I will be at the Cleveland Clinic Medical Innovation Summit next week. Cleveland Clinic, ranked America’s Top Heart Hospital, will host the 2007 Medical Innovation Summit, October 1-3 2007.

Cleveland Clinic’s Medical Innovation Summit is an international gathering of health care, business and media leaders, all offering insight into what drives medical innovation. The 2007 Medical Innovation Summit will highlight new techniques, economics and trends in cardiovascular technologies.

Also featured will be the Cleveland Clinic’s annual selection of the “Top 10″ health care innovations, live, interactive surgeries, and in-depth debates on industry challenges and opportunities.

The featured moderator is CNN’s Larry King but other speakers include Ted Strickland, Governor of Ohio, Bill Hawkins, CEO, Medtronic, Steve Hemsley, CEO, UnitedHealth Group, Kerry Clark, CEO, Cardinal Health, Sidney Taurel, CEO, Eli Lilly and George Buckley, CEO & President, 3M, among many others.

If you are planning to attend this year’s Summit, drop me a line and we can meet up for coffee (just not over live surgery).

Posted September 29th, 2007 by Stephen Albainy-Jenei in Conferences
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Ironically, within hours of President Bush signing the FDA Amendments Act of 2007 into law, a report is released finding the U.S. Food and Drug Administration doesn’t do enough to ensure the safety of patients who help test drugs in clinical trials

The New York Times quotes Daniel Levinson, the inspector general of the Department of Health and Human Services, as saying FDA officials do not know how many clinical trials are being conducted and have audited fewer than 1 percent of the testing sites.

While FDA inspectors often show up long after the tests have been completed, the agency said it lacks the resources to do the job properly — it has 200 inspectors responsible for 350,000 testing sites.

Being Washington, the report also blames the regulators noting that FDA officials downgraded negative findings from inspectors 68 percent of the time. Among the remaining cases, the agency almost never followed up with inspections to determine whether the corrective actions that the agency demanded had occurred, the report found.

The FDA disqualified researchers from conducting further clinical trials 26 times from 2000 to 2005 and disqualified their data twice, although it found serious problems at trial sites 348 times.

An inspector general’s report in 2000 criticized the oversight of clinical trials and noted that the inspections mostly focused on whether study information was accurate and not on whether human subjects were protected.

See the NY Times article here.

Posted September 28th, 2007 by Stephen Albainy-Jenei in FDA
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The FDA’s Office of Generic Drugs posted a letter requesting comment on certain 180-day exclusivity forfeiture and Orange Book patent “delisting” issues.  This concerns an ANDA submitted to the FDA containing a paragraph IV patent certification requesting FDA approval for a generic version of Bayer Pharmaceuticals’ PRECOSE (acarbose) Tablets.

Before marketing a new branded drug, the manufacturer must file with the FDA a New Drug Application (NDA), including evidence the drug is safe and effective, and the identifying number and expiration date of any patent or patents covering the drug. When it approves the NDA, the FDA must publish the patent information, which it does in Approved Drug Products with Therapeutic Equivalence Evaluations (a/k/a the Orange Book).

Before marketing a generic drug, the manufacturer may submit an Abbreviated New Drug Application (ANDA). The ANDA must contain “a certification … with respect to each patent which claims [a drug or a method of using a drug listed in the Orange Book] for which the applicant is seeking approval under this subsection and for which information is required to be filed under subsection (b) or (c) of this section - (I) that such patent information has not been filed, (II) that such patent has expired, (III) [that] such patent will expire [on a specified date], or (IV) that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted[.]”

The Act rewards the first manufacturer to file an approved ANDA containing the certification in paragraph IV by giving it a 180-day period of marketing exclusivity, which begins with the earlier of the applicant’s first commercial marketing of the generic drug or when the applicant prevails in a suit over infringement or the validity of the patents covering the branded drug.

