By Kurt R. Karst –      

As we predicted, Massachusetts-based The Medicines Company (“TMC”) has sued the U.S. Patent and Trademark Office (“PTO”) and FDA in connection with the company’s efforts to obtain a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering ANGIOMAX (bivalirudin).  FDA approved ANGIOMAX at 5:18 PM on Friday, December 15, 2000 under New Drug Application (“NDA”) 20-873, and TMC submitted its PTE application to the PTO on February 14, 2001 – 62 days after NDA approval (including the December 15, 2000 date of approval).

The Complaint and Motion for Summary Judgment, filed last week in the U.S. District Court for the Eastern District of Virginia (Alexandria Division), follows the PTO’s January 8, 2010 denial of TMC’s December 2009 Request for Reconsideration (see our previous post here) asking the PTO to employ a “rule of construction” under which the Office would consider the 60-day PTE application submission period at 35 U.S.C. § 156(d)(1) to commence on the first business day after the day the FDA transmits notice of NDA approval of the drug product if that transmittal occurs after normal business hours.  In the case of the PTE application for the ‘404 patent covering ANGIOMAX, that would mean the 60-day period would have begun on December 18, 2000 and the PTE application would have been timely filed within 35 U.S.C. § 156(d)(1).  The lawsuit also follows TMC’s failed attempts (see our previous post here) to get legislation enacted that would permit the PTO to accept late-filed PTE applications.  The ‘404 patent expires on March 23, 2010, but is subject to a 6-month period of pediatric exclusivity that will expire on September 23, 2010.  TMC claims that if a PTE were applicable to the ‘404 patent, it would extend the patent expiration date until December 2014. 

TMC’s Complaint alleges that the PTO’s denial of the company’s PTE application for the ‘404 patent and FDA’s decision regarding PTE application timeliness violated the Administrative Procedure Act (5 U.S.C. § 706(2)(A)).  Specifically, TMC alleges that:

The PTO’s denial of [TMC’s] application for a patent term extension, the PTO’s refusal to reconsider that determination, and the PTO’s and the FDA’s determinations that MDCO’s application for an extension of the term of [the ‘404 patent] was not timely filed under 35 U.S.C. § 156(d)(1) misinterpreted § 156, failed to provide adequate explanations for their conclusions, failed to respond to significant arguments raised by [TMC], reflected a misapprehension of agency authority under § 156, and misinterpreted agency regulations and, relevant case law.

Among other things, TMC argues that there is a discrepancy in how FDA (and the PTO) treats the dates of NDA receipt and approval:

[U]nder the government’s approach to [the PTE] statute, an application for approval of a new drug received by the FDA after business hours is deemed to be filed on the following business day.  By contrast, when a [NDA] is approved after business hours, the government deems the approval to have occurred on the same business day and takes the position that this day starts the 60-day period for filing a patent term extension application.  Despite this inconsistency, the PTO somehow concluded that its interpretation was mandated by statute and regulation.

As a result, TMC alleges that “[t]he PTO’s decision is not merely arbitrary and capricious; it is profoundly unfair and undermines the remedial design of the patent term restoration system.” 

TMC requests the court to vacate and set aside various PTO and FDA deicisions made in connection with the ‘404 patent PTE application, to declare that ANGIOMAX “received permission . . . for commercial marketing or use” within the meaning of 35 U.S.C. § 156(d)(1) no earlier than December 18, 2000 and that the company’s PTE application was timely filed, and to order the PTO to extend the ‘404 patent until December 2014.  TMC also requests the court to grant expedited consideration of the case and to “grant any preliminary injunctive relief necessary to maintain the status quo pending resolution of this case.” 

For heavily-regulated companies, such as those regulated by the Food and Drug Administration, it is common for companies to seek advice from in-house and outside counsel regarding whether proposed conduct would violate the law. It has become increasingly popular for federal prosecutors to target the company's actions that related to the legal advice that counsel previously rendered to a company or individual who is under criminal investigation or has actually been indicted.  A recently published article in the January/February 2010 issue of FDLI Update discusses the benefits and risks of a defendant presenting the testimony of a lawyer who previously provided legal advice.

By Kurt R. Karst –      

Is an ANDA applicant who cites a 505(b)(2) drug as the Reference Listed Drug (“RLD”) required to certify to Orange Book-listed patents covering the 505(b)(2) RLD drug as well as to Orange Book-listed patents covering the original listed drug approved under an NDA relied upon by the 505(b)(2) applicant for approval of its application?  No, according to FDA in a recent decision responding to a 2009 citizen petition submitted by Osmotica Pharmaceutical Corp. (“Osmotica”) involving Venlafaxine HCl Extended-Release Tablets. 

