Your patent counsel comes to you and tells you that the best way to fight off a patent infringement claim is to argue that your product offers a larger risk of adverse events than the other company's product, so it couldn't be infringing.

Say what?

That, however, was the strange argument developed by the legal minds at Johnson & Johnson (New Brunswick, New Jersey) in one of the company's patent disputes with Boston Scientific (Natick, Massachusetts). But that tactic was spurned by a judge last month — fortunately, since seeming to offer a rather large wedge into a precedent that would have companies telling customers one thing (it's safe) and the courts another (it's not so safe).

Judge Sue Robinson wasn't buying it, saying that the argument was "too speculative" for her to dismiss Boston Scientific's patent claim or to order a new trial on the case.

J&J/Cordis lawyers argued that the Boston Scientific patent covers stents with a "non-thrombogenic" coating, that is, a coating that does not cause clots. Thus, evidence that Cypher has a significant clotting problem might suggest it does not infringe on the patent and fell outside the safety profile of Boston Scientific's patent for its Taxus paclitaxel-eluting stent.

Such an argument of course undercuts the J&J/Cordis assertions to physicians, patients and the press that the Cypher is no more likely to induce clots than bare-metal stents (BMS).

Judge Robinson's ruling noted that while federal regulators had been concerned about studies showing potential medical risks in using Cypher and the Taxus stent, the only DES devices on the American market, they also had concluded that it was not clear what was causing the clotting problem, the stent, the drug, the drug-binding polymer or some other aspect of the devices.

Judge Robinson refused to throw out a jury verdict that the Cypher infringed on a Boston Sci patent covering drug coatings. And she upheld a jury verdict against J&J in a separate patent case involving the design of the underlying metal stent.

The J&J motion reflected the complexity of the legal maneuvering the companies have tried after back-to-back jury trials two years ago left them in a legal standoff. The juries decided that the companies had infringed each others patents.

Follow-up trials in which potential damages were to be weighed have been postponed while the two companies seek to overturn the infringement verdicts. The judge made all the verdicts final in her September rulings, but the companies said that they will now seek to overturn them by going to the Court of Appeals for the Federal Circuit in Washington.

Judge Robinson's ruling noted that while federal regulators had been concerned about studies showing potential medical risks in using Cypher and the Taxus stent, the only drug-coated stents on the American market, they had also concluded that it was not clear whether the drug-coating or some other aspect of the devices was at fault.


Angiotech in settlement with Conor related to paclitaxel stent

In other court-related action involving J&J, Angiotech Pharmaceuticals (Vancouver) reported in mid-September that it had reached an agreement with J&J subsidiary Conor Medsystems (Menlo Park, California) to settle all outstanding patent litigation with respect to Conor's CoStar paclitaxel stent. "With this agreement now in place, Angiotech expects that the resources required to defend and enforce our intellectual property should decrease," said William Hunter, MD, president/CEO of Angiotech.

The dispute centered on Angiotech's patents for the cancer drug paclitaxel to coat stents.

Earlier in the month, the company reported receiving a favorable decision from the Intellectual Property Office of New Zealand regarding the patent litigation. In mid-March, the company reported a favorable decision regarding its Hunter patent from the European Patent Office (EPO) in Munich, Germany.

Angiotech said that the EPO's Technical Board of Appeal rejected the attempt by Conor and Sahajanand Medical Technologies (Surat, India) to intervene and appeal an earlier decision by the Opposition Division of the EPO, which upheld the Hunter patent. Angiotech said that the decision found that these appeals were "inadmissible."

The Hunter patent also covers claims to stents coated with a composition of paclitaxel and a polymeric carrier.

But not all international rulings regarding Angiotech's patent have been favorable to the company.

In January, a UK appeals court upheld an earlier decision by the UK High Court of Justice to revoke the UK portion of European Patent (EP) 0 706 376 B1 to Angiotech. The patent is exclusively licensed to Boston Scientific.

In February 2005, Conor initiated proceedings against Angiotech and the University of British Columbia (Vancouver) in the High Court of Justice in the UK, requesting that the court invalidate the patent on the grounds that all claims of the patent either lack novelty or are obvious in light of the state of scientific knowledge at the priority date of the patent.

A year later the High Court of Justice rendered its decision, agreeing with those arguments, and Angiotech appealed the decision on May 31, 2006.


