By Kurt R. Karst –      

The number of citizen petitions pending at FDA concerning Hatch-Waxman exclusivity continues to pile up.  As we previously reported (here and here), FDA has already been asked on three separate occasions in 2013 to recognize 5-year New Chemical Entity (“NCE”) exclusivity for a fixed-dose combination drug product containing both a never-before-approved active moiety and a previously approved active moiety: (1) NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets (Docket No. FDA-2013-P-0471); (2) STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (Docket No. FDA-2013-P-0058); and (3) PREPOPIK (sodium picosulfate, magnesium oxide and citric acid) for Oral Solution (Docket No. FDA-2013-P-0119).  Later on in the year, Eisai Inc. (“Eisai”) petitioned FDA – Docket No. FDA-2013-P-0884 – arguing that the Agency erroneously triggered 5-year NCE exclusivity for BELVIQ (lorcaserin HCl) Tablets and FYCOMPA (perampanel) Tablets before the drugs were scheduled by the Drug Enforcement Administration (“DEA”) under the Controlled Substances Act (“CSA”), and thus, before commercial marketing could occur (see our previous post here).  Now come two more petitions on Hatch-Waxman exclusivity – one petition (Docket No. FDA-2013-P-1397) from UCB, Inc. (“UCB”) concerning 5-year NCE exclusivity for VIMPAT (lacosamide), and another petition (Docket No. FDA-2013-P-1376) from Covis Pharma S.à.r.l. (“Covis”) concerning 3-year new clinical investigation exclusivity for LANOXIN (digoxin) Tablets.  A denial of any one or more of these six petitions could very well end up in court with a potentially landscape-changing result.  Below is a run-down of the two latest citizen petitions.

VIMPAT (lacosamide) – Docket No. FDA-2013-P-1397

Similar to Eisai, UCB argues in its petition that FDA erroneously started the clock running on NCE exclusivity for lacosamide before scheduling of the drug under the CSA was completed by the DEA, thereby paving the way for UCB to market the product.  According to UCB, 233 days of exclusivity was lost, because lacosamide was not scheduled until May 21, 2009 when the DEA issued a final rule placing the drug into Schedule V,  “and the Department of Justice’s letter to each House of the Congress and the Comptroller General, transmitting the final rule scheduling lacosarnide, was received on June 9, 2009.” 

FDA has approved three NDAs for UCB’s lacosamide: NDA No. 022253 (tablets; approved on October 28, 2008), NDA No. 022254 (intravenous solution; approved on October 28, 2008), and NDA No. 022255 (oral solution; aproved on April 20, 2010).  In addition to the same two patents listed in the Orange Book for all three dosage form NDAs, the Orange Book also lists a period of NCE exclusivity that expired on October 28, 2013.  According to FDA’s Paragraph IV Certifications List, the Agency received ANDAs containing Paragraph IV certifications for generic versions of VIMPAT Oral Solution and VIMPAT Tablets on Monday, October 29, 2012 (the so-called NCE-1 date).  In fact, UCB says in the petition that the company received 19 Paragraph IV certification notices from 16 different companies!  (Possibly a new Hatch-Waxman record.)

Although UCB adopts the rational proffered by Eisai in its petition, UCB’s requested action differs somewhat from that of Eisai, likely because of the expired status of NCE exclusivity for the drug.  In addition to requesting that FDA “determine that the NCE exclusivity for lacosamide began on June 9, 2009, and thus will end on June 9, 2014,” UCB requests that FDA “confirm that the Agency will stay approval of [pending ANDAs], and any additional ANDA that meets the criteria under [FDC Act § 505(j)(5)(B)(iii)], absent another specified event under [FDC Act § 505(j)(5)(B)(iii)], until December 7, 2016.”  That is, UCB requests that the 30-month litigation stay on ANDA approval be extended from April 28, 2016, which is 7.5 years after NCE NDA approval, until December 7, 2016, which is 7.5 years after NCE NDA approval plus 223 days (or simply 7.5 years after UCB argues NCE exclusivity began). 

Curiously, UCB does not argue that each of the Paragraph IV ANDAs submitted to FDA on October 29, 2012 should be rejected as premature.  After all, if the NCE exclusivity began on June 9, 2009 as UCB argues, then the NCE-1 date for Paragraph IV ANDA submissions would have been June 9, 2013.  In that case, the ANDAs submitted in October 2012 were premature and should have been rejected by FDA. 

