By Kurt R. Karst –   

The decades-long saga over the withdrawal of approval of certain uses of certain classes of antibiotics in food-producing animals is likely to continue for some time given an August 8, 2012 decision from the U.S. District Court for the Southern District of New York.  The decision stems from a 2011 lawsuit filed against FDA by the National Resources Defense Council (“NRDC”) and three other member groups of “Keep Antibiotics Working.” 

As we previously reported (here, here, and here) the NRDC et al. sued FDA and initially sought to compel the Agency, by a court-ordered deadline, to withdraw approval of all subtherapeutic uses of penicillin in animal feed and nearly all subtherapeutic uses of tetracyclines (oxytetracycline and chlortetracycline) in animal feed and to issue final responses to two Citizen Petitions relating to hearing notices FDA issued in 1977 on the Agency’s withdrawal proposals.  FDA subsequently denied the petitions and took other action, and the Plaintiffs supplemented their lawsuit.  In a March 22, 2012 decision, Magistrate Judge Theodore H. Katz granted Plaintiffs’ Motion for Summary Judgment on their first claim for relief – that FDA withheld agency action in violation of both the Administrative Procedure Act (“APA”) and the FDC Act (§ 512(e)) by failing to implement withdrawal proceedings – and requested additional briefing on a schedule under which FDA must act.  FDA has appealed that decision to U.S. Court of Appeals for the Second Circuit (Case No. 12-2106).  In a June 1, 2012 decision, Magistrate Judge Katz denied FDA’s Motion for Summary Judgment and granted Plaintiffs’ Motion for Summary Judgment on another claim concerning the denial of the aforementioned Citizen Petitions.  Magistrate Judge Katz found that FDA violated the APA and the FDC Act when the Agency denied the two petitions.  FDA has not appealed that decision.

The August 8th decision from Magistrate Judge James C. Francis IV (who was assigned the case upon the retirement of Magistrate Judge Katz) concerns FDA’s proposed schedule pursuant to the Court’s March 22nd Order, as well as the Agency’s Motion for Stay requesting that the court stay the March 22nd Order pending resolution of the appeal (or impose an interim stay), and Plaintiffs’ Motion to Strike certain documents FDA submitted to the record.  The meat of the decision deals with FDA’s proposal and motion, so that’s where we’ll focus as well.

FDA proposed a timeline that would require reissuance of the hearing notices within 11 to 17 months, and an additional period of 41 months to complete the withdrawal process, including administrative appeals, but nevertheless asked the court to refrain from imposing a deadline because doing so would impermissibly re-order the Agency’s priorities.  Plaintiffs contended that FDA’s proposed schedule should be given a buzz cut so that the Agency would be required to reissue hearing notices within 125 days of commencement of the process and complete withdrawal proceedings within an additional two years. 

In deciding whether there has been unreasonable delay meriting the court’s the imposition of a schedule, Magistrate Judge Francis looked to the six so-called “TRAC” factors from the U.S. Supreme Court’s decision in Telecommunications Research & Action Center v. FCC, 750 F.2d 70 (D.C. Cir. 1984), and that the U.S. Court of Appeals for the District of Columbia Circuit laid out in In re Barr Laboratories, Inc., 930 F.2d 72 (D.C. Cir. 1991).  In Barr Laboratories, the Court refused to issue a writ of mandamus compelling FDA to act on ANDAs within the statutory 180-day period because “a judicial order putting [one ANDA sponsor] at the head of the queue simply moves all others back one space and produces no net gain.”   In finding that “FDA’s unreasonable delay merits the imposition of a schedule for compliance with the March 22 Order,” Magistrate Judge Francis distinguished the case at hand from the D.C. Circuit’s decision in Barr Laboratories:

In Barr Laboratories, the writ of mandamus would have effectively controlled the agency’s generic drug approval process, benefitting one enterprise at the expense of others, failing to improve the efficiency of the process of approving (or disapproving) generic drugs, and having no effect on human health and welfare.  Here, the FDA has utterly failed in its duty to initiate congressionally-mandated withdrawal proceedings.  Requiring it to do so promptly is not reordering the FDA’s priorities; it is correcting the agency’s misprision of its duty.  In Barr Laboratories, the court found that the contemplated order would have no effect on human health and welfare.  Here, in contrast, compelling the FDA to timely fulfill its obligations will speed adjudication on the issue of whether the non-therapeutic use of certain antibiotics in animal feed threatens human health and, if the sponsors or other interested parties cannot demonstrate the drugs’ safety, accelerate their compulsory withdrawal.

Moving on to the schedule for compliance with the March 22nd Order, Magistrate Judge Francis ultimately adopted FDA’s proposed 17-month (hearing reissuance) and 41-month (hearing process) timetable, saying that FDA “is in the best position to analyze the issue and propose a realistic schedule that is not based on unsupported assumptions, but rather on its expertise, and it has done so.”

FDA was not so fortunate, however, with its Motion to Stay the district court’s March 22nd Order pending the Second Circuit’s decision on its appeal (or, in the alternative, a stay pending the Second Circuit’s resolution of FDA’s planned application for a stay in that Court).  In denying the motion (for both a stay and an interim stay), Magistrate Judge Francis found that FDA did not show that it will be irreparably harmed if a stay is not granted, and that “given the substantial harm that further delay of withdrawal proceedings could visit on the plaintiffs and the public, the balance of the equities would not ‘weigh heavily in favor’ of a stay even if the Government had shown irreparable harm.”

The NRDC touted the district court decision as good news and commented that “FDA needs to move forward as rapidly as possible with the regulatory proceedings to address this pressing health threat and to rectify its decades-long neglect of this issue.”  In other related news, a baker’s dozen of U.S. Senators sent a letter to FDA commending the Agency for releasing a guidance document proposing voluntary reductions in the use of antibiotics in food-producing animals, but urging FDA to further strengthen the guidance. 

By Kurt R. Karst –      

Just before Congress recessed for the month of August, and less than a month after the July 9th enactment of the FDA Safety and Innovation Act, several FDA-related bills were placed in the hoppers in the U.S. Senate and U.S. House of Representatives.  With an election on the horizon and several other non-FDA-related issues to handle, it seems highly unlikely that Congress will be poised to tackle the FDA bills this year; however, they may provide some insight into some of the issues that will be debated in the 113th Congress come 2013.

