supremecourt.pngOn June 17, the U.S. Supreme Court released its decision in the controversial case regarding Hatch-Waxman patent settlements, FTC v. Actavis . In a 5-3 decision the Court held that lower courts reviewing so-called reverse-payment settlement agreements should apply a “rule of reason” antitrust analysis instead of the scope-of-the-patent test or the “quick look” approach, which had been advocated by the Federal Trade Commission (“FTC”). This was the first time the Court weighed in on whether reverse-payment Hatch-Waxman patent settlements between brand and generic pharmaceutical companies were subject to antitrust scrutiny, and, if so, what that level of scrutiny should be. A previous blog on the oral arguments to this case may be found here.

The Court acknowledged the policy that settlement of complex patent litigation is generally preferred, yet then identified five reasons why it believes that the Eleventh Circuit was wrong when it held that the FTC should not have the opportunity to prove its antitrust claims. First, a large reverse payment may risk significant anticompetitive effects. Second, a large reverse payment may not be justified given its anticompetitive effects. Third, the patent holder paying a large or unjustified reverse payment may have market power that permits it to cause potential anticompetitive harm. Fourth, even without litigating the case, a court may be able to determine the likely anticompetitive effects or potential justifications caused by the payment by examining the size of the payment. And fifth, parties are able to settle their patent disputes in other ways without using reverse payments.

FTC brought the case challenging the reverse-payment settlements Solvay (now part of Abbot Laboratories) entered into with a number of generic drug companies that resolved their Hatch-Waxman patent disputes involving Solvay’s AndroGel®–a testosterone-replacement drug. The settlement agreements involved the generics’ agreement to abandon their patent challenges and thereby delay generic entry for nine years. In addition, Solvay made certain payments to the generic manufacturers in exchange for their manufacturing and marketing support.
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Boston Convention Center and Exposition Hall.pngDuring the week of June 24, FLH Partner Brian J. Malkin will be attending the Drug Information Association’s (“DIA’s”) Annual Meeting, which is being held on June 23-27, 2013 in Boston. As in previous years, DIA’s Annual Meeting is expected to host more than 7,000 life science professionals from various levels who cover all disciplines involved in the discovery, development, and life cycle of medical products. Mr. Malkin plans to collaborate and meet with other life science professionals during the Meeting to help facilitate the type of innovation that leads to the development of safe and effective medical products and therapies to patients. This year the Annual Meeting features over 250 educational programs in 22 tracks with over 800 speakers and over 450 exhibitors. The Opening Plenary Session features Daniel Kraft, M.D., Executive Director, FutureMed, a program that explores convergent, exponentially developing technologies and their potential in biomedicine and healthcare.

In addition, during DIA’s Annual Meeting, there will be numerous networking events and lunches to permit the attending life science professionals learn how to perform their roles more effectively and forge new, productive relationships. For example, Mr. Malkin plans to attend the first “Outside the Beltway” Cocktail Reception hosted by the FDA Alumni Association (“FDAAA”). FDAAA’s core mission is to help FDA alumni stay in touch with the issues facing FDA and support the agency’s public health mission through expertise- and experience-sharing, training and outreach opportunities. Membership is open to the thousands of FDA alumni and current employees nationwide. The Reception will be on Tuesday, June 25 from 6-8pm EST at Lucky’s Lounge, 355 Congress Street, Boston.

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Written by Brian J. Malkin

DNApurple.jpgYesterday, the U.S. Supreme Court held that “a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but that cDNA is patent eligible because it is not naturally occurring.” The Court’s ruling decided the question: “Are human genes patentable?” We have been blogging on this issue for some time now, see for example here, our blog on the oral arguments at the Supreme Court with links to some previous blogs.