LANOXIN (digoxin) Tablets – Docket No. FDA-2013-P-1376

In what Covis says is a case of first impression, the company argues in its petition that FDA erroneously determined that periods of 3-year new clinical investigation that were granted with respect to two strengths of LANOXIN (digoxin) Tablets – 0.0625 mg and 0.1875 mg – have expired.  FDA approved six strengths of LANOXIN under NDA No. 020405 on September 30, 1997: 0.125 mg, 0.250 mg, 0.375 mg, 0.500 mg, 0.0625 mg, and 0.1875 mg.  Only two strengths have been marketed since NDA approval: 0.125 mg and 0.250 mg.  According to the 2000 edition of the Orange Book, the period of 3-year exclusivity for each strength (coded as “I-194” and defined in an Orange Book addendum as “CONGESTIVE HEART FAILURE”) expired on September 30, 2000. 

Although Covis does not disagree with FDA’s decision to aware 3-year exclusivity for all six strengths, the company contends that the periods of exclusivity for the 0.0625 mg and 0.1875 mg strengths did not begin to run until October 17, 2013 when FDA approved a Prior Approval Supplement (“PAS”) for them:

FDA’s complete administrative record for NDA 20-405 shows that the Agency only fully approved two of the six dosage strengths in that NDA.  This fact is confirmed by the Agency’s requirement that Covis submit a [PAS], CMC dissolution data for the new strengths (0 .0625 mg and 0.1875 mg), and draft labeling for the new strengths, and that FDA conduct a prior approval inspection.  The FDA inspector also directed Covis to be in compliance with all blend uniformity testing requirements. . . .  In the present case, the awarded exclusivity did not begin running for the four never-marketed strengths.  These four strengths could not have been fully approved in 1997 because FDA would not permit Covis to market the two new strengths before the Agency reviewed and approved new data and information.  Covis has only now submitted a PAS with necessary labeling – an approval requirement for an NDA or an [ANDA].  Furthermore, Covis has only now submitted contemporary CMC dissolution data, another pre-approval requirement.  These elements of approval, coupled with the prior approval inspection of Covis’ contract manufacturer and FDA’s direction that Covis comply with all appropriate blend uniformity testing requirements, confirm that this data and information are critical pre-approval and not post-approval requirements.  This conclusion is confirmed by the Agency’s administrative record for this NDA, particularly FDA’s 1997 approval letter and the 2012-2013 communications between FDA and Covis regarding the new strengths.

Although the petition does not specifically concern the two remaining never-before marketed strengths – 0.375 mg and 0.500 mg – Covis would presumably argue that a similar argument would apply to them if they are subsequently approved in a PAS.  

Accordingly, Covis requests that FDA:

(1) Confirm that the Agency did not fully approve the 0.0625 mg and 0.1875 mg tablets on September 30, 1997 in NDA 20-405 because of: (a) the language in the administrative record; (b) the recently-required submission of draft labeling and CMC dissolution data for the two new dosage strengths; (c) the recently-required submission of a PAS; (d) the recent prior approval inspection; and (e) the FDA inspector’s direction that Covis be in full compliance with all blend uniformity testing requirements;

(2) Confirm that three-year exclusivity was awarded but never began running for these two dosage strengths that have never been marketed under NDA 20-405, despite their listing in FDA’s Orange Book; and

(3) Confirm that Covis is therefore entitled to a period of three-year marketing exclusivity for the 0.0625 mg and 0.1875 mg dosage strength products that began running upon PAS approval.

In a separate citizen petition – Docket No. FDA-2013-P-1377 – Covis requests that FDA require ANDA sponsors seeking approval of generic LANOXIN Tablets, 0.0625 mg and 0.1875 mg, to meet certain requirements. 

By Ricardo Carvajal –

The National Nanotechnology Initiative ("NNI") released its draft 2014 Strategic Plan for comment.  The draft plan lays out the NNI’s goals and objectives, which remain largely unchanged from 2011 (see here).  As with the 2011 Plan, the draft 2014 Plan includes a description of FDA’s NNI-related activities.  Those activities continue to be primarily focused on the goal of supporting responsible development of nanotechnology.  However, the 2014 Plan more explicitly recognizes the potential impact of nanotechnology on the status of FDA-regulated products:

The use of nanotechnology can alter the safety, effectiveness, performance, and/or quality of FDA-regulated products.  For this reason, FDA is interested in additional scientific information and tools to help better detect and predict potential effects of such changes on human or animal health.

This statement is consistent with FDA’s issuance last year of nanotech-related draft guidance documents that address the safety of nanomaterials in cosmetic products, as well as the potential impact of manufacturing changes (including emerging technologies) on the safety and regulatory status of food ingredients and food contact substances (see our previous post here).  Those documents put industry on notice that FDA expects manufacturers to assess any potential impact of the use of nanotechnology on the regulatory status of their products prior to marketing.