In May 2008, FDA approved Osmotica’s 505(b)(2) application for Venlafaxine HCl Extended-Release Tablets based on the Agency’s previous findings of safety and effectiveness for EFFEXOR XR Extended-Release Capsules and Osmotica’s bioequivalence data.  EFFEXOR XR and Osmotica’s Venlafaxine HCl Extended-Release Tablets share two common Orange Book patent listings; however, there are several other Orange Book-listed patents covering EFFEXOR XR that are not listed for Osmotica’s drug product.  At the time of approval of Osmotica’s drug product, there was a pending ANDA based on an approved suitability petition for Venlafaxine HCl Extended-Release Tablets.  As we previously reported, FDA determined in November 2008 (in response to a citizen petition) that Osmotica’s Venlafaxine HCl Extended-Release Tablets drug product became the RLD and that any generic applicant with a pending ANDA for Venlafaxine HCl Extended-Release Tablets would be required to identify Osmotica’s drug product as the RLD and to submit a new ANDA with appropriate bioequivalence information. 

In July 2009, Osmotica once again petitioned FDA requesting that the Agency, among other things:

Clarify that when an ANDA applicant relies on an RLD, the approval of which was pursuant to a [NDA] that is described in section 505(b)(2) of the Act . . . , and that 505(b)(2) application itself relied on an earlier approved NDA, the ANDA applicant must certify not only to the Orange Book-listed patents that cover the 505(b)(2) listed drug on which it directly relied, but also to the Orange Book-listed patents that cover the earlier approval on which the 505(b)(2) applicant relied.

By way of background, FDA’s long-standing policy has been to require that an ANDA that is submitted against another ANDA that was itself submitted and approved pursuant to a suitability petition contain an appropriate certification with respect to any Orange Book-listed patents covering the original RLD NDA relied on by the ANDA suitability petition applicant for approval. 

In 2002, FDA was first faced with the question of whether a generic applicant must certify to Orange Book-listed patents covering the  original NDA on which the approval of the generic applicant’s proposed RLD was based in the context of ANDA No. 75-250 for Prednisolone Sodium Phosphate Oral Solution.  In that case, FDA approved WE Pharmaceuticals, Inc.’s (“WE’s”) ANDA on January 4, 2002, but quickly rescinded that approval on January 17, 2002 “in light of the patent certification requirements of the [FDC] Act.”  According to FDA:

The ANDA submitted by [WE] does not meet the statutory requirements for approval, and did not do so at the time it was mistakenly approved by FDA.  The mistake arose from the status of the WE ANDA as a subsequent ANDA to that approved for Ascent Pharmaceuticals Orapred (ANDA 75-117).  Both your ANDA and the Ascent ANDA are for drug products for which a suitability petition was approved for a change to a listed drug (87P-0237/CP1).  The listed drug referenced in the approved suitability petition is Celltech Pharmaceuticals, USA’s (Celltech) Pediapred (NDA 19-157).  The listed drug product referenced in ANDA 75-250, by recent amendment, was Ascent’s Orapred, which has no listed patent protection.  Pediapred is subject to patent protection that expires on December 22, 2002: U.S. Patent No. 4,448,774 (the ‘774 patent).

Although the Agency considers Ascent’s Orapred to be the [RLD] for bioequivalence purposes, this does not obviate the need for WE to provide a patent certification and notification to the holder of the original listed drug upon which the approved suitability petition was based. [(emphasis added)] 

FDA later approved ANDA No. 75-250 after WE amended its pending ANDA to include a certification with respect to the Orange Book-listed patents covering Celltech’s PEDIAPRED and after WE and Celltech reached a settlement agreement concerning those patents.    