Under changes made to the FDC Act by the 2003 Medicare Modernization Act (“MMA”), generic applicants that are “first applicants” are eligible for 180-day exclusivity, unless such eligibility is forfeited. 180-day exclusivity eligibility may be forfeited if, among other reasons, a “first applicant” “fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed” (FDC Act § 505(j)(5)(D)(i)(IV)), or if such applicant fails to market the drug “30 months after the date of submission of the application” (FDC Act § 505(j)(5)(D)(i)(I)(aa)(BB)).

The U.S. Court of Appeals for the District of Columbia Circuit already took on the question as to whether the FDA may delist a patent upon the request of the NDA holder after a generic manufaturer has filed an ANDA containing a paragraph IV certification so that the effect of delisting is to deprive the applicant of a period of marketing exclusivity.

The D.C. Circuit held that the FDA’s requirement that a generic manufacturer’s patent challenge give rise to litigation as a condition of retaining exclusivity when a patent is delisted is inconsistent with the Hatch-Waxman Act, which provides that the first generic manufacturer to file an approved application is entitled to exclusivity when it either begins commercially to market its generic drug or is successful in patent litigation.

The reference listed drug (RLD) for Acarbose Tablets is Precose Tablets, the new drug application (NDA) held by Bayer Pharmaceuticals (Bayer). There is one patent listed for Acarbose Tablets, U.S. Patent No. 4,904,769, which expires on September 6, 2009. As you probably are aware, for it appears on the Paragraph IV list on FDA’s website, at least one ANDA for Acarbose Tablets containing a paragraph IV certification was received by the agency on March 22, 2005. By virtue of this filing, at least one applicant became eligible for 180-day generic drug exclusivity.

As you know, the FDA makes determinations regarding 180-day exclusivity only when it is in the position to either approve an application that may be eligible for 180-day exclusivity, or to act on a subsequent applicant’s ANDA as to which final approval may be delayed by another application’s eligibility for exclusivity.

As of the date of this letter, which is more than 30 months from March 22, 2005, no first applicant’s ANDA has been approved. Also, on April 16, 2007, Bayer requested that the ‘769 patent be “delisted” as to Precose, i.e., they withdrew the patent information. On September 26, 2007, FDA indicated in the Orange Book that the request to delist this patent had been submitted on April 16, 2007.

To determine whether any ANDA referencing Precose is eligible for final approval, the agency must consider how the 180-day generic drug exclusivity forfeiture provisions at section 505(j)(5)(D) of the Federal Food, Drug, and Cosmetic Act (the Act) apply to this set of facts. As part of the process for making such a determination, we are seeking your views regarding the applicability of sections 505(j)(5)(D)(i)(IV) — failure to obtain tentative approval within 30 months — and 505(j)(5)(D)(i)(I)(aa)(BB) — failure to market by 30 months. We also are interested in your views regarding the applicability of section 505(j)(5)(D)(i)(I)(bb)(CC) — relating to the delisting of a patent.

The FDA asks that you submit your comments by close of business on Wednesday, October 10, 2007. Please include the Reference Number OGD #07-1254. If you have any questions, please contact Cecelia M. Parise, Regulatory Policy Advisor to the Director, Office of Generic Drugs, at 240-276-9310.

More at the FDA Law Blog.

Posted September 28th, 2007 by Stephen Albainy-Jenei in FDA
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President Bush has signed the FDA Amendments Act of 2007 into law. The Senate passed the bill, H.R. 3580, by unanimous consent on Sept. 20, a day after the House approved it in a 409-17 vote.

The massive 422-page FDA bill, the biggest overhaul to the FDA in the last decade, renews device and drug user fees for five years and strengthens product safety programs.

The new legislation pays for new safety initiatives through hefty increases to the user fees negotiated by FDA and industry. The negotiated fees are $396 million per year, plus adjustments for inflation and other factors. The new safety fees total $225 million across all five years, phased in at a rate of $25 million in fiscal 2008 with increases of $10 million per year through FY ‘12.