H.R. 6272 – The Trial and Experimental Studies Transparency (“TEST”) Act of 2012

According to a press release from the primary sponsor of the bill, Rep. Ed Markey (D-MA), the TEST Act would close certain “clinical trial loopholes and bring certainty and transparency to life-saving research studies.”  Among other things, the bill would amend the definitions of “applicable device clinical trial” and “applicable drug clinical trial” at PHS Act § 402(j)(1)(A) to require that “all interventional biomedical studies on humans” be registered at ClinicalTrials.gov “before the first participant is enrolled in the trial.”  Although current draft guidance on clinical study registration explains that certain studies conducted outside of the United States do not need to be reported on Clinicaltrials.gov, the TEST Act specifically applies to “any interventional study of a [drug or device] conducted outside of the United States the results of which are submitted to the Secretary in support of” a marketing application, including a PMA and 510(k) notification for devices, and an IND, NDA, BLA, or ANDA for drugs and biologics.  (Applications for biosimilars under PHS Act § 351(k) are not specifically mentioned in the bill, but the broad reference to PHS Act § 351 presumably includes them.)  An “interventional study” is defined in the bill to mean “a study in human beings in which individuals are assigned by an investigator, based on a protocol, to receive specific interventions to evaluate their effects on biomedical or health-related outcomes.”  Support for the TEST Act has already appeared in the pages of The New England Journal of Medicine (see here).

H.R. 6288 – The Patient Choice Act of 2012

According to Rep. Brian Bilbray (R-CA), who introduced H.R. 6288 (see here), the bill is intended to “speed up the approval process of drugs used in therapies and treatments of patients fighting life threatening diseases.”  It would do so by establishing a “provisional approval” system for a product designated by FDA as a “fast track” product under FDC Act § 506.  (FDASIA made several amendment to FDC Act § 506 – see here.) In order for FDA to grant a request for provisional approval, the Agency would have to determine that a product is “adequately safe.”  This term is defined in the bill to mean that “for at least one population, the risk of death or morbidity caused directly by an adverse effect of the drug, as determined in one or more safety studies or through other data that the Secretary determines are sufficient, is unlikely to be greater than the combined direct and secondary risks of death or morbidity, as established in the literature or historical data” of the target disease, among other things.  The bill also contains provisions on the requirements for products granted provisional approval, and on the timing of the start of marketing exclusivity.

H.R. 6342 – The Compassionate Freedom of Choice Act of 2012

The Compassionate Freedom of Choice Act of 2012 was introduced by Rep. Ron Paul (R-TX) (see here) and is intended to allow the importation, distribution, and sale of investigational drugs and devices by terminally ill patients if their physicians certify: “(i) such patients have no other treatment options; and (ii) the patient executes written, informed consent that they are aware of any potential risks from the drug, device, or treatment.”  According to one advocacy group, H.R. 6342 “would substantially limit FDA’s ability to second-guess treating physicians’ decisions concerning the standard and methods of care available to terminally ill patients.” 

S. 3506 – The Ethical Pathway Act of 2012

S. 3506 was introduced by Sen. Bernie Sanders (I-VT) and is intended to “eliminate requirements to undertake duplicative clinical testing of new pharmaceutical drugs, vaccines, biological products or medical devices, when such duplication is inconsistent with relevant ethical norms” (e.g., the Declaration of Helsinki).  To do this, the bill, if enacted, would require FDA to establish a mechanism by which an applicant may request a cost-sharing arrangement with the owner of existing regulatory test data.  The bill is in line with other legislation introduced by Sen. Sanders to create a prize-based system for new drugs, instead of one with patent and non-patent exclusivity incentives (see here and here). 

Hyman, Phelps & McNamara, P.C.’s Diane McColl will present at USP’s 2012 Science & Standards Symposium, which is dedicated to functional foods and dietary supplements.  The conference will address scientific and regulatory issues from an international perspective, and will feature speakers from USP and NIH’s Office of Dietary Supplements.  The conference is scheduled for September 18-20 in Boston, MA.  A copy of the conference brochure and registration information is available here.

Ricardo Carvajal will present the ASQ Food, Drug, and Cosmetic Division's 23rd West Coast Conference on Dietary Supplement Global Strategies.  The conference will address numerous issues of interest to dietary supplement manufacturers and distributors, including GMP’s, advertising claims, and new dietary ingredient notifications.  The conference will feature presentations by senior FDA and state officials. The conference is scheduled for September 14 in Anaheim, CA.  Conference registration information is available here.

Mr. Carvajal will also present at the European Food Law Association’s 19th International Congress, which will examine the evolution from agricultural to food law, with particular attention to regulation of food quality and safety.  The congress is scheduled for September 20-21 in Seville, Spain. A copy of the conference brochure and registration information is available here.

By Jennifer D. Newberger –

Perseverance can be an admirable quality, except when it is misguided.  So it seems to be with Representative Edward Markey and Senator Jeff Merkley, who seem intent on convincing the public that devices cleared through the 510(k) process pose great risks that must be remedied.

We previously posted on a bill introduced by Rep. Markey and Senator Merkley, the Safety of Untested and New Devices (“SOUND”) Act of 2012.   As we noted in that post, the bill seemed to be presenting a solution in search of a problem.  The latest efforts by Rep. Markey and Senator Merkley continue to search for a chimera: badly designed devices, cleared through the 510(k) process, regularly causing death and serious injury. 

On August 15, the congressmen sent a letter to Dr. Jeff Shuren, Director of the Center for Devices and Radiological Health (“CDRH”), expressing their concern “about weaknesses in the premarket review process used to evaluate most medical devices.”  To fix these “weaknesses,” the congressmen request CDRH “overhaul and streamline its Recalls and 510(k) Premarket Notification databases to provide publically available and easily searchable information regarding the safety of devices that rarely undergo clinical trials in humans prior to being sold on the market.”  Their premise is that the 510(k) process is substantially flawed.

Yet, when the Institute of Medicine released its report on the 510(k) process last summer (see here), one finding was very clear: there is not a “public-health crisis related to unsafe or ineffective medical devices.  Although the safety and effectiveness of preamendment Class II devices have not been systematically reviewed, their continued use in clinical practice provides at least a level of confidence in their safety and effectiveness.”  It would seem that this committee of experts—a committee notably lacking any industry representatives—is better qualified to assess the risks posed by 510(k)-cleared devices than the two congressmen.

Nevertheless, they will not let their cause go undeterred.  In the letter to Dr. Shuren, the congressmen assert that “thousands of patients have been harmed – in some cases grievously and irrevocably – by medical devices that were modeled after recalled devices.”  To remedy this purported “problem,” they believe FDA’s authority should be expanded “to enable it to reject clearance if a device repeats design flaws that have led to the voluntary recall of early products.”  Such expanded authority was proposed in the SOUND Act, which appears to be stalled in the House of Representatives.  Given the failure to move that bill forward, the congressmen sent the letter to Dr. Shuren, proposing ways to increase “transparency” about “devices recalled for serious design flaws.”

Specifically, the letter proposes the following measures:

• Update the 510(k) database to reflect if the device was the subject of a recall “because of a serious design flaw that negatively affected safety of [sic] effectiveness.”  It asks that FDA update the database within 30 days of learning that a “flaw triggering the recall was a serious one that could adversely affect safety or effectiveness.”

• Update the 510(k) database to reflect whether the device “was cleared on the basis of a predicate recalled for a serious design flaw that negatively affected safety or effectiveness.”

• The database should provide “a link to information about the predicate’s adverse event reports and recall, so that consumers and doctors can determine the nature of the earlier problem.”