Following FDA’s determination, the Agency amended the Orange Book Preface in 2003 to include the following passage:

Patent Certification(s) Reference Listed Drug based upon a suitability petition.  An [ANDA] that refers to a [RLD] approved pursuant to a suitability petition must demonstrate that the proposed product is bioequivalent to the RLD, and it must include appropriate patent certification(s) and an exclusivity statement with respect to the listed drug which served as the basis for the approved suitability petition. [(emphasis added)]

Subsequent editions of the Orange Book have included this statement.  And in the 28th edition (2008), the statement was expanded to state:

Patent Certification(s) Reference Listed Drug based upon a suitability petition.  An [ANDA] that refers to a [RLD] approved pursuant to a suitability petition must demonstrate that the proposed product is bioequivalent to the RLD, and it must include appropriate patent certification(s) and an exclusivity statement with respect to the listed drug which served as the basis for the approved suitability petition.  This concept also applies to an ANDA applicant that cites a RLD that was based upon an NDA that is still covered by patent(s) and/or exclusivity, e.g. a second RLD that was selected when the in vivo determination of bioequivalence of the original RLD is self evident and the waiver of the in vivo determination of bioequivalence may be granted. [(emphasis added)]

Citing a 2004 FDA citizen petition response concerning Fenofibrate, Osmotica argued that FDA applies an analogous requirement with respect to a 505(b)(2) applicant who seeks to rely on the Agency’s findings of safety or effectiveness for a listed drug that is a 505(b)(2) application that itself relied on a previous 505(b)(1) NDA for approval.  Specifically, FDA stated in 2004 that:

Where a 505(b)(2) application seeks to rely on the finding of safety or effectiveness for a listed drug that is a 505(b)(2) NDA which, itself, relied on a previous finding of safety and effectiveness, the 505(b)(2) applicant should certify to the patents of the 505(b)(2) NDA relied on, as well as to the patents of any underlying NDA on which that approved 505(b)(2) NDA relied for approval. [(emphasis added)]

Given these precedents, Osmotica argued that:

FDA should announce and apply a similar policy here, where the ANDA applicant . . . relies on FDA’s previous findings of safety and effectiveness of a listed drug (Osmotica’s venlafaxine product) that was the subject of  a 505(b)2) application which, itself, relied on a previous finding of safety and effectiveness, namely FDA’s finding of safety and effectiveness of Effexor XR Capsules.

FDA determined otherwise, however, stating that “[t]here is no basis in the Hatch-Waxman statutory scheme and our implementing regulations for requiring an ANDA applicant seeking approval of a ‘duplicate’ of the RLD to provide a patent certification or statement with respect to any patents other than those filed by the NDA holder for the RLD for listing in the Orange Book.”  With respect to FDA’s policy that an ANDA that is submitted against another ANDA that was itself submitted and approved pursuant to a suitability petition must contain an appropriate certification with respect to any Orange Book-listed patents covering the original RLD NDA relied on by the ANDA suitability petition applicant for approval, FDA commented that:

There is a clear regulatory distinction between reliance on an RLD approved for safety and effectiveness under section 505(c) of the Act (i.e., a stand-alone NDA or a 505(b)(2) application) and reference to a petitioned ANDA designated as the RLD for bioequivalence testing. . . .  unlike a 505(b)(2) applicant, an ANDA applicant is not required (or permitted) by statute to file patent information with FDA for listing in the Orange Book.  Thus, a subsequent ANDA applicant that refers to a petitioned ANDA is required to submit an appropriate patent certification or statement for the listed drug identified in the suitability petition upon which the ANDA necessarily relies.  In the absence of this patent certification requirement, a subsequent ANDA applicant could circumvent the patent certification process by submitting an ANDA that references another ANDA and for which no patents can be listed . . . .

And with respect to FDA’s 2004 statement concerning 505(b)(2) applicants, FDA provided a hypothetical situation and commented that:

Although we noted in the Fenofibrate Petition Response that a 505(b)(2) applicant seeking approval for a drug product that relies upon FDA’s finding of safety and/or effectiveness for a drug product approved through the 505(b)(2) pathway ‘should certify to the patents of the 505(b)(2) NDA relied on, as well as to the patents of any underlying NDA on which that approved 505(b)(2) NDA relied for approval’ . . . this was not the situation at issue in the Fenofibrate Petition.  We subsequently have required an appropriate patent certification or statement to an ‘underlying NDA’ only if the subsequent 505(b)(2) applicant specifically relied for approval on the drug product approved in the underlying NDA. . . .” (italics in original; bold italics added).

By Ricardo Carvajal & Diane B. McColl –

In the fourth and most recent draft of the framework of its Animal Feed Safety System (“AFSS”), FDA provides a comprehensive overview of the system and of the significant gaps in that system that FDA intends to address (the AFSS is “FDA’s program for animal feed aimed at protecting human and animal health by ensuring production and distribution of safe feed,” and it covers both feed for food-producing animals and pet food).  FDA’s task is daunting, as illustrated by this partial list of items on FDA’s to-do list:

• In accord with the FDA Amendments Act of 2007 (“FDAAA”), FDA’s Center for Veterinary Medicine (“CVM”) intends to establish feed ingredient standards and definitions through notice-and-comment rulemaking.  Before enactment of the FDAAA, FDA had planned to establish a policy recognizing the acceptability of ingredients defined in the Association of American Feed Control Officials’ (“AAFCO”) Official Publication.