Myriad concerns the “discover[y of] the precise location and sequence of what are known as the BRCA1 and BRCA2 genes.” Specifically, Myriad discovered that “[m]utations in these genes can dramatically increase an individual’s risk of developing breast and ovarian cancer.” Myriad subsequently obtained a patent including such claims as “[a]n isolated DNA coding for a BRCA1 polypeptide” that included a specific amino acid sequence. The isolated DNA existed in nature before Myriad found them, the Court noted, and Myriad’s principle contribution involved determining the precise location and genetic sequence of these polypeptides. The Court said that finding the location of the genes does not make the genes themselves patentable, nor does the extensive effort involved in discovering them. Additionally, the Court found that isolating certain DNA from the human genome by severing chemical bonds would be not enough to render the matter patent eligible, because the “claims are simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA.” As a result, the Court held the claims invalid since “genes and the information they encode are not patent eligible under [35 U.S.C.] § 101 simply because they have been isolated from the surrounding genetic material.”

Another issue was whether the cDNA sequence claimed in the patent (as opposed to the full DNA sequence) would be patent-eligible. Here, the Court said that “cDNA cannot be isolated from nature, but instead must be created in the laboratory.” The Court noted that “cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments.” So, even though “cDNA retains the naturally occurring exons of DNA, [] it is distinct from the DNA from which it was derived.” For this reason, the Court concluded, “cDNA is not a ‘product of nature’ and is patent eligible under § 101, except insofar as . . . a short strand of cDNA may be indistinguishable from natural DNA.”
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spongescrub.pngOn June 4, FDA announced in the Federal Register that they were considering release of de-identified data sets in an effort to provide greater access to clinical and preclinical study data for researchers. This collaboration with the National Institutes of Health (“NIH”) would presumably work like other public databases NIH has supported over the years to provide access to medical data for research purposes. As a researcher, I (Eric) used NIH databases like the Lung Image Database Consortium (“LIDC”) and Reference Image Database to Evaluate Response (“RIDER”) sets of Lung computer tomography (“CT”) scans to gather anatomic information about the potential patient population to make product design choices. FDA’s proposal offers both potential benefits and harms to consider.

FDA recognizes that clinical study data sets are underutilized for the scientific understanding that they can provide. As a rule, preclinical and clinical studies are very expensive propositions that produce high quality data but receive limited publication, granting few in the research community with access to the raw data. This is understandable, in part, because sponsors wish to both protect their clinical data from competitors who may copy or undermine it, as well for protection of their intellectual property. This limited access prevents that data from being included in certain meta analyses studies. Meta analysis provides the numbers needed to identify lower frequency events and weaker correlations in the data. If a correlation does not reach the widely recognized p-value of 0.05 or lower, the scientific community is hard pressed to consider it a proven hypothesis. Meta analysis combines several studies and can produce “significant” results based on the increased size of the dataset. FDA has access to the raw data from clinical studies submitted with new product applications as well as other databases, however, it does not have the resources or mandate to perform this type of research.

FDA notes that there are potential hazards to this disclosure. FDA’s call for comments states that FDA is not a covered entity for the purposes of the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”). However, patients who have signed up for clinical trials generally have agreed to have their information used for certain purposes, often including publication. For the most part, patients understand that such data may be reported in the aggregate.
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pharmacy.jpgCompounding pharmacies are petitioning against a recent bill that would give FDA greater control over compounding manufacturers of sterile products. S.959, The Pharmaceutical Compounding Quality and Accountability Act, was unanimously passed by the Senate Health, Education, Labor and Pension Committee on May 22, 2013, and places compounding manufacturers that sell sterile products over state lines under FDA control.

The Bill, authored by Senator Tom Harkin, was a response to a deadly meningitis outbreak reported by FDA in October of 2012. The U.S. Centers for Disease Control and Prevention (“CDC”) traced the outbreak to fungal contamination in three lots of methylprednisolone acetate used for epidural steroid injections made by the New England Compounding Center (“NECC”). The CDC reported that the NECC meningitis outbreak has made 745 people sick and has caused 58 deaths in the United States. On May 24, 2013, another meningitis outbreak was announced. This recent outbreak was reportedly caused by Tennessee-based Main Street Family Pharmacy’s methylprednisolone acetate injections. The recent outbreak has sickened 24 people in Illinois, North Carolina, Florida, and Arkansas. These meningitis outbreaks have spurred the legislation that is being petitioned against.