As the 2014 Plan was being released for comment, the New York Academy of Sciences hosted a conference on potential scientific and regulatory gaps that could be holding back the growth and development of nanomedicine (defined as “the application of nanotechnology for the treatment, diagnosis, monitoring, and control of biological systems”).  Among other things, the conference touched on the following issues:

• Characterization – The National Characterization Laboratory ("NCL") of the National Cancer Institute addressed the challenges associated with characterization of nanomaterials (NCL provides free characterization and safety testing of nanoparticles intended for use as cancer therapies or diagnostics – see here).
• “Nanosimilars” – Several presenters discussed follow-on therapeutics, referred to in this context as nanosimilars, with particular attention to the differences that slight changes in manufacturing could have on a product’s safety and efficacy (see, e.g., here).
• Regulatory and patent issues – Summaries were provided of the FDA’s and the European Medicines Agency’s approaches to regulation of products derived through nanotechnology, as well as obstacles posed by the proliferation of nanotech-related patents (see, e.g., here).
• Classification and nomenclature – The definition of nanotechnology in the context of pharma R&D continues to be an issue of concern to some observers (see here).

Notwithstanding these and other challenges, case studies of several marketed products made clear that success is possible, and suggest that the potential benefits of nanotechnology in the medical products sector have only just begun to be tapped.

By Kurt R. Karst –      

After more than three years of litigation that started with a July 2010 Complaint filed in the U.S. District Court for the Southern District of New York (see our previous post here), and that went up to the U.S. Court of Appeals for the Second Circuit (see our previous post here), the Natural Resources Defense Council (“NRDC”) recently announced that FDA agreed to finalize its topical antimicrobial drug products Over-the-Counter (“OTC”) drug monograph with respect to triclosan.  The agreement comes in the form of a Consent Decree in which FDA agreed to timetables for completing action on various topical antimicrobial drug product monograph subcategories involving triclosan: Consumer Antiseptic Hand Wash Products Monograph; Healthcare Antiseptic Products Monograph; and Consumer Antiseptic Hand Rub Products Monograph.  (These subcategories are laid out by FDA in a Declaration submitted to the district court in August 2013 explaining the Agency’s plans for the topical antimicrobial monograph.) 

The use of triclosan in OTC drug products, such as in soaps and hand sanitizers, has been controversial.  It has been alleged by some – including the NRDC and some Members of Congress (here and here) – to be an endocrine disruptor that has been linked to reproductive and developmental harm. 

As we previously reported (here and here), the NRDC initially alleged that FDA has unreasonably delayed in violation of the Administrative Procedure Act the publication of a final OTC drug monograph with respect to both triclosan and a related ingredient, triclocarban.  FDA challenged the NRDC’s standing to sue in this matter, and in January 2011, the New York District Court ruled from the bench granting FDA’s Motion to Dismiss for lack of standing.  The NRDC appealed that decision to the Second Circuit, which vacated that decision in March 2013 with respect to triclosan (but not triclocarban) and remanded the case to the district court for further proceedings.  The NRDC subsequently filed an Amended Complaint limited to triclosan. 

At a July 19, 2013 status conference before district court Judge Alvin K. Hellerstein, FDA agreed to submit a specific, non-binding timetable for completing its regulation of triclosan.  That ultimately led to the Consent Decree, which includes the following terms (timetables) for addressing triclosan in OTC drug products:

a. Consumer Antiseptic Hand Wash Products Monograph

i.  Publication of tentative final monograph.  December 16, 2013

ii. Comment period for tentative final monograph.  June 16, 2014

iii.  End of period to submit new data and information for tentative final monograph.  December 16, 2014

iv. Rebuttal comment period for tentative final monograph.  February 17, 2015

v. FDA review of comments, data, and information; drafting of the final monograph; and final review and approval by FDA, Department of Health and Human Services, and Office ofManagement and Budget.  August 31, 2016

vi.  Publication of Final Monograph.  September 15, 2016

b. Healthcare Antiseptic Products Monograph

i.  Publication of tentative final monograph.  April 30, 2015

ii.  Comment period for tentative final monograph.  October 31, 2015

iii.  End of period to submit new data and information for tentative final monograph.  April 30, 2016

iv. Rebuttal comment period for tentative final monograph.  June 30, 2016

v. FDA review of comments, data, and information; drafting of the final monograph; and final review and approval by FDA, Department of Health and Human Services, and Office of Management and Budget.  December 31, 2017

vi.  Publication of Final Monograph.  January 15, 2018

c.  Consumer Antiseptic Hand Rub Products Monograph

i.  Publication of tentative final monograph.  June 30, 2016

ii.  Comment period for tentative final monograph.  December 31, 2016

iii.  End of period to submit new data and information for tentative final monograph.  June 30, 2017