• CVM plans to develop process control regulations (e.g., HACCP) to address “feed safety issues associated with the manufacture, packaging, storage, and distribution of non-medicated feed ingredients and mixed feed” (such controls are already in place for medicated feed).

• CVM intends to modernize the GMP regulations for medicated feeds.

• As required by the FDAAA, CVM plans to issue a regulation that sets standards for the provision of nutrition and ingredient information on the label of pet foods.

The draft also confirms that CVM plans to start a pilot program to process voluntary notifications of self-determinations of Generally Recognized as Safe (“GRAS’) status for animal feed and pet food ingredients. An Ingredient Safety Team has been created in CVM’s Division of Animal Feeds to review the GRAS Notices. CVM's pilot GRAS Notice program is expected to commence upon publication of a forthcoming Federal Register notice, which we understand will explain the differences between the CVM GRAS Notice program and the Center for Food Safety and Applied Nutrition GRAS Notice program for human food ingredients.

By Kurt R. Karst –      

Now that we are a little more than six years after the December 8, 2003 enactment of Title XI of the Medicare Modernization Act (“MMA”), which, among other things, amended the FDC Act to create a new 180-day exclusivity regime for generic drugs – and as we patiently wait for FDA to issue proposed regulations to implement the forfeiture provisions, as well as a decision from the D.C. Circuit in the generic COZAAR/HYZAAR 180-day exclusivity litigation – we thought it would be a worthwhile exercise to take stock of the cases in which FDA has made a determination about 180-day exclusivity forfeiture. 

The MMA added six 180-day exclusivity forfeiture provisions at FDC Act § 505(j)(5)(D)(i).  Based on our research, FDA has made a total of 13 forfeiture decisions since 2003, with most (10) of those decisions concerning a first applicant’s failure to obtain tentative approval within 30 months of ANDA submission (FDC Act § 505(j)(5)(D)(i)(IV)).  However, we note that of these 10 decisions, 5 of them are so-called “punts” in which FDA did not make a formal forfeiture determination at the time of ANDA approval and stated it would do so only if another applicant becomes eligible for approval within 180 days after exclusivity is triggered.  None of these determinations were affected by a citizen petition.  (Congress clarified FDC Act § 505(j)(5)(D)(i)(IV) in the 2007 FDA Amendments Act, in which it provided that for an applicant eligible for 180-day exclusivity, if “approval of the application was delayed because of a 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)).)  In addition, there has been one case in which tentative approval was not obtained within 30 months of ANDA submission, but FDA determined that exclusivity was not forfeited because of a change in or review of ANDA approval requirements – ANDA No. 77-532 (Acarbose Tablets, 25 mg, 50 mg, and 100 mg); FDA Letter Decision (FDA ruled “that a change in bioequivalence requirements resulted in a delay in obtaining a tentative approval” and did not result in a forfeiture under FDC Act § 505(j)(5)(D)(i)(IV)).  In the Acarbose case, altough a citizen petition was submitted to FDA, because the petition was submitted after the date that was 30 months after ANDA submission, it did not implicate FDC Act § 505(q)(1)(G). 

Of the 3 remaining decisions, 2 of them (both litigated) are under the failure to market provisions (FDC Act § 505(j)(5)(D)(i)(I)) and one is under the withdrawal of application provision (FDC Act § 505(j)(5)(D)(i)(II)).  There do not appear to be any decisions with respect to 3 forfeiture provisions – amendment of certification (FDC Act § 505(j)(5)(D)(i)(III)), agreement with another applicant (FDC Act § 505(j)(5)(D)(i)(V)), expiration of all patents (FDC Act § 505(j)(5)(D)(i)(VI)).  The table below summarizes FDA’s forfeiture decisions by year and type.

Information on each of the 180-day exclusivity forfeiture decisions in the table above is provided below.