• The database “should be updated retrospectively to reflect previous recalls due to serious design flaws, to the extent that reliable information about older recalls is available.”  It does not specify how many years back the database should be updated, but notes that if the database “does not include serious recalls going back at least several years, its usefulness to companies attempting to ascertain which predicates to avoid will be severely limited.”

The letter also suggests that if a new device “repeats the same serious design flaw that caused the predicate to be recalled,” FDA should notify the sponsor in writing that the failure to fix the design flaw “puts the device at risk of being deemed misbranded or adulterated[.]”  This notion is particularly misguided, since it implies that FDA would be willing to clear a device that it knows, prior to clearance, would be misbranded or adulterated by virtue of its design. 

The letter also asks that FDA revise the 510(k) database to indicate whether a device “repeats the same design flaw that caused a predicate’s recall,” and “develop a mechanism for identifying certain 510(k) entries to reflect instances where a device’s clearance traces back to a predicate recalled for a serious design flaw adversely impacting its safety, even if the original problematic device is not the immediate predicate.” 

Our conclusion stated in the prior blog post remains true: Congress, industry, and FDA should all consider how to best assure that marketed devices are safe.  However, the proposals in this letter (and the SOUND Act) do nothing to further that goal.

By Kurt R. Karst –      

Efforts to include a 12-year period of exclusivity for biological products in the Trans-Pacific Partnership (“TPP”) agreement chapter on intellectual property rights are alive and well as folks ramp up for the 14th negotiating round of the TPP, which will take place in Leesburg, Virginia from September 6-15, 2012 (see here).  Such a move would align the TPP agreement with the 12-year period of reference product exclusivity provided by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  As we previously reported (here and here), the TPP is a free trade agreement being hammered out among the United States – specifically, the United States Trade Representative (“USTR”), Ron Kirk – and several other partners, and is intended to further liberalize the economies of the Asia-Pacific region.  The TPP, which has been controversial and shrouded in secrecy, has also been touted as a model for all future U.S. trade and investment agreements. 

Although copies of the draft intellectual property chapter had previously been leaked and posted in the Internet, Representative Darrell Issa (R-CA), who is chairman of the House Oversight and Government Reform Committee, “officially leaked” the draft intellectual property chapter in May 2012.  Article 9 of the draft chapter (from February 2011), titled “Measures Related To Certain Regulated Products,” covers pharmaceutical products and includes placeholders for “provisions related to data protection for pharmaceutical products” and “provisions related to patent term/data protection relationship.”  Another leaked version of selected provisions of the chapter from September 2011 includes some additional details on Article 9, but still has a placeholder for specific provisions applying to biologics. 

In June 2012, Teresa Stanek Rea, Deputy Director of the U.S. Patent and Trademark Office, testified before the House Judiciary Subcommittee on Intellectual Property, Competition and the Internet and commented that the Obama Administration was seeking a period of 12-year exclusivitity for biologics in the TPP agreement.  This is contrary to the Obama Administration’s 2013 budget proposal, which seeks to reduce the 12-year exclusivity period under the BPCIA to 7 years.  According to Knowledge Ecology International, Ms. Rea subsequently retracted her comments and the USTR issued a statement that it has “not proposed a specific term for data exclusivity for biologics” and that “discussions on issues relating to biologics are continuing.”

Perhaps as a result of the flap in testimony, and in anticipation of the next round of TPP negotiations, a new round of letters have been sent to President Obama by several Members of Congress.  In a July 12th letter, Senators Patty Murray (D-WA) and Maria Cantwell (D-WA) say that “the TPP negotiations must ensure consistency with U.S. law, which provides 12 years of data protection for biologics,” and that 12-year exclusivity is “vitally important” and “an important foundation for a vibrant U.S. biopharmaceutical industry and workforce.”  Similarly, several members of the Massachusetts delegation – Representatives Edward Markey (D), Richard Neal (D), John Olver (D), James McGovern (D), John Tierney (D), Stephen Lynch (D), Niki Tsongas (D), and William Keating (D) – state in a July 13th letter that “[a]n agreement that reflects U.S. law on biologics exclusivity standards will help Massachusetts companies continue to expand and compete in the global economy.”  In the most recent letter from earlier this month, Senator Claire McCaskill (D-MO) says that TPP negotiations “should sustain the high standards on intellectual property rights that are the hallmark of U.S. law,” and that it is “especially important that the negotiations protect the 12 years of exclusivity that U.S. law now provides” for biologics.

By Kurt R. Karst –      

It’s been nearly nine years since the enactment of the Medicare Modernization Act (“MMA”), which, among other things, changed the regime for 180-day generic drug marketing exclusivity from a “patent-by-patent” approach (under which shared exclusivity can exist for cross-Paragraph IV filers to different patents) to a “first applicant to any patent” approach.  Yet, the lawsuits against FDA involving pre-MMA 180-day exclusivity keep popping up.  Last year, there was the controversy over generic LIPITOR (atorvastatin calcium) Tablets.  Earlier this year there was the case involving generic PROVIGIL (modafinil) Tablets (see here).  The latest case, filed on August 15th in the U.S. District Court for the District of Columbia by Watson Laboratories, Inc. (“Watson”), involves generic versions of Takeda Global Research & Development Center, Inc.’s (“Takeda’s”) diabetes drug ACTOS (pioglitazone HCl) Tablets, 15 mg, 30 mg, and 45 mg.  Watson, through its Complaint and Motion for a Temporary Restraining Order and a Preliminary Injunction, seeks to enjoin FDA from granting final approval (or causing or allowing final approval to be granted) to any ANDA for generic ACTOS prior to granting final approval to Watson’s ANDA No. 076798, or, alternatively, to require FDA to approve ANDA No. 076798 if FDA grants final approval to any other ANDA for generic ACTOS.

Like almost all pre-MMA 180-day exclusivity cases, this case is complicated; but we’ll try to be brief.  FDA approved ACTOS on July 15, 1999 under NDA No. 021073 and granted a period of 5-year new chemical entity exclusivity.  At the time the first ANDA containing a Paragraph IV certification could be submitted to FDA on July 15, 2003, the Orange Book listed several patents for ACTOS.  One of those patents expired in 2006, and the others, which are referred to by Watson in its court filings as the Composition Patents and the Combination Therapy Patents, expire in 2016. 

Watson, and apparently Mylan (ANDA No. 076801) and Ranbaxy (ANDA No. 076800), all submitted ANDAs to FDA on July 15, 2003 containing Paragraph IV certifications to the Composition Patents and to the Combination Therapy Patents.  Prior to “receiving” (i.e., filing) the Watson ANDA on September 9, 2003, FDA instructed Watson (and presumably the others ANDA sponsors as well) to amend its proposed labeling and to change its Paragraph IV certifications to the Combination Therapy Patents to section viii statements (i.e., for labeling carve-out purposes).  Watson disagreed with FDA’s position, but made the certification change. 