iv. Rebuttal comment period for tentative final monograph.  August 31, 2017

v. FDA review of comments, data, and information; drafting of the final monograph; and final review and approval by FDA, Department of Health and Human Services, and Office of Management and Budget.  March 31, 2019

vi.  Publication of Final Monograph.  April 15, 2019

In addition, FDA agreed to submit to the district court and to the NRDC status reports every 6 months (until each monograph is completed) containing a description of the actions taken by FDA to meet the terms of the Consent Decree during the previous 6 months, and what actions the Agency intends to take during the next 6 months.

Although the Consent Decree applies only to triclosan OTC drug monograph proceedings, it seems highly unlikely that FDA will limit work on these monographs to that condition.  Instead, FDA will likely work to complete them in their entirety.

The NRDC case is not the first time FDA has been sued – or otherwise pressured – to take action on long-pending administrative actions.  As we previously reported, the NRDC successfully sued FDA over the Agency’s failure to take action to withdraw approval of certain uses of certain classes of antibiotics in food-producing animals pursuant to notices FDA issued in 1977.  In addition, in the OTC drug arena, Congress has had to step in to pressure FDA to take action with respect to sunscreen drug products (see here and here).  

The American Conference Institute will be holding its inaugural forum on controlled substances in Washington, D.C. from Thursday January 16 to Friday, January 17, 2014.  A copy of the conference program can be obtained here.  Hyman, Phelps & McNamara, P.C.’s John A. Gilbert will be presenting at the conference in a session titled “Setting the Stage: Overview of DEA and FDA Regulation of Pharmaceutical Controlled Substances.”  The conference will include presentations from other regulatory and legal experts on myriad topics, including presentations from key government officials, such as Drug Enforcement Administration Chief Counsel Wendy Goggin, and US Department of Justice Assistant United States Attorney (Civil Fraud Section) Shana T. Mintz. 

FDA Law Blog is a conference media partner.  As such, we can offer FDA Law Blog readers a special $300 discount off the current price tier.  The discount code is: FLB.  We look forward to seeing you at the conference.

We at the FDA Law Blog (and Hyman, Phelps & McNamara, P.C.) have a lot to be thankful for this Thanksgiving and holiday season.  Thanks to our loyal readers, earlier this week, the American Bar Association (“ABA”) named our blog to the 2013 (and 7th Annual) ABA Journal Blawg 100 – the top 100 best blogs for a legal audience.  This is the third time we have made the list, and it means we get to add to our blog home page yet another coveted badge.

We share the 2013 Blawg 100 honors with several other blogs we regulary read, including Drug and Device Law blog, which is another blog in the “Torts” category the ABA placed us into, and Patent Docs in the “IP” category.  In addition to naming the 2013 Blawg 100, the ABA Journal has added 10 more bloggers to its Blawg 100 Hall of Fame, which was started in 2012.  We hope to make it on to that list of esteemed bloggers one day.

“In our 7th year selecting the Blawg 100, we recognize that it takes more than luck to make it onto our list.  Bloggers with the creativity to attract readers to their blogs and keep them engaged continue to be a pleasure to celebrate each year,” said ABA Journal Editor and Publisher Allen Pusey.  And with respect to the FDA Law Blog, one reader’s comment was singled out as to why we won her vote.  “I really enjoy posts from this blog as the authors manage to extract the essentials and present them in layman’s words for all to understand,” said Jennifer Ng from Abbott Point of Care in Ottawa, Canada.  “We all have access to similar information from the government (e.g., FDA draft guidances, etc.) but this blog not only explains the changes well, it also analyzes the parallels with similar previous situations—and references!  This is the one blog that I read every day.”  Thanks Jennifer – and thanks to all of our readers for a making 2013 another banner year for the FDA Law Blog (our 7th)! 

Now that the editors have made their picks, the ABA Journal is asking readers to weigh in and vote on their favorites in each of the 7th Annual Blawg 100’s 13 categories.  You can place your vote here after a quick (and free) registration.  Voting ends at close of business on Dec. 20, 2013.  Our competition in the “Torts” category includes Drug and Device Law blog, Overlawyered, Litigation & Trial, and Abnormal Use.