If Congress increases appropriations for postmarket safety, the new safety user fees would be reduced, dollar for every dollar appropriated on top of inflation-adjusted current levels. FDA also is given authority to assess fees in FY ‘12 to create three months of operating reserves that can be used to pay for new drug reviews during the first three months of FY ‘13. This gives FDA a funding cushion should Congress once again delay reauthorizing the fees until close to their Sept. 30, 2012 expiration date.

The Act also adds transparency to FDA and industry discussions about user fee levels and agency performance goals, including a provision from the House bill that would place on the FDA Web site the minutes from all negotiations with representatives from industry and patient and consumer advocacy groups.

Safety Changes

The bill represents a change in standards for making sure that drug side effects are known and promptly dealt with since Merck’s withdrawal of the painkiller Vioxx three years ago. Now, the FDA will now be able to dictate what claims companies can make about their drugs.

In addition, the FDA will be able to force drug makers to do clinical trials even after a medicine is approved and fine them if they don’t follow through. Previously, many big clinical trials requested by tge FDA weren’t finished. Finally, there will be more money to study side effects of new medicines post-approval. Companies will pay more in fees when they submit drug applications, increasing the amount of money the FDA gets from industry by 25%.

The Act gives the FDA authority to require label changes and to set timelines for negotiations. If a company is informed that new safety information must be included in a drug’s labeling, the firm has 30 days in which to submit a change or contest the requirement. If FDA disagrees with the response, it shall begin discussions with the company. These may last for no more than 30 days.

Once the discussions have concluded, FDA can order a labeling change and the company has 15 days in which to submit a supplement containing the change, or five days in which to appeal, through a dispute resolution proceeding. The process may be accelerated if the labeling change is needed to protect public health.

Additional post-approval clinical studies and trials can be required to assess a known serious risk, signals of a serious risk or to identify an unexpected serious risk, on the basis of scientific data, including chemically-related or pharmacologically-related drugs. Post-approval studies may be required if other reports and active surveillance are insufficient to answer safety questions.

New Device Fees

The act makes important changes to device user fees, originally established five years ago under the Medical Device User Fee and Modernization Act.

Fees will still be tied to individual premarket submissions, including PMAs and 510(k)s, but in the new program these submission-specific fees will be reduced and supplemented by four new fee categories.

The act allows FDA to collect $287 million in fees from device manufacturers over fiscal years 2008 through 2012. The fees will be dedicated to increasing the speed of review of device applications and for assuring the safety and effectiveness of devices,” the legislation states.

In addition, the act authorizes congressional appropriations totaling $39 million over five years for FDA’s device center to collect and evaluate postmarket safety information - a new earmark responding to growing sentiment that FDA needs to do more to monitor the safety of marketed devices. The new act also sets annual user fee increases at 8.5%, lending predictability to the fee system.

Medical Device Review

In return for paying user fees, device manufacturers are given assurance that FDA will meet specified premarket review goals. The goals, enumerated in letters from HHS to congressional leaders, are documented in the Congressional Record and referenced in the legislation.

Slightly more rigorous than the current goals, the new set requires, for example, that FDA in 2008 make a decision on 60% of regular PMAs within 180 days - versus 50% under the current performance goals.

More significantly, the new scheme eliminates premarket review “cycle goals” pertaining to the number of days FDA has to take various interim actions, such as issuing a PMA “major deficiency letter” to a company.

In other provisions, the Act requires the agency to establish a system under which manufacturers will be required to label their devices with unique identifiers unless they receive a waiver. This is intended to facilitate recalls and other postmarket safety activities.

Title III of the act, dealing with pediatric medical devices, contains provisions relating to the development and safety of devices used in children. It authorizes $6 million a year for pediatric device development projects, and allows FDA to order companies to conduct postmarket surveillance on devices expected to be used in pediatric patients.

Penalties Capped

The $50 million cap on penalties for continuing violations adjudicated in a single proceeding has been changed to $10 million, and the provision allowing fines of as much as $1 million per day was dropped.