After FDA received ANDA No. 076798, Watson provided notice of the Paragraph IV certifications as to the Composition Patents to Takeda and was sued for patent infringement, as were other ANDA sponsors.  Ultimately, the patent infringement litigation was settled and Takeda granted Watson, Mylan, and Ranbaxy a non-exclusive license to the Composition Patents and to the Combination Therapy Patents as of August 17, 2012.  Under FDA’s regulation at 21 C.F.R. § 314.94(a)(12)(v), “if the [ANDA] is for a drug or method of using a drug claimed by a patent and the applicant has a licensing agreement with the patent owner,” the application must contain a Paragraph IV certification as to that patent “and a statement that it has been granted a patent license.”  All three ANDA sponsors apparently amended their respective ANDAs to include Paragraph IV certifications Combination Therapy Patents.  But it is unclear when this happened exactly.  Timing is, of course, critical for 180-day exclusivity purposes.

According to Watson, “[b]ased on the simultaneous filing of the Watson ANDA with Mylan and Ranbaxy’s ANDAs, Watson has expected to share the period of 180-day exclusivity with Mylan and Ranbaxy (as well as with a fourth generic manufacturer, Teva Pharmaceuticals (‘Teva’), that has been granted a license by Takeda).”  In August 2012, however, Watsons says that “FDA informed Watson for the first time that approval of the Watson ANDA would be delayed.  FDA informed Watson it had reached a decision to award another filer or filers a period of 180-day exclusivity, to the exclusion of Watson’s ANDA, and to delay approval of Watson’s ANDA until the expiration of that exclusivity period.”  In other words, FDA presumably determined that one (or more) ANDA sponsor was first to convert its section viii statements to the Combination Therapy Patents to Paragraph IV certifications as a result of the settlement agreement, and that Watson subsequently converted.

Watson argues in its court papers that at the very least the company is entitled to shared exclusivity.  Watson’s primary arguments, however, are that FDA’s decision in this case that Watson’s ANDA cannot be approved as a result of another sponsor’s 180-day exclusivity “(i) contravenes the plain language of the statute and regulations, which only bars approval of later filed applications; and (ii) is contrary to FDA’s regulations and past practice, which deny exclusivity to any ANDA applicant for patents that are the subject of withdrawn or amended Paragraph IV certifications” (emphasis in original).  Accordingly, Watson says that the company is “entitled to an order requiring FDA not to approve any other pioglitazone ANDAs before it approves Watson’s ANDA.”

The case number is 12-cv-01344-ABJ. A hearing has been scheduled for August 15th.  We'll update this post with additional information.

UPDATE:

• August 15, 2012 Minute Entry: "Motion Hearing held on 8/15/2012 re [3] MOTION for Temporary Restraining [Order]; Motion heard and denied without prejudice."
• August 17, 2012 Minute Order: "As stated by the Court in its August 16, 2012 oral ruling, plaintiff's renewed motion for a temporary restraining order is denied. To demonstrate entitlement to a temporary restraining order or preliminary injunction, a litigant must show 1) a substantial likelihood of success on the merits; 2) that it would suffer irreparable injury if the injunction is not granted; 3) that an injunction would not substantially injure other interested parties; and 4) that the public interest would be furthered by the injunction. See Mova Pharm. Corp. v. Shalala, 140 F.3d 1060 (D.C. Cir. 1998) (setting forth standard for a preliminary injunction); Sterling Commercial Credit–Michigan LLC v. Phoenix Indus. I, LLC, 762 F. Supp. 2d 8, 78 (D.D.C. 2011) (stating that the same standard applies to temporary restraining orders and preliminary injunctions). For the reasons explained at the August 16, 2012 hearing, the Court finds that plaintiff did not show a substantial likelihood of success on the merits in its motion for a temporary restraining order concerning its abbreviated new drug application ("ANDA") for generic pioglitazone hydrochloride 15 mg, 30 mg, and 45 mg tablets ("Generic Pioglitazone"). Specifically, plaintiff was told by the Food and Drug Administration ("FDA") on August 15, 2012 that its application was deficient and that it was required to submit additional information. The Court denied plaintiff's initial motion for a temporary restraining order without prejudice in view of the FDA's request. Plaintiff then responded to the FDA's request and renewed its motion. During the August 16 hearing on plaintiff's renewed motion, the FDA informed plaintiff that it had not submitted sufficient information in response to the August 15 request. Accordingly, at that time, plaintiff's application was still deemed deficient by the FDA and plaintiff was unable to demonstrate a likelihood of success on the merits; indeed, plaintiff's counsel conceded that the Court could not grant injunctive relief if its application was deemed deficient. Even if plaintiff had provided sufficient information to the FDA prior to the August 17, 2012 release date of Generic Pioglitazone, however, the Court finds that plaintiff did not present the Court with any case law or other legal authority that would persuade the Court that it has the authority to compel the FDA to immediately process and approve Watson's ANDA under the facts of this case. Plaintiff's alternative requests for relief also fail. Plaintiff requested, inter alia, that the Court enjoin the FDA from approving any other company's ANDA for Generic Pioglitazone if the FDA were not to approve Watson's ANDA on August 17, 2012. This request fails because such relief would plainly cause substantial injury to the other providers of Generic Pioglitazone who would have been approved on August 17, 2012. Furthermore, the public interest would not be furthered by an injunction that prevents approved companies from selling a generic drug. Accordingly, for the reasons stated by the Court on August 16, 2012 and for the reasons explained above, plaintiff's motion for a temporary restraining order is DENIED. Signed by Judge Emmet G. Sullivan on August 17, 2012."

By Riëtte van Laack –

The Organic Food Products Act of 1990 (“OFPA”) established national standards for the marketing of certain agricultural products marketed as organically produced.  It directed USDA to issue regulations specifying the requirements for certification and labeling of organic agricultural products.  In promulgating the NOP regulations, the USDA decided that the labeling of cosmetics was outside the scope of the OFPA.  Although the USDA’s position appears to have changed over time, USDA has not amended its NOP regulations to apply to organic claims for cosmetics.

The California Organic Products Act of 2003 (“COPA”) prohibits any product handled, processed, sold, advertised, represented or offered for sale in California from being sold as organic unless it is labeled with terminology similar to terminology set for in the regulations by the National Organic Program (“NOP”). COPA specifically applies to cosmetic products sold or labeled as organic or made with organic.  Under COPA, cosmetics with organic claims must contain at least 70 percent organically produced ingredients.  Unlike OFPA, which may be enforced only by USDA, COPA is enforceable by any person who may bring an action for injunctive relief.

In 2011, R. Brown et al. filed a complaint against The Hain Celestial Group, Inc. (“Hain”), claiming that Hain sold organic cosmetics in violation of COPA because these cosmetics did not contain 70% or more organic ingredients.  Hain filed a motion to dismiss arguing that COPA’s requirements for cosmetics are expressly preempted by the federal OFPA.