Despite questions, panel backs anti-adhesive Repel CV PMA

Repel CV, an anti-adhesion barrier for neonatal cardiac surgery, made by SyntheMed (Iselin, New Jersey) received a recommendation for PMA approval from the FDA's circulatory systems advisory panel last month, despite panelists voicing a variety of questions and concerns. Key to the positive recommendation and an 8-3 vote backing PMA approval appeared to be the opinions of practicing physicians. The surgeons on the panel asserted that reducing adhesions is a benefit they said is clinically meaningful.

Repel is a bioresorbable anti-adhesive film for use in patients undergoing cardiac surgery via sternotomy and likely to need a second procedure.

The patients in the pivotal trial, average age 12 days old, underwent staged restructuring of the heart, due to congenital defects, but the firm hopes to get an indication without age restrictions. At present, there is no FDA-approved anti-adhesive product for this use, though the company obtained a CE mark in June 2006.

The FDA summary acknowledged that "finding a feasible population for study of this device in a reasonable time span is a major challenge," in part because of the requirement for the patient needing a second surgery, but the primary driver behind the patient selection for the study.

Yunling Xu, an FDA statistical analyst, said that the pivotal study showed a 26% absolute reduction in adhesions, deemed statistically significant. But Xu said that because the device showed a large tendency toward allowing either many or very few adhesions, the validity of some of the statistical analyses was questionable. "Several potential issues included center effect," Xu said, a number of centers (of 13 total) demonstrating a 50% drop in adhesions, and two centers showing increases.

Wolf Sapirstein, MD, a medical officer at the FDA's Office of Device Evaluation, said the agency "acknowledges the reasons for enrollment of only pediatric patients," because, in part, an "assurance of re-operation within a defined timeframe." Going forward, the agency and SyntheMed assumed, he said, "that the study outcome could be extrapolated to other populations" because the "pathogenesis [of adhesions] is similar for all ages."

Sapirstein said that adverse event rates were similar, 69.9% for study patients vs. 71% of controls. Six of the study subjects' events were felt to be treatment-related, whereas only one event in the control group was felt to be treatment-related.

Synthemed made the case that the rate of adverse events was within parameters described in the literature. And Sapirstein agreed, saying that mortality rates "are consistent with the literature," and that adverse events and serious adverse events were similar between the two study arms.

Panelist Eugene Blackstone, MD, head of clinical research at the Cleveland Clinic, said, "There is clear incremental benefit in the product," although "the product does not perfectly protect."


Bioheart IPO seeks $46.9M to back stem cell heart therapy

Bioheart (Sunrise, Florida), a company hoping to commercialize cell therapy for regeneration of the heart — a sector that so far has produced successes only in only small numbers of patients and with no regulatory approvals to speak of — last month filed with the U.S. Securities and Exchange Commission to raise $46.9 million in an IP. Bioheart said it expects the offering, which totals 3.6 million shares, to price between $14 and $16 per share.

The company has given the underwriters an option to buy up to another 536,250 shares to cover over-allotments.

Bioheart is developing therapies that use autologous cells — meaning cells from the patient's own body — to treat heart damage. Bioheart said it plans to use the IPO proceeds to fund clinical trials, make payments related to its license agreements, further develop its intellectual property portfolio, build a sales and marketing force and repay accrued interest on certain debt obligations. Bioheart said it will proceed with a Phase II/III trial of its lead product candidate, MyoCell, in North America, Europe and Israel. It said it expects to have final data available for the trial by 3Q09.

For the six months ended June 30, Bioheart widened its losses to $5 million, from $3.9 million in the prior-year period. During the same period, the company increased its revenues to $208,000, from $75,000.

Among the risks listed in its SEC filing, the company notes that no company has won U.S. or European regulatory approval for a cell-based therapy product for the treatment of heart damage. "Cell-based therapy products, in general, may be susceptible to various risks, including undesirable and unintended side effects, unintended immune system responses, inadequate therapeutic efficacy or other characteristics that may prevent or limit their approval by regulators or commercial use."

The company also says that it does not hold patent rights to protect its technology outside the U.S.


Ischemic stroke trial closed, Penumbra awaits data collection

According to the American Stroke Association (ASA; Dallas), each year about 580,000 Americans suffer an ischemic stroke resulting from an obstruction within a blood vessel supplying blood to the brain. Generally, only 3% to 5% of these patients arrive at a hospital within the three-hour time window required to receive IV drug therapy.

One young neurovascular-focused company is working to extend the time window available to patients suffering from acute ischemic stroke using a non-drug-based platform.

Penumbra (San Leandro, California), a company focused on developing and manufacturing products to treat patients suffering from stroke and other neurovascular diseases, in mid-September reported the completion of a stroke trial evaluating the Penumbra system in the revascularization of more than 100 patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease.