Currently, individual States oversee their own compounding pharmacy operations. The potential shift from State to FDA control is worrisome to many pharmacists, doctors, and their patients. Specifically, there is concern that the FDA may ban compounded bio-identical hormones used to treat chemical imbalances.
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GSK FDA.pngOn June 6, an FDA’s joint Endocrinologic and Metabolic Drugs Advisory Committee (“EMDAC”) and Drug Safety and Risk Management Advisory Committee (“DSaRM”) recommended that the FDA lift restrictions on controversial drug Avandia® (rosiglitazone).

Avandia®, first approved for commercial marketing in the United States on May 25, 1999, was once the world’s bestselling treatment for diabetes. Now, it is rarely sold or prescribed. Avandia® began to lose popularity in 2007, when a Cleveland Clinic cardiologist published an aggregate study suggesting the drug caused heart problems. In response, FDA issued a warning restricting its use. A flurry of controversy followed the drug, damaging the drug’s reputation with physicians and fueling allegations in the U.S. Senate that GlaxoSmithKline (“GSK”)–the manufacturer of the drug–failed to inform patients its effect on cardiovascular risk.

In an attempt to salvage the drug’s reputation, GSK sponsored a new study on Avandia®’s cardiovascular risk in 2009, called the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (“RECORD”). This clinical study seemed to suggest that Avandia® had no measureable effect on cardiovascular risks. But the damage had already been done to Avandia®’s reputation, and other researchers criticized the trial as flawed due to missing data and alleged trial design defects. GSK failed then to improve the drug’s reputation with the RECORD trial.
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safe harbor.jpgThe Supreme Court has heard additional briefing―in the form of Amphastar Pharmaceuticals, Inc.’s Brief in Opposition and Momenta Pharmaceuticals, Inc. and Sandoz Inc.’s Reply Brief―about whether to review Momenta Pharm., Inc. v. Amphastar Pharm., Inc. and further clarify the scope of the safe-harbor provisions of 35 U.S.C. § 271(e)(1). As previously blogged on here, Momenta Pharmaceuticals, Inc. (“Momenta”) and Sandoz Inc. (“Sandoz”) petitioned the Supreme Court to determine:

Whether the use of a patented invention in the course of post-approval manufacture of a drug for commercial sale, where the FDA requires that a record of that manufacturing activity be maintained, is exempt from liability for patent infringement under Section 271(e)(1) as “solely for uses reasonably related to the development and submission of information under a Federal law which regulations the manufacture, use, or sale of drugs.

In its Opposition, Amphastar framed the issue as:

Whether the Federal Circuit correctly vacated a preliminary injunction on the ground that petitioners had no likelihood of success on the question of whether a generic manufacturer’s compliance with FDA-mandated, pre-marketing safety testing falls within the Hatch-Waxman Act’s statutory safe harbor provision, 35 U.S.C. § 271(e)(1).

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shareball.jpgOn May 10, Prometheus Laboratories Inc. (“Prometheus”) filed a Citizen Petition (FDA Docket No. FDA-2013-P-0572) requesting “complete notice and comment rulemaking establishing the standards and processes for a single, shared REMS [Risk Evaluation and Mitigation Strategies]” and waivers for the requirement for a single, shared REMS. Prometheus also requested that it be given notice and the opportunity to engage in any process used by FDA to determine whether to grant a waiver from the requirement for a single, shared REMS for Lotronex® (alosetron hydrochloride).

REMS are a type of risk management plan structure established by the Food and Drug Administration Act of 2007 (“FDAAA”) in September 27, 2007. REMS are required for a drug to be approved or post approval based on new safety information if FDA determines “it is necessary to ensure that the benefits of the drug outweigh the risks of the drug.” FDA may require a REMS to include a medication guide, patient package insert, and a communication plan. Where REMS get more complicated are when they include elements to assure safe use (“ETASU”), which generally involve more restrictive REMS, such as controlled distribution, special training for the physicians who prescribe the drug, typically to manage a serious risk, such as a severe side effect that may occur without such controls. REMS also involve a timetable for assessment to ensure that the REMS is controlling the risk for administering the drug. If a drug has a REMS, then generic version must have the same general elements and either share the same REMS with ETASU with the innovator or have its own essentially equivalent REMS with ETASU.