Judge Beeler of the U.S. District Court for the Northern District of California disagreed, however, in a decision from earlier this month.  Although the title of the OFPA may suggest otherwise, the Court concluded that OFPA covers cosmetics that use agricultural products.  However, the court held that OFPA only expressly preempts a narrow set of state certification requirements and does not bar state law labeling provisions that do not conflict with OFPA’s and NOP’s provisions.  In the alternative, even if (contrary to the Court’s interpretation) OFPA does not extend to agricultural cosmetics, USDA has approved COPA.  In either case, COPA’s provisions regarding organic claims for cosmetics are not preempted.  Therefore, the Court denied the Hain’s motion to dismiss.

By Jennifer D. Newberger –

On August 10, 2012, FDA issued a draft guidance, “Refuse to Accept Policy for 510(k)s.”  This draft guidance largely mirrors the recently issued draft guidance for premarket approval applications, “Acceptance and Filing Review for Premarket Approval Applications (PMAs),” on which we previously commented here. 

The draft guidance includes checklists for traditional, abbreviated, and special 510(k)s, based largely on the regulatory requirements for 510(k)s outlined in 21 C.F.R. § 807.87.  Included in the checklist are elements that will not necessarily be applicable to all devices, e.g., biocompatibility testing.  If a submitter believes that a particular element is not relevant to the submission, it should provide a justification for not including the information.

Within 15 days of receipt of the submission, FDA must inform the submitter if the submission is administratively complete, or, if not, identify the missing elements.  The submitter may then respond by providing the missing information, and FDA will then have another 15 days to perform the acceptance review.  The submitter should provide the information under the originally assigned 510(k) number.  FDA will not require a complete new submission, nor will the submitter be required to pay a new user fee upon providing the missing information.

The guidance states that if FDA fails to complete the acceptance review within 15 days, the submission should be considered accepted, but “FDA may ask for any information during the substantive review that may have been unintentionally overlooked during the acceptance review.”  The review clock for MDUFA goal purposes will not begin until FDA determines that the submission is administratively complete.  This review does not assess whether the contents of the application are substantively sufficient to make a substantial equivalence determination. 

The guidance contains certain principles that it suggests reviewer and submitters should heed in determining whether a 510(k) submission is complete:  1) acceptance should not be based on a substantive review of the submission; 2) reviewers should consider any justifications provided by the submitter as to why certain elements are not included, and; 3) submitters should review any applicable guidance or standards to ensure the submission contains all necessary information for that device type.

The guidance provides preliminary questions to be addressed by the reviewer prior to determining whether the submission contains all elements in the checklist.  These questions include:  (1) Is the product a device? (2) Is the submission within the correct center (e.g., CDRH or CBER)?  (3) Is a 510(k) is the appropriate regulatory submission?  (4) Is there a pending PMA for the same device with the same indications?  (5) If clinical data are submitted, is the submitter subject to the Application Integrity Policy (AIP)?  Though most of these questions could be easily answered during a preliminary review, determining whether the 510(k) path is appropriate could require a more substantive review, and may not always easily be determined.  For some products, it also may not be as clear as to whether the product is a device (see, e.g., here).  If a submitter is unsure of the appropriate regulatory path prior to providing a submission to FDA, it should consider submitting a 513(g) to determine FDA’s likely regulatory approach. 

It’s that time of year again when we at FDA Law Blog turn to our loyal readers and ask for your help.  The American Bar Association (“ABA”) announced that it is now accepting nominations for the 2012 Blawg 100 (the top 100 legal blogs – or “blawgs” – in the blogosphere).  With your help we made the top 100 list in 2009 and 2010, and we would really like to do so again in 2012!  We’d like another merit badge to add to the growing “Awards and Honors” collection posted on our blog. 

We ask that FDA Law Blog readers use the ABA’s Blawg 100 Amici Form – available here – and nominate the FDA Law Blog!  Although it’s called a “friend-of-the-blawg brief,” filling out the form will take only a couple of minutes.  In fact, you only have 500 characters to say why you’re a fan of the blog (something pithy).  Remember, when you complete the nomination form, our URL is www.fdalawblog.net.  Friend-of-the-blawg briefs are due no later than Friday, September 7th.

ABA editors make the final decisions about what’s included in the Blawg 100.  We hope they’ll be impressed with what our readers have to say about us.  Thank you!

By Kurt R. Karst –      

That’s the picture conjured up when we plugged some dates into the new model for calculating forfeiture of 180-day generic drug marketing exclusivity for certain ANDAs – what we are calling “window ANDAs” – covered by Section 1133 of the recently enacted FDA Safety and Innovation Act (“FDASIA”).

FDASIA § 1133 concerns FDC Act § 505(j)(5)(D)(i)(IV), which is one of the six 180-day generic drug exclusivity forfeiture provisions added to the FDC Act by Title XI of the 2003 Medicare Modernization Act.  Under FDC Act § 505(j)(5)(D)(i)(IV), 180-day exclusivity eligibility is forfeited if:

The 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.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final Agency action on the petition (inclusive of such beginning and ending dates) . . . .” FDC Act § 505(q)(1)(G). 

FDASIA § 1133 covers two cohorts of ANDAs – one under subsection (a) and another under subsection (b).  For both sets of ANDAs covered by FDASIA, the intent of the law is two-fold.  First, FDASIA accounts for FDA’s growing median ANDA approval time – about 32-33 months today – which has led to many companies forfeiting 180-day exclusivity eligibility.  Second, FDASIA § 1133 addresses FDA’s strict interpretation of FDC Act § 505(j)(5)(D)(i)(IV), such that when an ANDA sponsor who amends a long-pending ANDA to include a Paragraph IV certification to an Orange Book-listed patent and qualifies as a “first applicant,” that sponsor may simultaneously forfeit 180-day exclusivity eligibility for failure to obtain timely tentative approval.  This has happened because FDA counts 30 months from the ANDA submission date rather than from the first Paragraph IV certification date (see our previous post here).

FDASIA § 1133(a) covers ANDAs submitted to FDA between January 9, 2010 (actually, January 11, 2010, because January 9th is a Saturday) and July 9, 2012 initially containing a Paragraph IV certification to a patent listed in the Orange Book for the Reference Listed Drug (“RLD”), or that is amended between January 9, 2010 and July 9, 2012 to first contain a Paragraph IV certification to a patent listed in the Orange Book for the RLD.  It provides that the time to obtain timely tentative approval (or final approval if tentative approval is not warranted) is 40 months during the period of July 9, 2012 and September 30, 2015, and not 30 months.  During the period beginning on October 1, 2015 and ending on September 30, 2016, the period is 36 months and not 30 months.

FDASIA § 1133(b) covers ANDAs first amended after July 9, 2012 to contain a Paragraph IV certification.  Specifically, this subsection provides that for an ANDA submitted to FDA prior to July 9, 2012 that is first amended on July 10, 2012 and up to September 30, 2017 to contain a Paragraph IV certification to a patent listed in the Orange Book for the RLD, the date of the amendment starts to 30-month tentative approval forfeiture period instead of the original ANDA submission date. 