REMINDER: You can follow FDA Law Blog on Twitter @fdalawblog

By Kurt R. Karst –      

“Oddities” are not the sole domain of the world of antiques and other rarities (for those of you who are fans of the television show that focuses on the day-to-day operation of Obscura Antiques & Oddities).  Food and drug law – and in particular Hatch-Waxman – has its own oddities.  Over the years we’ve seen a lot of Hatch-Waxman oddities.  And they’re often discovered in the listings of patent information in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (“Orange Book”) for various drug products.  For example, perhaps a company neglected to notify FDA of a patent term extension for a particular patent covering a brand-name drug, leaving the drug exposed to premature generic competition.  Or perhaps a company obtained staggered approvals of various drug product strengths and forgot to inform FDA – through the submission of a Form FDA 3542 – that the patents listed for the initial strength also apply to subsequently approved strengths.  What’s the harm of that?  That’s the odd story that’s the topic of today’s post: Two ANDA approvals for generic versions of FOCALIN XR (dexmethylphenidate HCl) Extended-release Capsules, 30 mg, that left a lot of people wondering what happened.

FOCALIN XR is approved under NDA No. 021802 in several strengths: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg.  The 8 strengths were approved in a staggered fashion, instead of simultaneously:

• May 26, 2005 – The 5 mg, 10 mg, 20 mg strengths were approved
• August 1, 2006 – The 15 mg strength was approved
• October 23, 2009 – The 30 mg strength was approved
• August 11, 2010 – The 40 mg strength was approved 
• April 21, 2011 – The 25 mg and 35 mg strengths were approved

Patent information was added to the Orange Book (as shown in the respective Orange Book Cumulative Supplement) for each of the 8 approved strengths as follows:

• September 2005 Cumulative Supplement –  5 mg, 10 mg, 20 mg strenghts
• February 2007 Cumulative Supplement – 15 mg strength
• November 2010 Cumulative Supplement – 30 mg and 40 mg strengths
• May 2011 Cumulative Supplement – 25 mg and 35 mg strengths

Comparing these two sets of bullet points, one strength in particular stands out as an oddity: the October 23, 2009 approval of the 30 mg strength, for which patent information was shown as added with the November 2010 Orange Book Cumulative Supplement, which was published on FDA’s website around December 20, 2010.  Information on those patents, however, was not timely submitted to FDA for Orange Book listing because more than 30 days had passed since the October 23, 2009 approval of the new strength NDA supplement.  See FDC Act § 505(c)(2).

Just days earlier, on December 15, 2010, one ANDA sponsor (either through amendment or submission of an original ANDA), certified to patents listed in the Orange Book for FOCALIN XR, 30 mg, and became eligible for a period of 180-day exclusivity.  That fact became known with FDA’s February 21, 2011 update of the Agency’s List of Paragraph IV Certifications.  Fast-forward to August 28, 2013 when FDA approved Mylan’s ANDA No. 202580.  As a first applicant, Mylan was eligible for 180-day exclusivity, which would be triggered by the company’s first commercial marketing of the drug product.  According to a press release, that exclusivity was triggered on November 18, 2013.

But something else happened on November 18, 2013 . . . .  FDA approved a second ANDA for generic FOCALIN XR, 30 mg: Intellipharmaceutics’ ANDA No. 078992.  And then a third ANDA was approved just days later on November 21, 2013: Watson’s ANDA No. 079108.  What gives?

There are a few possibilities as to how FDA was able to approve ANDA Nos. 078992 and 079108.  It is possible that Mylan, Intellipharmaceutics, and Watson were serially certifying to patents they anticipated would be listed in the Orange Book for the 30 mg strength and were co-first applicants that would share 180-day exclusivity eligibility.  A second possibility is that Mylan selectively waived 180-day exclusivity in favor of Intellipharmaceutics and Watson.  A third possibility is that Intellipharmaceutics and Watson sought approval of the 30 mg strength before the patents were listed, and because the patents were late listed, the companies decided not to certify to them, while Mylan did decide to (or was otherwise required to) certify to them.  It turns out that this third possibility – or some variation of it – is the case.

Under FDA’s regulation at 21 C.F.R. § 314.94(a)(12)(vi):

If a patent on the listed drug is issued and the holder of the approved application for the listed drug does not submit the required information on the patent within 30 days of issuance of the patent, an applicant who submitted an [ANDA] for that drug that contained an appropriate patent certification before the submission of the patent information is not required to submit an amended certification.  An applicant whose [ANDA] is submitted after a late submission of patent information, or whose pending abbreviated application was previously submitted but did not contain an appropriate patent certification at the time of the patent submission, shall submit a certification under paragraph (a)(12)(i) of this section or a statement under paragraph (a)(12)(iii) of this section as to that patent. [(Emphasis added)]

In other words, a company with a pending ANDA is not required to certify to patent information listed in the Orange Book that was late-listed.  Of course, such an ANDA sponsor may voluntarily certify to late-listed patent information; however, doing so may make that ANDA sponsor subject to another ANDA sponsor’s 180-day exclusivity. 