Lotronex® was approved on February 9, 2000 to treat irritable bowel syndrome in women whose predominant bowel syndrome is diarrhea. Soon after Lotronex® was marketed, FDA received reports of obstructed or ruptured bowels as a complication of severe constipation and sudden swelling/inflammation of part of the colon that occurs when there is a temporary loss of, or reduction in, blood flow to the colon. On November 28, 2000, Lotronex® was voluntarily withdrawn by its then sponsor GlasxoSmithKline (“GDK”).
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Thumbnail image for mortar and pestle.jpgOn May 10, FDA denied a Citizen Petition submitted on behalf of Endo Pharmaceuticals Inc. (“Endo”). The Petition requested that FDA: (1) determine that Opana® ER (oxymorphone hydrochloride) Extended-Release Tablets (“OP”) were discontinued for safety reasons, (2) refuse to approve any pending abbreviated new drug application (“ANDA”) for a generic version of OP, and (3) suspend and withdraw the approval of any ANDA referencing OP as the reference listed drug. By statute, if a drug was withdrawn from sale for reasons of safety or effectiveness, FDA must refuse to approve any pending ANDA and suspend or withdraw any approved ANDA referencing the drug.

FDA initially approved the New Drug Application (“NDA”) for OP held by Endo on June 22, 2006. The approved label advised that the product should be swallowed whole and warned against crushing, chewing, snorting, or injecting the dissolved product to prevent uncontrolled delivery, overdose, and death. FDA approved two ANDAs referencing OP in December 2010. Generic versions of the product entered the market in July 2011 and January 2013, respectively.

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Written by Shelly Fujikawa. Ph.D

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FDA approved an NDA for a reformulated version of OP, also called Opana® ER (oxymorphone hydrochloride) Extended-Release Tablets (“OPR”), held by Endo on December 9, 2011. FDA found that OPR could still “dose dump” and approved a label for ORP that was virtually identical to the approved label for OP. Endo ceased shipping OP on May 31, 2012 and submitted the present petition in August 2012 which was subsequently supplemented with preliminary postmarketing data and analysis concerning the abuse of OP, generic versions of OP, and OPR.
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plan b.pngThe fight over whether versions of the emergency contraceptives Plan B and Plan B One-Step (collectively “Plan B”) should be available without a prescription to all women continued yesterday. Lawyers for FDA appeared before Judge Edward Korman of the Eastern District of New York urging him to stay his April 4 Order requiring the Agency to lift age restrictions on access to emergency contraceptives by May 10. FDA has appealed that ruling to the Second Circuit. The Agency has yet to implement the court’s directive, but in late April it approved a supplemental new drug application (“sNDA”) that lowers the age at which women can obtain these drugs without a prescription from 17 to 15. Judge Korman expressed skepticism as to the timing of the approval and criticized the Agency for not following his order. A ruling on the stay is expected by the end of this week.

FDA’s actions have received mixed reviews. Last week, President Barack Obama reiterated his support of FDA’s and the Department of Health and Human Services’ (“DHHS’s”) determination that the age-restriction should be fifteen. He said that he was “very comfortable with the decisions they’ve made.” Others have been more critical. Nancy Northup, President and CEO of the Center for Reproductive Rights, speaking after the Department of Justice’s appeal to the Second Circuit said, “We are deeply disappointed that just days after President Obama proclaimed his commitment to women’s reproductive rights, his administration has decided once again to deprive women of their right to obtain emergency contraception without unjustified and burdensome restrictions.”

The approval of Plan B has a long history. Originally approved in 1999 for prescription-only use, Plan B became the United States’ first emergency contraceptive. In February 2001, sixty-six organizations filed a Citizen Petition with FDA urging the Agency to switch Plan B, as well as any other emergency contraceptives, from a prescription-only drug to an over-the-counter (“OTC”) drug and remove all age and point-of-sale restrictions. Despite repeated claims that it would address the outstanding petition, the Agency waited over five years to rule–denying the Petition in June 2006. FDA claimed that the petitioners had failed to provide sufficient data or information to meet the statutory and regulatory requirements of an OTC switch to any age group.
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