H.R. 3580 permits fines of no more than $250,000 per violation, not to exceed $1 million for all violations adjudicated in a single proceeding. If a violation continues after written notice to the responsible party, the same amounts can be charged for the first 30 days, doubling for every 30-day period thereafter, subject to the $10 million cap.

Clinical Trials Database

One of the biggest changes is a new requirement that drug companies list all of their clinical trials in a registry maintained by the National Institutes of Health accessible to anyone with an Internet browser. After the studies finish, the results will also have to be posted. Additionally, the legislation calls for studies on the 510(k) premarket notification process, the prevalence of device-related infections, and the safety and quality of genetic tests.

The Act expands the existing registry of clinical trials to cover more drugs. It also creates a new trial results database, as envisioned by H.R. 2900, but this would be done in a series of steps and with HHS given the regulatory authority to determine the details.

Within a year of enactment, the registry is to include the demographic and baseline characteristics of patient samples and primary and secondary outcomes for clinical trials for approved drugs. This deadline can be extended to 18 months at the discretion of HHS. Not later than three years after enactment, regulations are to be issued to further expand the database and determine whether trials for unapproved drugs should be included.

There remains the question of whether the new authorities for the FDA are self-implementing or whether they need clarification in the form of regulations or other guidance (FDA Legislative Watch).

Posted September 28th, 2007 by Stephen Albainy-Jenei in FDA
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A newly formed nonprofit corporation unites industry, academia and government in first large-scale study of genetics and drug safety. The Serious Adverse Event Consortium (SAEC) will work to identify genetic markers that may help predict which individuals are at risk for serious drug-related adverse events (SAEs).

Pharmacogenetics and pharmacogenomics deal with the genetic basis underlying variable drug response in individual patients. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. On the other hand, pharmacogenomic studies encompass the sum of all genes, i.e., the genome. Numerous genes may play a role in drug response and toxicity, introducing a daunting level of complexity into the search for candidate genes. Pharmacogenomic analysis can identify disease susceptibility genes representing potential new drug targets.

Current concepts in drug therapy often attempt treatment of large patient populations as groups, irrespective of the potential for individual, genetically-based differences in drug response. In contrast, pharmacogenomics may help focus effective therapy on smaller patient subpopulations which although demonstrating the same disease phenotype are characterized by distinct genetic profiles. Whether and to what extent this individual, genetics-based approach to medicine results in improved, economically feasible therapy remain to be seen.

The SAEC’s research studies will examine the impact genes can have on how individuals respond to medicines. In addition to supporting original research of drug-related SAEs, the SAEC will:

• Establish open-use research practices and standards
• Encourage greater efficiency by pooling talent and resources under a common leadership with public safety-driven goals
• Enhance the public’s understanding of how the industry, academia and government are partnering to address drug-related adverse events

The SAEC is also exploring partnerships with other private and government institutions to continue their research. If their initial studies are successful, the SAEC hopes to examine other major drug-related adverse events to determine their underlying genetic causes.

Posted September 27th, 2007 by Stephen Albainy-Jenei in Biotech News
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About Biotech talks about Biotech Business Models this week, such as the Platform, Product and Vertical models for early-stage biotech companies. In all cases, patents and IP rights are noted to be at the core of any venture. Noteably is that the Platform business model has persevered, combined with contract research and services for the generation of revenue.

However, the Fully Integrated Pharmaceutical Company (FIPCO) model is making a comeback. The Ernst & Young Beyond Borders: Global Biotechnology Report 2007 has been released and provides a good outlook of unprecedented financing totals and deal activity that indicates a continuation of the strong growth trend that appeared in the 2006 report.

According to a press release by E&Y, the global increase in capital raised was reported to be 42% and double-digit increases in revenues were reported in Canada, the USA and Europe. In addition, the outlook for the biotechnology industry in 2007 is exceptionally good saying that the biotechnology sector “is comfortably on track to become a $100 billion revenue industry before the end of the decade.”