That’s what happened with Intellipharmaceutics ANDA.  The company voluntarily certified to the late-listed Orange Book patents in early February 2011 and was sued for patent infringement in March 2011 (see here).  Once FDA updated its Paragraph IV Certification List on February 21, 2011 to reflect a December 15, 2010 first filing date for the 30 mg strength, Intellipharmaceutics realized that the company was not a first applicant and would be subject to the first applicant’s 180-day exclusivity unless it reneged on its Paragraph IV certification.  And because Intellipharmaceutics’s Paragraph IV certification was voluntary to a late-listed patent, FDA allowed the company to rescind the certification.  As such, the company would not be subject to the first applicant’s 180-day excluivity.  Of course, had the patents for the 30 mg strength been timely listed, ANDA sponsors would not have had the option to certify to them. Thus, it is possible that the brand-name sponsor would have had only a single generic entrant to contend with instead of three. 

Indeed, that was the somewhat similar scenario that played out earlier this year when a new patent, U.S. Patent No. 8,481,565, came out of the blue and was promptly (and timely) listed in the Orange Book for ARICEPT (donepezil HCl) Tablets, 23 mg, approved under NDA No. 022568.  In that case, the first companies to certify to the patent (likely through serial Paragraph IV certifications) were granted 180-day exclusivity (here and here), while other ANDA sponsors not as quick were left in the starting blocks until 180-day exclusivity expires. 

The Hatch-Waxman morals of these stories: If you are an NDA sponsor, ensure the accuracy of your Orange Book patent listings as soon as possible after approval (and on a continuing basis); and if you are an ANDA sponsor, look for the errors in Orange Book patent listings and be vigilant in monitoring new patent listings on a daily basis.  

By Kurt R. Karst –       

In what appears to be the first dismissal (Docket No. FDA-2012-E-0491) of a Patent Term Extension (“PTE”) application in what has been referred to as a “reverse Photocure” scenario, the Patent and Trademark Office (“PTO”) has determined that U.S. Patent No. 6,132,766 (“the ‘766 patent”) covering Pacira Pharmaceuticals, Inc.’s (“Pacira’s”) EXPAREL (bupivacaine), approved on October 28, 2011 under NDA No. 022496, is ineligible for a PTE, as well as an interim PTE.  The decision likely foreshadows another “reverse Photocure” case pending before the PTO that may ultimately end up in court.

By way of a refresher, under the PTE statute at 35 U.S.C. § 156, the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred” (35 U.S.C. § 156(a)(5)(A)) (emphasis added).   The term “product” is defined at 35 U.S.C. 156(f)(2) to mean, in relevant part, “the active ingredient of – a new drug, antibiotic drug, or human biological product . . . including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient.” 

For several years, the PTO interpreted the term “product” to mean “active moiety” rather than “active ingredient.”  In PhotoCure v. Kappos, 603 F.3d 1372 (Fed. Cir. 2010), the Federal Circuit interpreted the term “product” in the PTE statute to mean active ingredient rather than active moiety.  In reaching this decision, the Federal Circuit relied on its 1990 decision in Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392 (Fed. Cir. 1990) (“Glaxo II”) (which affirmed a 1989 district court decision in Glaxo v. Quigg, 706 F. Supp 1224 (E.D. Va. 1989) (“Glaxo I”)), where the Court construed the term “product” in 35 U.S.C. § 156(a)(5)(A) to mean “active ingredient.”  The Federal Circuit also pointed out that according to the Court’s 1997 decision in Hoechst-Roussel Pharms. Inc. v. Lehman, 109 F.3d 756 (Fed. Cir. 1997), “[f]or purposes of patent term extension, [the] active ingredient must be present in the drug product when administered.”  Photocure also contains dicta to the effect that a patent – in that case, U.S. Patent No. 6,034,267 covering the drug product METVIXIA (methyl aminoevulinate HCl) – is eligible for a PTE not only because methyl aminoevulinate HCL is a different chemical compound from previously approved aminolevulinic acid, but because “it is not disputed that they differ in their biological properties, warranting separate patenting and separate regulatory approval, although their chemical structure is similar.”

Post-Photocure, the PTO has framed PTE eligibility as a three-part inquiry applying the analyses used in Hoechst and Glaxo I: (1) Has the active ingredient been previously approved?; (2) Has a salt of the active ingredient been approved?; and (3) Has an ester of the active ingredient been approved?  A “yes” to any of these questions means that permission does not meet the first permitted commercial marketing prong of the statute.