Failure to Market (FDC Act § 505(j)(5)(D)(i)(I)) – 

• ANDA No. 77-847 – Dorzolamide HCl, 2%; Timolol Maleate, 0.5%, Ophthalmic Solution (October 28, 2008); FDA Letter Decision

• ANDA No. 77-532 – Acarbose Tablets, 25 mg, 50 mg, and 100 mg (May 7, 2008); FDA Letter Decision

Withdrawal of Application (FDC Act § 505(j)(5)(D)(i)(II)) – 

• Guaifenesin Extended-Release Tablets, 600 mg and 1.2 gm (FDA Paragraph IV List notation added to June 15, 2009 list update)

Amendment of Certification (FDC Act § 505(j)(5)(D)(i)(III)) – None

Failure to Obtain Tentative Approval (FDC Act § 505(j)(5)(D)(i)(IV)) – 

Actual Forfeiture

• ANDA No. 77-461 – Nateglinide Tablets, 60 mg and 120 mg (September 9, 2009); FDA Letter Decision 

• ANDA No. 78-267 – Norethindrone Acetate, 0.02MG; Ethinyl Estradiol, 1 mg  (September 1, 2009)

• ANDA No. 77-170 – Cetirizine HCl, 5 mg; Pseudoephedrine HCl, 120 mg Extended-Release Tablets (February 25, 2008)

• ANDA No. 77-219 – Irinotecan HCl Injection, 20 mg/mL (February 20, 2008)

• ANDA No. 77-631 – Cetirizine HCl Chewable Tablets, 5 mg and 10 mg (January 11, 2008)

180-Day “Punt”

• ANDA No. 78-804 – Aspirin, 25 mg; Dipyridamole, 200 mg Extended-release Capsules (August 14, 2009)

• ANDA No. 78-104 – Triamcinolone Acetonide Nasal Spray, 0.055 mg (July 30, 2009)

• ANDA No. 78-115 – Carbamazepine Extended-Release Tablets, 100 mg, 200 mg, 400 mg) (March 31, 2009)

• ANDA No. 77-527 – Drospirenone, 3 mg; Ethinyl Estradiol, 0.03 mg Tablets (May 9, 2008)

• ANDA No. 76-969 – Metoprolol Succinate Extended-Release Tablets, 25 mg, 50 mg, 100 mg, 200 mg (July 31, 2006)

Agreement with Another Applicant, the Listed Drug Application Holder, or a Patent Owner (FDC Act § 505(j)(5)(D)(i)(V)) – None

Expiration of All Patents (FDC Act § 505(j)(5)(D)(i)(VI)) – None

Hyman, Phelps & McNamara, P.C.’s Josephine Torrente will be co-chairing and speaking at ACI’s upcoming two-day Risk Evaluation and Mitigation Strategies Conference.  Ms. Torrente will be presenting on post-marketing safety requirements and applicants’ obligations under FDAAA.  The conference is scheduled for April 19-20 at the Carlton on Madison in New York City.  Registration information is available here.  FDA Law Blog readers get a discount by using the code “FDA Law” when registering.

By James R. Phelps –

By a series of treaties, the nations of the world have given the United Nations (“UN”) a significant role in the development of systems of regulation of substances, including vitally needed medicines, that might be abused.  The World Health Organization (“WHO”) provides the medical and scientific recommendations for control of these medicines that the UN will make, and which the nations are committed to follow.  So the UN decisions concerning these substances have very real consequences and the WHO recommendations are critical to the process.

The WHO review of substances for potential regulation is in the hands of expert committees that make recommendations that the agency usually accepts without change.  Last week the executive board of WHO accepted a new set of guidelines – lugubriously called “Guidance on the WHO review of psychoactive substances for international control: proposed revision” – that those committees will use in arriving at their recommendations.  This is an important development.

The new guidelines direct WHO to assure that the committees use peer-reviewed reports in their deliberations.  They provide that interested parties will have an opportunity to participate in the process to present data.  They also provide that WHO will make the reports and recommendations of the committees available for public review.  In short, the new guidelines are a significant step toward ensuring a comprehensive review of substances that may be subject to international control and creation of the kind of processes and protections that are found in the U.S. Administrative Procedure Act. 

Adoption of these new guidelines helps to improve the ability of WHO to discharge its duties with a firmer scientific and medical base.

Members of this firm actively participated in development of the guidelines.

By Ricardo Carvajal –

According to a press release issued by Senator Mark Pryor's office, Senator Pryor (D-AR) has teamed up with Senator Benjamin Cardin (D-MD) to introduce the Nanotechnology Safety Act of 2010.  The bill, introduced on January 21, 2010 as S. 2942, is intended "to address potential health and safety risks about products that contain nanotechnology materials."  The legislation would "establish a program within the [FDA] to assess the health and safety implications of nanotechnology in everyday products and develop best practices for companies who employ nanotechnology."  Further, the legislation would authorize $25 million per year from 2011 through 2015 for the program; currently, FDA does not receive nanotechnology-specific funding.  We will provide a summary of the legislation when it becomes available.