While all seems well with the FDASIA § 1133(b) window ANDAs, there appears to be a problem with the FDASIA § 1133(a) window ANDAs.  In particular, the 36-month extension date is inapplicable (absent an applicable 505(q) citizen petition, or some change in review that occurs during the last 6 months of the 36-month period making the forfeiture provision irrelevant).  By the time this provision takes effect on October 1, 2015, the youngest ANDA to which it could apply – i.e., an ANDA submitted to FDA on July 9, 2012 – will be nearly 39 months old.  If such an ANDA is tentatively approved on September 30, 2015 when the tentative approval period is still 40 months, there would not be a forfeiture.  If, however, that same ANDA is tentatively approved one day later, on October 1, 2015, there would be an automatic forfeiture.

In addition, we note that the youngest window ANDA to which FDASIA § 1133(a) can fully apply (i.e., an ANDA that could potentially enjoy the full 40-month period absent an applicable 505(q) citizen petition) is an ANDA submitted on May 30, 2012 and tentatively approved on September 30, 2015.  Such an ANDA would be tentatively approved within the 40-month period (depending on what it means to be tentatively approved “within” the specified timeframe – see our previous post here.)  An ANDA submitted after May 30, 2012 would not enjoy the full 40-month period. 

By Larry K. Houck –
 
The Drug Enforcement Administration (“DEA”) recently amended its regulations to allow practitioners to issue electronic prescriptions for controlled substances (“EPCS”) in lieu of hardcopy paper prescriptions.  See 75 Fed. Reg. 16,236 (March 31, 2010).  DEA requires that any electronic prescription application or pharmacy application used for EPCS must be reviewed, tested and determined by a third party to meet all of the required technical specifications.  21 C.F.R. § 1311.300(a).  As an alternative to the third party audit requirements of 21 C.F.R. §§ 1311(b)-(d), an electronic prescription or pharmacy application may be verified and certified as meeting DEA requirements by a certifying organization whose certification process has been approved by DEA.  21 C.F.R. § 1311.300(e).  DEA stated that it would notify registrants of any approved third party certifications on its website.  75 Fed. Reg. 16,243.

DEA announced on August 1, 2012 that it has approved the certification processes developed by two certifying organizations (77 Fed. Reg. 45,688 (Aug. 1, 2012)) and has posted relevant information about those approvals, and about an earlier approval, on the DEA Diversion Control website.   

By Kurt R. Karst –      

There’s a first time for everything!  And on August 8th, 2012, FDA decided, for the first time since the enactment of the Orphan Drug Act, to rescind a period of 7-year orphan drug exclusivity.  The decision came in the form of a response granting in part and denying in part a citizen petition (Docket No. FDA-2011-P-0213) CSL Behring (“CSL”) submitted to FDA in March 2011 requesting that the Agency: (1) revoke the orphan drug designation and the period of orphan drug exclusivity FDA subsequently granted to Octapharma USA, Inc. (“Octapharma”) for the December 4, 2009 approval of WILATE (von Willebrand Factor/Coagulation Factor VIII Complex (Human)) under BLA No. 125251 “for the treatment of spontaneous or trauma-induced bleeding episodes in patients with severe von Willebrand disease (VWD) as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated;” and (2) “refrain from making any orphan drug designations and approval decisions based on hypothetical claims of superiority.”  FDA decided not to revoke orphan drug designation for WILATE, and also denied CSL’s request regarding “hypothetical claims of superiority.”

WILATE is the “same drug” as HUMATE-P (Antihemophilic Factor/von Willebrand Factor Complex (Human)) for orphan drug purposes.  That is, FDA considers them to be “chemically the same drug” and for the same orphan indication.  FDA approved HUMATE-P on April 1, 1999 for the same orphan disease as WILATE.  Because WILATE is the “same drug” as HUMATE-P, the issue of “clinical superiority” comes into play – for obtaining orphan drug designation and for obtaining orphan drug exclusivity.

FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan-drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug.”  FDA’s orphan drug regulations define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways: (1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials; (2) greater safety in a substantial portion of the target population; or (3) demonstration that the drug makes a major contribution to patient care.

As FDA explains in the petition response (as well in the Agency’s 2011 proposed rule – see our previous post here):

Though the sponsor of a subsequent orphan drug must set forth a plausible hypothesis of clinical superiority over the previously approved drug at the designation stage, such a sponsor faces a higher standard at the time of approval.  At approval, the sponsor of a drug which was designated on the basis of a plausible hypothesis of clinical superiority must demonstrate that its drug is clinically superior to the previously approved drug.  Should the sponsor fail to do so, then the subsequent drug will be considered to be the same drug as the previously approved drug, and will not be able to gain marketing approval if the previously approved drug’s orphan-drug exclusive approval period is still running.  Once this exclusivity has expired, the subsequent drug may be approved . . . , but it will not be eligible for orphan-drug exclusivity because the same drug has already been approved for the same orphan indication.

In the case of WILATE, FDA designated the drug as an orphan drug in April 2007 after determining that there was a plausible hypothesis of clinical superiority.  Specifically, FDA determined that WILATE “may be safer than [HUMATE-P] in a substantial portion of the target population due to its two dedicated viral inactivation steps compared to a single dedicated viral inactivation step for [HUMATE-P].”  After approving WILATE, FDA allowed Octapharma to make its case for a demonstration of clinical superiority, and on June 24, 2010, FDA determined that WILATE “appeared to be clinically superior to [HUMATE-P] because of greater viral safety,” and, in fact, “had been shown to be clinically superior to [HUMATE-P] within the meaning of the FDA’s orphan drug regulations . . . .”  As such, FDA granted a period of 7-year orphan drug exclusivity retroactive to December 4, 2009 when FDA approved WILATE.

CSL subsequently contacted FDA and questioned the evidentiary support for FDA’s exclusivity decision.  FDA requested that CSL raise its concerns in a citizen petition, which CSL submitted in March 2011.  CSL’s main premise is that the evidence Octapharma presented to FDA to support clinical superiority of WILATE over HUMATE-P does not meet the applicable regulatory standards. 

After reanalyzing available evidence, FDA concluded that WILATE had not, in fact, been demonstrated to be clinically superior to HUMATE-P due to greater safety.  According to FDA, “the record does not contain sufficient evidence to support a finding that Wilate is clinically superior to Humate due to its ‘[g]reater safety in a substantial portion of the target population.’”  Accordingly, FDA withdrew its clinical superiority determination, and, as a result, rescinded the orphan drug exclusivity for WILATE. 