Applying this analysis to the ‘766 patent PTE request for EXPAREL, the PTO determined that a PTE is not available:

Applying the Hoescht [sic] and Glaxo I analyses here, the active ingredient of EXPAREL® is bupivacaine.  The first question to ask is what active ingredient is physically present in the drug product; here, it is bupivacaine.  The next question to ask is whether bupivacaine has been previously approved.  The answer to that question is no.  Although bupivacaine itself has not been previously approved, a complete analysis requires asking whether any salt or ester of bupivacaine has been previously approved by FDA.  The answer to that question is yes.  Because a salt of bupivacaine, bupivacaine hydrochloride, has been approved first, i.e., before the approval of EXPAREL®, the grant of permission to commercially market or use EXPAREL® is NOT the first permitted commercial marketing or use of the product/active ingredient as required by section 156(a)(5)(A) in light of the approval of Marcaine hydrochloride in 1972. . . .  Accordingly, the ‘766 patent is ineligible for extension under the provisions of section 156.

In addition, the PTO addressed the comments in Photocure, and raised in the PTE application for EXPAREL, concerning separate patenting:

Notwithstanding the statutory requirements, the comments of the Photocure court serve to buttress the conclusion that the approval of Metvixia complied with § 156(a)(5)(A), but did not provide additional criteria to confer eligibility.  Applicant appears to attempt to garner support for an extension for EXAREL® by indicating that a “bupivacaine liposome injectable suspension warrants separate patenting and separate regulatory approval.”  Application at 4.  Although the court in Photocure commented that Metvixia was separately patented [from Levulan] and underwent separate regulatory review [from Levulan], nothing in section 156 requires analyzing biological properties of a drug product to determine eligibility.  Additionally, any “new drug,” as defined in 21 U.S.C. § 321(p), must undergo separate regulatory approval as per 21 U.S.C. § 355 (stating that no person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug).  Since the additional circumstances discussed by the Photocure court in finding that the approval of Metvixia could support an extension of Photocure’s patent are not statutory requirements of 35 U.S.C. 156, similar circumstances cannot confer eligibility.

Finally, the PTO determined that because the ‘766 patent, which expired on November 16, 2013, is ineligible for a PTE, an interim extension of up to one year pursuant to 35 U.S.C. § 156(e)(2) is also not available.

Although the PTO has not been challenged on its decision with respect to a PTE for the ‘766 patent covering EXPAREL (and will not be because the patent has expired), the Office’s decision foreshadows a final decision for another pending PTE application.  As we previously reported, the PTO has signaled that U.S. Patent No. RE 41,571, a method-of-use patent listed in the Orange Book covering BUTRANS (buprenorphine) Transdermal System, approved on June 30, 2010 under NDA No. 021306, is not eligible for a PTE because the product does not meet the first permitted commercial marketing prong of the PTE statute.  That PTE docket (Docket No. FDA-2012-E-0152) has remained relatively silent since FDA, in June 2012, sent a letter to the PTO stating that the Agency’s record “indicate that BUTRANS does not represent the first permitted commercial marketing or use of the product, as defined under 35 U.S.C. § 156(f)(1).”  In November 2011, in a letter submission to the PTO, the PTE applicant addressed the Office’s initial, non-final determination of PTE ineligibility, saying that the PTO’s initial determination is erroneous and contrary to the PTE statute and Federal Circuit decisions. 

 By John A. Gilbert & Delia A. Stubbs –

In a decision published this week, DEA denied an application for a pharmacy registration on the basis that the owner-pharmacist had previously ignored “red flags” and generally failed to exercise her corresponding responsibility in filling prescriptions.  Wheatland Pharmacy; Decision and Order, 78 Fed. Reg. 69,441 (Nov. 19, 2013).  While these factors have been used by DEA on numerous occasions to deny or revoke DEA registrations, it is worth noting that in this case the pharmacist had apparently self-reported to DEA concerns about suspicious prescriptions received at the pharmacy.  However, DEA found that the pharmacist had otherwise misrepresented her involvement and culpability in filling prescriptions that were not for a legitimate medical use.  DEA also found that the pharmacist had filled prescriptions even after her prior DEA registration had been voluntarily surrendered.  To be sure, the pharmacist’s attempt to curry favor with DEA seems rather short-sighted in light of other actions that clearly violated the law and DEA regulations.  But the lesson here is that registrants should not expect to receive brownie points for reporting suspicious activity, especially if their own conduct raises serious compliance concerns.