By Peter M. Jaensch & John R. Fleder –

The January 21, 2010 Federal Register contains a notice that the United States Sentencing Commission has proposed amendments to the Sentencing Guidelines and their Commentary concerning corporations and other business organizations.  In addition, the Commission has raised an issue seeking public comment.

The proposed amendments address steps corporations are expected to take when the corporation detects that it has engaged in criminal conduct. The organization “should respond appropriately”, including, where there is an identifiable victim or victims, making restitution and remediating the harm caused, presumably even before a company is convicted of a crime.  The Commission believes that compliance might require self-reporting and cooperation with authorities, as well as other forms of remediation. Organizations would also be expected to evaluate their compliance and ethics program and make necessary changes to avoid recurrences of criminal behavior.  Further, the amendment adds to the responsibilities of high-level personnel, specifying that such employees “should be aware of the organization’s document retention policies” and should ensure that these policies are consistent with an effective compliance program.

The notice also opens for comment the question whether an organization should receive a reduction in the level of the offense, thereby lowering the sentencing range, if it: (a) structures responsibility so that operational compliance officers report directly to the company’s board, (b) the compliance section of the company detects a violation prior to actual or likely discovery outside the organization, and (c) the organization reports the violation promptly to the authorities.

If enacted, these amendments could have significant effect on corporate structure and decision-making.

The Commission has invited public comments to be submitted by March 22, 2010.  It has indicated that it will also hold a public hearing on the proposed amendments discussed above, as well as the other amendments to the Sentencing Guidelines that are included in the January 21, 2010 Federal Register notice.

By Kurt R. Karst –      

FDA’s Office of Orphan Products Development (“OOPD”) surpassed the 2,000 orphan drug designation mark in 2009 and designated a near-record 160 products for orphan (i.e., rare) diseases and conditions.  FDA also approved 17 orphan products in 2009, according to data taken from OOPD’s new orphan drug designation database.  The 2009 orphan drug designation figure continues a trend in an increase in designations in recent years.  As we previously reported, in 2008, OOPD designated a record 165 products. 

The tables below illustrate OOPD’s designation and FDA’s orphan drug approval track record since the enactment of the Orphan Drug Act in 1983.

Coincidentally, the Tufts Center for the Study of Drug Development just issued an Impact Report (subscription required) analyzing orphan drug designations.  According to that report:

• During the 2000s, orphan products comprised 22% of all new molecular entities (NMEs) and 31% of all significant biologics (SBs) receiving U.S. marketing approval.

• Orphan products receiving priority review status rose from 35% of all orphan NMEs in 2000-02 to 50% in 2006-08; during the same time the share of orphan SBs receiving priority review status rose from 17% to 67%.

• While biotech firms during the 2000s garnered, on average, about one-third of all orphan drug approvals, they received just over 50% of orphan drug designations.

• Sponsors engaged in clinical development funded through orphan grants reported that 22% of their programs led to approvals, which compares with a clinical approval success rate of 16% among mainstream drug developers.

By Kurt R. Karst –      
 
Massachusetts-based The Medicines Company (“TMC”) has lost its latest battle with the U.S. Patent and Trademark Office (“PTO”) for a Patent Term Extension for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering ANGIOMAX (bivalirudin), a drug product FDA first approved late on Friday, December 15, 2000 under New Drug Application (“NDA”) 20-873.  The ‘404 patent expires on March 23, 2010, but is subject to a 6-month period of pediatric exclusivity that will expire on September 23, 2010, when generic competition is anticipated (notwithstanding the recent addition of two new patents to the Orange Book for ANGIOMAX).  As we previously reported, TMC submitted a PTE application to the PTO 62 days after FDA approved the company’s ANGIOMAX NDA.  Under 35 U.S.C. § 156(d)(1), the submission of a PTE application must occur “within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use” (i.e., within 60-days of the date of NDA approval).  In March 2002, and again in April 2007, the PTO denied the PTE request as untimely.  Since then, TMC has agressively – and thus far unsuccessfully – sought a PTE for the ‘404 patent at the PTO and on Capitol Hill (see our previous posts here, here, and here). 