FDA decided not to rescind orphan drug designation for WILATE, however.  FDA’s orphan drug regulations provide three independent bases under which orphan drug designation can be revoked – if FDA finds that: 

(1)  The request for designation contained an untrue statement of material fact; or

(2)  The request for designation omitted material information required by [21 C.F.R. Part 316]; or

(3)  FDA subsequently finds that the drug in fact had not been eligible for orphan drug designation at the time of submission of the request therefor. [(21 C.F.R. § 316.29(a))] 

FDA rarely rescinds orphan drug designation.  We are aware of only three instances:

(1) Papaverine – On February 6, 1992, OOPD designated Pharmedic Co.’s papaverine topical gel for the “treatment of sexual dysfunction in spinal cord injured patients.”  FDA revoked the designation on September 16, 1993 after additional information showed that the potential target population of the drug could be significantly larger than originally stated.

(2) Methylnaltrexone – On June 17, 1996, FDA designated the University of Chicago’s methylnaltrexone for the “treatment of chronic opioid-induced constipation unresponsive to conventional therapy.”  FDA revoked the designation on January 9, 1998 after new information indicated that the drug could be used in a significantly larger patient population.

(3) Pancreatic Enzymes – On January 23, 2002, FDA designated Altus Biologics Inc.’s TheraCLEC-Total, a microbially-derived pancreatic enzyme product containing amylase, lipase, and protease, as an orphan drug for the “treatment of exocrine pancreatic insufficiency.”  FDA revoked the designation on June 28, 2007 based on information showing that the drug could be used in a significantly larger patient population – specifically HIV/AIDS patients who suffer from fat malabsorbtion (see our previous post here).

In each of these cases, orphan drug designation was revoked because FDA determined (see 21 C.F.R. § 316.29(a)(3)) that the drug “had not been eligible for orphan drug designation at the time of submission of the request.”  In 2011, FDA denied a petition seeking the revocation of orphan drug designation for MAKENA (then known as GESTIVA), which is another orphan drug the orphan drug exclusivity of which has been in the news as of late (see here).

With respect to the orphan drug designation for WILATE, FDA concluded that although WILATE’s “hypothesis of clinical superiority has not been demonstrated to be true,” that does not mean that the plausible hypothesis of clinical superiority “was implausible ‘at the time the [designation] request was submitted.’  The salient fact is that, at the time Octapharma advanced it, the designation request presented a plausible hypothesis.”  As such, according to FDA, none of the grounds in FDA’s regulation to rescind designation apply.

FDA also denied CSL’s second request concerning “hypothetical claims of superiority,” because “‘hypothetically plausible’ is the very standard that the Agency applies to designation requests under its orphan drug regulations.”

Octapharma submitted comments to the petition docket advancing several arguments.  Among other things, Octapharma claimed that the company has “a Constituionally-protected interest” in the orphan drug exclusivity FDA granted for WILATE, and that FDA may not rescind exclusivity without providing the company an opportunity to defend its exclusivity interest at a formal hearing.  FDA reiterated the Agency’s position that “a manufacturer has no property right in its orphan-drug exclusivity that would entitle it to the sort of process to which Octapharma claims it is entitled.” 

By Carmelina G. Allis –

On August 2, 2012, the FDA published a final rule amending its regulations in 21 C.F.R. Part 807 to reflect the 2007 statutory amendments to the device registration and listing provisions of the Federal Food, Drug, and Cosmetic Act ("FDC Act").  This final rule also facilitates the FDA’s collection of additional registration information in order to comply with the 2002 Bioterrorism Act.

The most significant change is that all contract manufacturers and contract sterilizers must now register and list.  This change eliminates the long standing exemption for contract manufacturers and sterilizers who performed these activities for another party who both initiated the specifications and commercially distributed the device.  77 Fed. Reg. 45,927, 45,941 (Aug. 2, 2012) (amending 21 C.F.R §§ 807.20(a)(3) and (c)(1) to remove this exemption).

The usual registration user fee will apply.  The FY 2012 establishment registration fee is $2,020.  In FY 2013, the fee will be $2,575 (see our previous post here).

There also are new requirements for foreign establishments to identify all known importers and to register/list even when their devices enter a foreign trade zone.  According to FDA, these requirements will comply with the Bioterrorism Act, and help increase the Nation’s ability to prepare for an respond to acts of bioterrorism and other public health emergencies.

The regulation also has been revised to require that all registration and listing information be submitted electronically to FDA (absent a waiver).  This formally implements the 2007 statutory amendments, although FDA in fact has been requiring electronic regulation for several years now.

The effective date of the final rule is October 1, 2012.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Anne Walsh will moderate a panel on “Trends and Priorities in Enforcement” at this year’s Food and Drug Law Institute’s (“FDLI”) Advertising and Promotion Conference.  The conference will be held in Washington, DC on October 1-2, 2012.  Panelists will include speakers from the HHS OIG, DOJ, and the states, and will complement Ms. Walsh’s former experience at FDA.  They will discuss what can be learned from recent settlements involving medical product advertising and promotion. 

FDLI’s annual Advertising & Promotion conference brings together regulated industry and the regulators responsible for overseeing the advertising and promotion of prescription drugs, medical devices, biologics, and animal drugs. Top-level officials from FDA’s four medical product-related Centers (CBER, CDER, CDRH, and CVM), and speakers from GlaxoSmithKline, Abbott, Pfizer, Merck and Medtronic (a full list of speakers is online) will provide helpful insight and be available to answer your questions during panel discussions and networking opportunities.

This conference is attended by experienced professionals in the fields of regulatory, legal, public relations, marketing and management who work in the pharmaceutical, medical device, diagnostic, biologics and veterinary medicine industries. The conference is also beneficial for consultants in the areas of advertising, public relations, law and marketing communications.

FDA Law Blog readers can receive a 15% discount off the conference registration price.  To receive the discount, use the following promotional code: AP2012.  For more information and to register, visit the program website.

By Kurt R. Karst –      

We were eager to delve into the Federal Circuit’s recent 2-1 decision in Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc. (Docket Nos. 2012-1062, -1103, -1104) concernng the scope of the Hatch-Waxman “safe harbor” provision at 35 U.S.C. § 271(e)(1), particularly in light of the Court’s prior decision in Classen Immunotherapies v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011), which is on appeal to the U.S. Supreme Court (Docket No. 11-1078).  Although the 2012 London Olympics captured most of our attention over the weekend, we did find some time to look over the decision.  And we weren’t disappointed – at least insofar as the decision, and Chief Judge Randall Rader’s dissent, provided some legal entertainment.