Currently there is only one FDA-approved treatment for an acute ischemic stroke: intravenous (IV) delivery of tissue plasminogen activator (t-PA) (Activase), which is a thrombolytic agent. The agent is designed to dissolve the blood clot that is blocking blood flow to the brain. IV t-PA is currently limited in use since it must be used within a three-hour window from the onset of the stroke and it appears to carry an increased risk of bleeding.

Adam Elsesser, the CEO, director and founder of Penumbra, told Cardiovascular Device Update that "the primary endpoint of the study is the ability for our system to recanalize the occluded target vessels; and also to record the incidence of device-related and procedure-related serious events."

The Penumbra system works on the proximal surface of the occlusion, thereby eliminating the need for navigation through or beyond the occlusion. The first component of the system is a clot debulking and aspiration platform that allows soft clots to be gently aspirated out of the vessel. The second component includes a thrombus removal ring that allows hard or fibrous occlusions, such as from the heart, to be captured and extracted without the need to cross through the clot.

A total of 125 patients were enrolled in this single arm trial at 24 centers in the U.S. and Europe. Patient enrollment was completed on June 5, less than one year from the start of the trial, and the three-month follow-up period is now complete. Patients could be enrolled if they arrived at the hospital within eight hours of stroke symptom onset and were ineligible for or refractory to IV tPA therapy, among other criteria.


Florida Atlantic U. receives patent for cardiac cell differentiation

Florida Atlantic University (FAU; Boca Raton) received the patent "Promoting Cardiac Cell Differentiation," based on an invention which induces and restores cardiac muscle function.

The invention was discovered by FAU researcher and VP for research Larry Lemanski, PhD, and his postdoctoral fellow, Chi Zhang, PhD. Their research has focused on understanding the mechanisms that regulate myocardial (heart muscle mass) cell differentiation and myofibrillogenesis (the process by which proteins in the heart are changed into heart muscle cells) in the developing heart. From their findings, these researchers hope to repair myocardial deficiencies in the human heart which are caused by either congenital heart defects or heart attacks.

Lemanski, Zhang and colleagues at FAU have been looking at the cellular, molecular and genetic signals that affect heart cell differentiation and regulation of the synthesis of contractile proteins within cardiac muscle cells that allows cells to contract.

"When an individual has a heart attack with a significant region of the heart muscle damaged, recovery to pre-heart attack levels are rarely achieved," said Lemanski. "Strategies to regenerate damaged cardiac tissue could be significant in the treatment of cardiovascular disease."

Adult heart muscle cells lack the ability to regenerate following injury because of terminal differentiation. The number of heart cells is determined at birth and once damaged cannot repair themselves. Furthermore, many congenital abnormalities are thought to be caused by improper signaling between cells and tissues as a result of abnormal genes.

Observing cardiac mutant Mexican axolotls (salamanders), these researchers identified a major protein that was deficient in these axolotl hearts which prevented the organization of myofibrils (contractile machinery) and the ability to beat. Using these findings, Lemanski, Zhang and their colleagues were able to show that this mutant defect could be rescued by treatment with specific and unique RNA (ribonucleic acid) derived from the anterior endoderm (gut) of normal animal model embryos. Lemanski termed this discovery as "myofibrillogenesis-inducing RNA," or MIR.

Additional studies have shown that humans have a similar, most likely identical, mechanism as the axolotls, for the formation of functional contracting heart muscle cells. It may also be possible to produce new functional cardiac muscle tissue in areas of human hearts that require these cells and tissues for restoration of normal function.

Taken into the clinical setting, a human version of this MIR may allow patients who have suffered from heart attacks and have impaired physical activities due to scar tissue in their hearts to have those scarred areas replaced with new cardiac muscle.


Cytori wins $250,000 grant for stem cell therapy of vascular disease

Cytori Therapeutics (San Diego) has received a $250,000 grant from the National Institutes of Health to develop fat-derived regenerative cells as a treatment for vascular disease. Regenerative cells within fat tissue include adult stem cells and other cell types that have been shown to increase blood flow in and around damaged and oxygen-deprived tissues, according to Cytori.

Marc Hedrick, MD, president of Cytori, said, "Due to the shared mechanism of these cells in vascular and heart disease, this research will complement and provide valuable insight into our clinical-stage development of treatments for cardiovascular disease."

The grant work will study fat-derived regenerative cells in preclinical vascular disease models. This will involve looking into which cells within fat tissue are optimal for remodeling and promoting growth of both small and larger blood vessels. In addition, the research will explore the capacity of fat-derived regenerative cells in patients with a history of smoking, hypertension, and diabetes.