As we recently reported, in December 2009, TMC submitted a Petition and a Request for Reconsideration of its PTE application to the PTO.  The Petition requested that the PTO suspend its regulations at 37 C.F.R. § 1.750 “to the extent they limit requests for reconsideration of patent term extension applications to a single submission within the times specified in the rule.”  TMC previously requested reconsideration of the PTO’s denial of a PTE for the ‘404 patent on the basis that the date of approval of the ANGIOMAX NDA was in fact first effective as of Monday, December 18, 2000, the next business day after the December 15, 2000 NDA approval.

The Request for Reconsideration requested the PTO to employ a “rule of construction” under which the Office would consider the 60-day PTE application submission period at 35 U.S.C. § 156(d)(1) to commence on the first business day after the day the FDA transmits notice of NDA approval of the drug product if that transmittal occurs after normal business hours.  In the case of the PTE application for the ‘404 patent covering ANGIOMAX, that would mean the 60-day period would have begun on December 18, 2000 and the PTE application would have been timely filed within 35 U.S.C. § 156(d)(1). 

Among other things, TMC argued that its Request for Reconsideration is “particularly appropriate in this case” given the PTO’s “newly announced approach to counting days under § 156(d)(1).”  The PTO, after being challenged as to the date on which the 60-day period at 35 U.S.C. § 156(d)(1) begins, ruled in the context of another PTE application that although the PTO had in some instances started counting the 60-day period on the date after NDA approval, “[b]y not counting the date of FDA approval as one of the sixty days included in the time period for filing a PTE application, the USPTO was failing to comply with section 156 and case law.” 

In its January 8, 2010 decision, the PTO granted TMC’s Petition, stating:

The USPTO is persuaded by Applicant's argument for suspension of Rule 750 under the terms of Rule 183. That latter regulation states: "In an extraordinary situation, when justice requires, any requirement of the regulations in this part which is not a requirement of the statutes may be suspended or waived by the Director or the Director's designee, sua sponte, or on petition of the interested party, subject to such other requirements as may be imposed." 37 C.F.R. § 1.183. Since the USPTO has corrected its methodology of counting the time period of 35 U.S.C. § 156(d)(1) to conform with the express language of the statute and first applied its corrected counting methodology in finally denying Applicant's PTE application, the USPTO finds that justice favors giving Applicant the opportunity to address the denial of its PTE application under the USPTO new counting methodology. Accordingly, Applicant's petition filed under Rule 183 to suspend Rule 750 is GRANTED. [(italics and emphasis in original)]

However, TMC ultimately lost when the PTO denied the company’s Request for Reconsideration:

Applicant raises numerous arguments why the USPTO should consider its PTE application for the ' 404 patent based on the regulatory review period for Angiomax® (bivalirudin) timely filed under section 156(d)(1). Distilling those arguments to their core, Applicant asserts that the 60-day time window of section 156(d)(I) should not commence until an applicant can "be deemed to be on notice" of the FDA approval. Request for Reconsideration at 11. Because the USPTO finds that the section 156(d)(1) expressly sets forth the trigger date for compliance with section 156(d)(1) as the date the applicant may commercially market or use the approved product, which is the date of NDA approval, and does not take an applicant's receipt of such notice into consideration, the USPTO considers Applicant's arguments to be unpersuasive. The present request for reconsideration of the denial of the PTE application for the '404 patent therefore is DENIED. [(emphasis in original)]

TMC’s latest loss at the PTO is unlikely to be the last we hear from the company on this topic.  A lawsuit against the PTO is not out of the question.  And although TMC’s efforts to lobby Congress to pass legislation that would amend 35 U.S.C. § 156 to permit the PTO to accept the late filing of a PTE application for the ‘404 patent have not yet been fruitful, we understand that a deal is in the works (or at least was until the Massachusetts election on Tuesday) to include a provision in the Health Care Bill that would extend the '404 patent. 

Hyman, Phelps & McNamara, P.C.’s Ricardo Carvajal will be speaking at FDLI’s upcoming Introduction to Food Law and Regulation: A Program on Understanding How the Government Regulates the Food Industry.  Mr. Carvajal will be presenting on food safety and unintended components/contaminants in food.  The conference is scheduled for January 25-26 at the Park Hyatt Hotel in Washington, DC.  This conference will be immediately followed by a second FDLI conference, Food Hot Topics, scheduled for January 27-28.  Registration information for both conferences is available here.