The revenues of publicly traded U.S. bio-tech companies grew by over 14 percent in 2006. Public companies’ research and development (R&D) grew by 38 percent, and net loss increased by 151 percent, from $1.4 billion in 2005 to $3.5 billion in 2006. However, these swings resulted largely from some very significant acquired in-process R&D (IPR&D) charges related to large acquisitions. Factoring out the impact of these deal-related charges, which totaled in excess of $4 billion for the industry, R&D expense would have grown by about 14 percent, essentially keeping pace with top-line revenue growth. If the biotech industry had kept R&D flat during 2006, it would have made money.

The number of alliances more than doubled compared to 2005, and their total value reached an all-time high of $23 billion — a 69 percent increase. M&As also soared, reaching the second highest total recorded in the industry’s history.

This was also a banner year for biotech financing. U.S. biotech companies raised a total of $20.3 billion, making this the best year on record, excluding the bubble year of 2000. Venture capital financing set a record at $1.9 billion. Worldwide, venture capital reached $5.4 billion. The initial public offering (IPO) markets remained challenging for many companies. For the third year in a row, the vast majority of IPOs failed to go public within their desired price ranges.

The U.S. had another strong year for product approvals, with 36 product approvals, including 25 New drug applications (NDA) and biologic license application (BLA) approvals. This compares favorably with 2005, when the industry secured 33 approvals, including 21 NDAs and BLAs.

The biotech industry employs directly about 191,000 people (public companies only), 69% in the U.S., 21% in Europe, 4% in Canada and remaining 6% are in Asia-Pacific.

Posted September 26th, 2007 by Stephen Albainy-Jenei in Bioventures, Biotech News
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In an appeal from a summary judgment of noninfringement of U.S. Patent 6,054,482, the Fed Circuit concluded that the district court erred in determining that there were no genuine issues of material fact concerning whether Warner Lambert failed to meet its burden of proof that the accused products infringe the asserted claims of the ’482 patent.

See: In Re Gabapentin Patent Litigation (involving Warner-Lambert, Pfizer and Godecke Aktiengesellschaft v. Purepac Pharma, Faulding, Watson Pharma, Danbury Pharma, Teva, Zenith Labs, Ivax, Apotex, Torpharm and Eon Labs) United States Court of Appeals for the Federal Circuit (06-1572).

Warner Lambert sells Neurontin®, a drug used to treat certain cerebral disorders, including epilepsy. The active ingredient in Neurontin® is a compound called gabapentin, which is covered by Warner Lambert’s ’482 patent, directed towards a process for the preparation of, and compositions containing, gabapentin substantially free from a lactam contaminant.

Under certain conditions gabapentin has a tendency to form a lactam, which makes the drug unstable and unsafe. The lactam was shown to be twenty-five times more toxic than gabapentin, and is linked to causing seizures, rather than preventing them. In an effort to minimize the formation of lactam, Warner Lambert developed a process involving two limitations to achieve stable formations of gabapentin.

First, gabapentin must be highly purified before being formulated into the pharmaceutical preparation. The ’482 patent discloses that:

The active materials of formula (I) must be prepared as highly purified, nonderivatized free amino acids, for example, from the corresponding hydrochloride by ion exchange. The proportion of remaining hydrochloride admixtures should thereby not exceed 20 ppm. The same also applies to other mineral acids.

Second, certain adjuvants that reduce the stability of gabapentin must be avoided. The ’482 patent further discloses that:

The following adjuvant materials, for example, reduced the stability of the compounds (I) and should be avoided in the preparation of pharmaceutical compositions: modified maize starch, sodium croscarmelose, glycerol behenic acid ester, methacrylic acid co-polymers (types A and C), anion exchangers titanium dioxide, and silica gels such as Aerosil 200.

The district court granted summary judgment of noninfringement becuase Warner Lambert failed to adduce sufficient evidence to establish that the accused products meet the limitation that the anions of a mineral acid do not exceed 20 ppm (”the 20 ppm limitation”). Based on the undisputed fact that the test had a ± 5 ppm margin of error, the court determined that that evidence was insufficiently precise to prove infringement.