The case involves a generic version of LOVENOX (enoxaparin), which FDA approved after addressing active ingredient sameness criteria (i.e., “standards for identity”) in a citizen petition response (see our previous post here), U.S. Patent No. 7,575,866 (“the ‘866 patent”) assigned to Momenta that generally relates “to methods for analyzing heterogeneous populations of sulfated polysaccharides” such as enoxaparin, and 35 U.S.C. § 271(e)(1), which states: 

It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention (other than a new animal drug or veterinary biological product (as those terms are used in the Federal Food, Drug, and Cosmetic Act and the Act of March 4, 1913) which is primarily manufactured using recombinant DNA, recombinant RNA, hybridoma technology, or other processes involving site specific genetic manipulation techniques) solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

Momenta sued Amphastar for patent infringement alleging that Amphastar infringed the ‘886 patent by manufacturing for commercial sale enoxaparin using the patented method.  Ultimately, the U.S. District Court for the District of Massachusetts granted Momenta a preliminary injunction and denied two emergency motions filed by Amphastar for relief from the preliminary injunction.  (Copies of those decisions are available here, here, and here.)  Among other things, the District Court ruled that Amphastar’s activity fell outside of the “safe harbor” provision at 35 U.S.C. § 271(e)(1), because:

although the safe harbor provision permits otherwise infringing activity that is conducted to obtain regulatory approval of a product, it does not permit a generic manufacturer to continue in that otherwise infringing activity after obtaining such approval. . . .  Here, the alleged infringing activity involves use of plaintiffs’ patented quality control testing methods on each commercial batch of enoxaparin that will be sold after FDA approval.  Thus, it is not exempted under § 271(e)(1).

In coming to its decision, the District Court relied on the U.S. Supreme Court’s decision in Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005), and on the Hatch-Waxman legislative history of 35 U.S.C. § 271(e)(1) quoted by the Federal Circuit in Classen; namely that:

[T]he only activity which will be permitted by the bill is a limited amount of testing so that generic manufacturers can establish the bioequivalency of a generic substitute . . . .  [T]he generic manufacturer is not permitted to market the patented drug during the life of the patent; all that the generic can do is test the drug for purposes of submitting data to the FDA for approval.  [H.R. Rep. No. 98–857, at 8 (1984)]

In Integra, the Supreme Court stated that the text of 35 U.S.C. § 271(e)(1) “makes clear that it provides a wide berth for the use of patented drugs in activities related to the federal regulatory process,” and that there is “no room in the statute for excluding certain information from the exemption on the basis of the phase of research in which it is developed or the particular submission in which it could be included.”  In Classen, which concerned whether a vaccine license holder was required to report to FDA certain adverse event information, the Federal Circuit held that 35 U.S.C. § 271(e)(1) “does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained.”

Amphastar appealed each of the District Court’s preliminary injunction decisions to the Federal Circuit and argued that the District Court improperly took a restrictive view of the “safe harbor” provision.  Momenta argued that the District Court’s decisions were correct and that, among other things, the Federal Circuit in its Classen decision previously ruled that 35 U.S.C. § 271(e)(1) does not apply to routine reports to FDA post-approval, such as the batch testing Amphastar carried out as a condition to ANDA approval of its generic LOVENOX.  (Copies of the Amphastar and Momenta Federal Circuit briefs are available here, here, and here.)

The Federal Circuit first sought to ascertain the scope of 35 U.S.C. § 271(e)(1) and focused on the the passage in the “safe harbor” provision stating “solely for uses reasonably related to the development and submission of information under a federal law.”  According to the Court:

Congress could not have been clearer in its choice of words: as long as the use of the patented invention is solely for uses “reasonably related” to developing and submitting information pursuant to “a Federal law” regulating the manufacture, use, or sale of drugs, it is not “an act of infringement.” . . .  Limiting the scope of 35 U.S.C. § 271(e)(1) to just the submission of information pursuant to the [FDC Act] generally, or to the ANDA provision of the [FDC Act] in specific, would read words into the statute in violation of the express language chosen by Congress.

Moreover, while the statute does include a limitation – that the use must be “for uses reasonably related to the development and submission” – the term “reasonably related,” says the Court, citing and quoting Integra, “does not mean that the use of the patented invention must necessarily result in submission of information to the FDA.”   Rather, “[a]s long as the accused infringer has a reasonable basis for believing that use of the patented invention might yield information that would be appropriate to include in a submission to the FDA, that use is ‘reasonably related’ to the ‘development and submission of information’ . . . .”  (internal quotations omitted).

(Although this question is perhaps best reserved for another day, given the Federal Circuit’s broad reading of the “safe harbor” provision, would the Court perhaps include in its interpretation of 35 U.S.C. § 271(e)(1) information related to a biosimilar application under PHS Act § 351(k)?)  

Noting that the information Amphastar produced was not actually submitted to FDA, but rather is retained by the company, the Federal Circuit next addressed whether such information can nevertheless be “submitted” for purposes of 35 U.S.C. § 271(e)(1).  And the court said “yes,” stating:

We think that the requirement to maintain records for FDA inspection satisfies the requirement that the uses be reasonably related to the development and submission of information to the FDA. . . .  The fact that the FDA does not in most cases actually inspect the records does not change the fact that they are for the “development and submission of information under a Federal law.”

Then came the big issue: whether Amphastar’s submissions are within the 35 U.S.C. § 271(e)(1) “safe harbor.”  Here again, the Federal Circuit said “yes” (because they are required “submissions”), and in doing so addressed the Classen decision:

This case . . . fits well within Classen because the information submitted is necessary both to the continued approval of the ANDA and to the ability to market the generic drug.  Here, the submissions are not “routine submissions” to the FDA, but instead are submissions that are required to maintain FDA approval. . . .

Under a proper construction of 35 U.S.C. § 271(e)(1), the fact that Amphastar’s testing is carried out to “satisfy the FDA’s requirements” means it falls within the scope of the safe harbor, even though the activity is carried out after approval.  Unlike Classen, where the allegedly infringing activity “may” have eventually led to an FDA submission, there is no dispute in this case that Amphastar’s allegedly infringing activities are carried out to “satisfy the FDA’s requirements.”  The district court’s interpretation of § 271(e)(1) was erroneous.  Under the correct construction, Momenta cannot establish a likelihood of success on infringement and the preliminary injunction must be vacated.

The Federal Circuit also disagreed with Momenta’s argument that Amphastar’s testing is not protected under 35 U.S.C. § 271(e)(1) because there are non-infringing alternatives available that are endorsed by FDA. 

Chief Judge Rader, who hesitantly noted that he was present through the Hatch-Waxman legislative process (see here), lodged a blistering 29-page dissent that begins and ends with the conclusion that Amphastar is a trespasser.  In between, Chief Judge Rader provides a history of 35 U.S.C. § 271(e)(1), saying that the provision “won approval because it was limited in time, quantity, and type,” and that the majority opinion runs counter to legislative intent and significantly expands the scope of the provision.  According to Chief Judge Rader:

This new interpretation would allow almost all activity by pharmaceutical companies to constitute “submission” and therefore justify a free license to trespass.  The FDA can inspect records of any drug manufacturer and seller.  See 21 U.S.C. § 374.  Thus, the drug manufacturer need only make a record, which could potentially be inspected by the FDA, and then any activity could satisfy this new meaning of “submission.”

Moreover, says Chief Judge Rader, the majority decision cannot be reconciled with the Federal Circuit’s Classen decision, and the “decision should instead request the entire court to resolve the issue en banc.”  Although we’ve made such predictions before and they did not pan out (to our surprise), this Federal Circuit decision seems destined to further appeal.