By Peter M. Jaensch –

On January 14, 2010, the U.S. Attorney’s Office for the District of Massachusetts issued a statement  announcing the charging of Doctor Scott Reuben, a former Chief of Acute Pain at Bay State Hospital in Springfield, Massachusetts, with one count of health care fraud (18 U.S.C. §1347), alleging that Dr. Reuben falsified medical research.

The Information filed in the case alleges that Dr. Reuben sought and obtained research funding to study drugs used in multimodal analgesia therapy from companies manufacturing such drugs. In his proposals to these companies, Dr. Reuben represented that he would perform clinical trials and present the results in an article for publication. However, the government alleges that he never enrolled any patients and simply fabricated his results, which he then presented as legitimate research. Although the government alleges an overarching course of conduct extending back to at least 1999, the specific charges are based on the defendant’s alleged fraud against Pfizer, Inc. in connection with a study of its drug Celebrex.

Dr. Reuben has entered a plea agreement with the government in which he agrees, among other things, to make substantial restitution to several pharmaceutical companies. The agreement has not yet been accepted by the court. What effect the revelation of this fraud may have in the wider healthcare and clinical research communities remains to be seen.

By Ricardo Carvajal –

While calling for further research on bisphenol A ("BPA"), a chemical used in the manufacture of some plastics, FDA has acknowledged that it has "some concern about the safety of BPA:" 

At this interim stage, FDA shares the perspective of the National Toxicology Program that recent studies provide reason for some concern about the potential effects of BPA on the brain, behavior, and prostate gland of fetuses, infants and children.  FDA also recognizes substantial uncertainties with respect to the overall interpretation of these studies and their potential implications for human health effects of BPA exposure.  These uncertainties relate to issues such as the routes of exposure employed, the lack of consistency among some of the measured endpoints or results between studies, the relevance of some animal models to human health, differences in the metabolism (and detoxification) of and responses to BPA both at different ages and in different species, and limited or absent dose response information for some studies.

FDA is pursuing additional studies to address the uncertainties in the findings, seeking public input and input from other expert agencies, and supporting a shift to a more robust regulatory framework for oversight of BPA to be able to respond quickly, if necessary, to protect the public.

In addition, FDA is supporting reasonable steps to reduce human exposure to BPA, including actions by industry and recommendations to consumers on food preparation.  At this time, FDA is not recommending that families change the use of infant formula or foods, as the benefit of a stable source of good nutrition outweighs the potential risk of BPA exposure.

The agency is directing consumers to a list of "reasonable steps families and parents can take to minimize exposure to BPA" issued by the Department of Health and Human Services ("HHS").  According to HHS, domestic manufacturers have largely abandoned the use of BPA in the manufacture of bottles and cups for infants.  With respect to liquid infant formula sold in cans, HHS made clear that "[i]nfant formula in this packaging can offer important health advantages for some infants, and the proven benefit of good nutrition outweighs the potential risk of BPA exposure."  With respect to powdered infant formula mix, HHS noted that it "typically has no detectable level of BPA."

FDA's statement that it is "supporting a shift to a more robust regulatory framework for oversight of BPA" is of special interest to manufacturers.  The current food contact uses of BPA were approved through the issuance of food additive regulations before the advent of the notification process currently used for food contact substances.  Food additive regulations are not specific to manufacturers; thus, any manufacturer can use BPA consistent with an approving regulation without notifying the agency.  Further, amending or revoking a food additive regulation requires FDA to engage in rulemaking.  In contrast, food contact notifications are specific to manufacturers, and FDA can deem a food contact notification to no longer be "effective" upon written notice to the notifier and publication of a Federal Register notice – a mechanism that is much less burdensome than rulemaking. 

By Susan J. Matthees –

In July 2008, we blogged about the U.S. District Court for the Central District of California’s decision that found Purely Juice, Inc. liable under the Lanham Act for false advertising related to its pomegranate juice product.  Last month, the U.S. Court of Appeals for the Ninth Circuit affirmed the lower court’s decision, meaning Purely Juice must pay POM Wonderful damages of over $1 million, attorneys fees of over $600,000, and a disgorgement of profits of over $300,000. 

Purely Juice’s appeal contended, in part, that the district court’s standard for purity interfered with the authority of FDA.  The Ninth Circuit stated “POM did not sue to enforce the FDCA, and the facts show no encroachment on the FDA’s authority.”  The Ninth Circuit also held that the district court did not err by finding the Purely Juice had the requisite knowledge that its product was not 100% pure pomegranate juice and without sugar added, and that the president and founder of Purely Juice was personally liable.