Dr. Venter's synthetic cell:

• Dr. Mark Bedau, professor of philosophy and humanities at Reed College in Oregon, noted four issues to keep in mind when forming opinions on Venter's discovery.  First, we now have an unprecedented opportunity to learn about life.  Second, even the simplest forms of life have unpredictable, emergent properties.  Third, these new powers create new responsibilities, since we cannot be sure about the consequences of making new forms of life, and we must "expect the unexpected and the unintended."  Finally, Dr. Bedau notes that we are moving ever-closer to creating life.  Dr. Bedau also notes "a prosthetic genome hastens the day when life forms can be made entirely from nonliving materials."

• Dr. George Church, a geneticist at Harvard Medical School, is of the view that no artificial life was created.  Dr. Church notes that the new bacterium is not changed from the wild-type state in any fundamental sense.  Dr. Church relies on the metaphor that "[p]rinting out a copy of an ancient text isn't the same as understanding the language."  He notes that geneticists already had the ability to make synthetic DNA and get it to function in cells, and that Venter's discovery was exercising that ability on a grander scale.  Dr. Church was interested, however, in the research potential of trimming down genomes, as Dr. Venter did, in order to understand what elements of the genome are essential for speed, efficiency, and robustness.

• Dr. Steen Rasmussen, a professor of physics at the University of Southern Denmark, disputes even calling the discovery a "synthetic cell" because Dr. Venter has only rewritten the genetics "program" running on the "hardware" of the modern cell.  Dr. Rasmussen contrasts the "top-down" approach, which Dr. Venter's discovery represents, and "bottom-up" approaches, which Dr. Rasmussen practices.  According to Dr. Rasmussen, a true synthetic cell can only be created using the "bottom-up" approach, which aims to "assemble life -- including the hardware and the program -- as simply as possible, even if the result is different from what we think of as life."

• Dr. Arthur Caplan, a professor of bioethics at the University of Pennsylvania, stands out from the other commentators by ruling the magnitude of Dr. Venter's discovery as immense, declaring it as "one of the most important scientific achievements in the history of mankind."  Dr. Caplan's commentary is more philosophical than scientific, describing the achievement as undermining a fundamental belief about the nature of life -- that no manipulations of the inorganic would permit the creation of any living thing.  Dr. Caplan fears Dr. Venter's achievement would seem to "extinguish the argument that life requires a special force or power to exist."

• Dr. Steven Benner, of the Foundation for Applied Molecular Evolution, viewed the magnitude of the discovery as mere "synthesis" -- a research strategy that can be applied to any field in which technology allows scientists to design new subject matter.  Dr. Benner finds the discovery analogous to chemical synthesis.  Nonetheless, Dr. Benner was impressed with the discovery, rejecting it as a trivial enhancement of previous gene synthesis.  Dr. Benner also noted the potential to resurrect species of ancient bacteria, so that evolutionary sciences, among others, may benefit from the work.

• Dr. Martin Fussenegger, a professor of biotechnology and bioengineering at ETH Zurich, finds that Dr. Venter's discovery is a "technical tour-de-force," but not much of a conceptual advance.  Indeed, chimera organisms have long been created through breeding and through the transfer of native genomes into denucleated target cells.  Dr. Fussenegger does note, however, that this latest technology will increase the speed with which new organisms can be generated, a thought that he acknowledges as "discomforting."

• Dr. Jim Collins, professor of biomedical engineering at Boston University, echoes the commentary downplaying the advancement as revolutionary.  His view is that Dr. Venter has made an important advance in our ability to re-engineer organisms, yet it does not represent the making of new life from scratch.  Dr. Collins finds Dr. Venter's microorganism to be analogous to a patient who has received an artificial, synthetic heart.  Dr. Collins admits that scientists simply do not know enough about biology to create life.  He states:  "It is like trying to assemble an operational jumbo jet from its parts list -- impossible."

• Dr. David Deamer, professor of biomolecular engineering at University of California, Santa Cruz, also states that Dr. Venter has not created artificial life, noting that the cytoplasm of the recipient cell, among other things, is not synthetic.  However, Dr. Deamer is encouraged that the discovery has the potential for understanding the "origin of life" as we know it.  Dr. Deamer notes that currently "all life arises from existing life.  But perhaps not for much longer."

As can be seen, it appears generally that Dr. Venter's discovery is not going to incite the bioethical pushback it potentially could have, for most scientists surveyed in the Nature article have recognized that DR. Venter has not actually "created" life.  Fortunately, the popular media has also noted this distinction.  In a May 30th New York Times editorial entitled "One Cell Forward," Dr. Venter's discovery of a "synthetic cell" was lauded as "overstated," because it "makes it sound as though [Dr.] Venter had constructed the entire cell, molecule by molecule.  What he has done is create a synthetic genome -- the longest string of DNA to be assembled in a laboratory -- and place it in a bacterium."  Nonetheless, the editorial recognizes that Dr. Venter's discovery is another step closer to artificial life, albeit not as large of a step as claimed, and recognizes that "[t]his newest step in [D]r. Venter's research brings a fresh urgency to the debate -- and the need for some profound decisions."

Patent Docs will continue to update our readers on the debate and decisions regarding Dr. Venter's "synthetic cell" technology.

For additional information regarding this and other related topics, please see:

• "Venter Denies Synthetic Cell Discovery Is Artificial Life, Vatican Agrees," June 6, 2010
• "Dr. Craig Venter Creates First Cell Controlled Entirely by Synthetic DNA," June 1, 2010
• "Playing the Bioterror Card in the Synthetic Biology Debate," December 19, 2007
• "The Synthetic Biology Sky Is Not Falling," December 16, 2007
• "Patenting Life (Really)," June 11, 2007

James DeGiulio has a doctorate in molecular biology and genetics from Northwestern University and is a third-year law student at the Northwestern University School of Law.  Dr. DeGiulio was a member of MBHB's 2009 class of summer associates, and he can be contacted at degiulio@mbhb.com.