The parties gave conflicting expert opinions, based on different evidence and different methods of testing, regarding whether Teva’s samples infringed the ’482 patent. As such, Warner Lambert argues that genuine issues of material fact exist in the record, and thus summary judgment was not appropriate.

First, appellees challenged the accuracy and reliability of the pH testing method. Appellees assert that the pH testing method yielded inaccurate results because, inter alia, Warner Lambert’s expert failed to calibrate the standards used for the test. Second, appellees argued that pH testing is not competent proof of infringement in light of the test’s lack of precision.

The Federal Circuit agreed with Warner Lambert that genuine issues of material fact existed.

In moving for summary judgment of noninfringement based on Warner Lambert’s inability to meet its burden of proof, appellees informed the district court that:

It is important to note for the record that Defendants strongly dispute the capability of pH testing to make any scientifically meaningful distinctions between gabapentin samples at the trace levels of acidity relevant to the ’482 patent. However, for purposes of this motion, Defendants have placed that dispute to one side (as they must), and focused on the undisputed limitations on the precision of such comparative pH measurements.

At the summary judgment hearing, appellees expressly stated that:

Teva’s experts vehemently dispute the validity of the data [Dr. Bartlett] relied on, but I want to ignore that dispute. Those factual issues are in dispute, but should not be part of this motion, and we, you can ignore them.

Thus, appellees limited their summary judgment motion to the issue of the undisputed limits of the test’s precision, viz., the ± 5 ppm margin of error, which we have considered. As such, appellees waived any argument challenging the validity, including challenges to the accuracy or reliability, of the pH testing method for purposes of summary judgment.

Appellees also argued that the court erred in its construction of the “anion of a mineral acid” and adjuvant claim limitations, and that they should still be awarded judgment. They asserted that “anion of a mineral acid” refers to anions from any source capable of forming a mineral acid. That is, that the term refers to total chloride content and is not limited to acid-derived chloride ions.

The court stated:

We agree with the district court that the proper construction is “anion derived from a mineral acid.” “It is a ‘bedrock principle’ of patent law that ‘the claims of a patent define the invention to which the patentee is entitled the right to exclude.’” Phillips v. AWH Corp., 415 F.3d 1303, 1327 (Fed. Cir. 2005) (quoting Innova/Pure Water, Inc. v. Safari Water Filtration Sys., Inc., 381 F.3d 1111, 1115 (Fed. Cir. 2004)). Here, the plain language of the claim supports the construction that the anion specifically is derived from a mineral acid. Appellees’ assertion that the claimed anion refers to total chloride ions or anions from any source that is “capable of” forming a mineral acid is unsupported by the claim language. Had the patentees intended the anion to refer to any anion, regardless of its source, the patentees could have simply claimed “anions” and omitted the phrase “of a mineral acid.”

We have also held that claims “must be read in view of the specification, of which they are a part.” Phillips, 415 F.3d at 1315. While appellees argue that the specification provides no support for their construction, we find that the specification provides further support for the construction adopted by the district court. The specification teaches a multi-step process for making gabapentin that is substantially free from lactam.

Posted September 26th, 2007 by Stephen Albainy-Jenei in IP Litigation
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We currently have a client interested in making an acquisition in the U.S.  The criteria are listed below:

Location: Anywhere in the 48 Contiguous States, excluding California

Size in Sales: $5,000,000 to $15,000,000

Type of Business: Manufacturing, Non-Union, with a successful history

Type of Ownership: Privately Owned/Held or a Division/Subsidiary of Public Company

Type of Purchase: Asset Purchase

Type of Industry: Not “O.E.M.” Automotive, Not High Environmental Issues, Not High Labor Intensive

If you know of any companies that meet the above criteria and are looking to be acquired, please contact me.

Posted September 21st, 2007 by Stephen Albainy-Jenei in Ventures, Frost IP
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