This case also raises several procedural and substantive issues worth noting.  First, DEA issued a final order denying the pharmacy’s application, despite the pharmacy’s request that the application be withdrawn and where the pharmacy requested to waive its right to a hearing.  Id. at 69,441.  Pursuant to 21 C.F.R. § 1301.37, if the Administrator finds the registration is inconsistent with the public interest, DEA may serve upon an applicant an Order to Show Cause (“OTSC”) why the application should not be denied.  Prior to issuance of an OTSC, the Administrator must grant an applicant’s request to withdraw his application.  Id. § 1301.16(a).  After issuance of an OTSC, the Administrator may, but is not required by regulation, to permit withdrawal of the application.  Id.  In Wheatland, the Deputy Assistant Administrator denied the applicant’s request to withdraw the application for registration (the record is silent, but we presume the request was made after the OTSC).  78 Fed. Reg. 69,441.  The applicant subsequently waived its right to a hearing, and DEA then filed a request with the Administrator pursuant to DEA regulations that permit the Administrator to issue a final order based on the “findings of fact and conclusions of law upon which the order is based.”  21 C.F.R. §§ 1301.43(e), 1301.46. 

This summary judgment process used in Wheatland is not commonly exercised by DEA, but may signal a wave of the future.  The process was previously considered in a decision issued earlier this year, where DEA, overruling prior agency precedent, held that the Administrator may deny an application based on findings made in an OTSC on the person’s prior application – where the person declined to request a hearing on that OTSC.  The Administrator ruled its decision was permitted by the doctrine of res judicata.  See Jose G. Zavaleta, M.D.; Decision and Order, 78 Fed. Reg. 27,431 (May 10, 2013).

Second, the decision states that the government argued that the pharmacist had previously violated the law and regulations by dispensing a prescription to someone other than the “ultimate user.”  The Administrator noted that the definition of ultimate user means a person who “has lawfully obtained” and possesses a controlled substance.  78 Fed. Reg. at 69,446.  The Administrator found that the pharmacist had filled prescriptions written by a physician assistant that were fraudulent.  Thus, the Administrator ruled that the persons obtaining the medicine could not be the “ultimate user because the prescriptions themselves were fraudulent.  Interestingly, the Administrator did not address another potential “ultimate user” issue described in the case.  The government found that the pharmacist delivered or dispensed controlled substances to a home healthcare service provider for dispensing to the patients.  Id. at 69,444.  If we read this correctly, the pharmacist was not delivering or dispensing to the “ultimate user” in this case either.  However, the decision does not address this issue, but rather focuses on the facts that the dispensing occurred after the pharmacist had lost her registration.  This highlights what, in our opinion, has been an ongoing controversy of whether non-family members (e.g., hospice nurses) may pick up prescriptions and/or whether patients can designate an agent to pick up prescriptions.

Finally, the opinion cites to the affidavit of a Special Agent wherein the Special Agent states that DEA instructed the pharmacist “to fill some of the prescriptions,” so that law enforcement could monitor an alleged fraudulent patient.  Id. at 69,442.  So while DEA found that the pharmacist knowingly filled prescriptions that were not legitimate as a basis for a prior immediate suspension of the pharmacy registration, the Special Agent also apparently instructed the pharmacy to fill some of these fraudulent prescriptions to assist DEA in its investigation.  We always recommend that registrants who cooperate with DEA obtain a written agreement so as to avoid potential liability in the future.  In this case, such cooperation apparently was not enough to save the pharmacist from a revocation and later a denial of a new application. 

By Karla L. Palmer –

On Monday, November 18, 2013, DEA released the 2013 National Drug Threat Assessment Summary, which provides an assessment of the threat posed to the United States by trafficking and abuse of illicit substances and non-medical use of controlled prescription drugs.  The Summary also provides an analysis of the domestic drug situation during 2012 based on available law enforcement, intelligence, and public health data.  DEA took over responsibility for preparation of the Summary in June 2012 as a result of the closure of the National Drug Intelligence Center.  DEA considered both quantitative data from various sources (seizures, investigations, arrests, drug purity or potency, and drug prices; law enforcement surveys; laboratory analyses; and interagency production and cultivation estimates) and qualitative information (subjective views of individual agencies on drug availability, information on smuggling and transportation trends, and indicators of changes in smuggling and transportation methods).

Highlights include the following:

• The trafficking and abuse of illicit drugs continue to constitute a “dynamic and challenging” threat to the United States.
• Controlled prescription drug abuse continues to be the United States’ fastest growing drug problem.  The rate of abuse of controlled prescription drugs remains high; abuse remains at a higher rate than any illicit drug except marijuana.  Pain relievers are the most common type of abused prescription drug, and are most commonly involved in overdose incidents.
• The availability of heroin continued to increase in 2012, likely due to high levels of heroin production in Mexico, and Mexican traffickers expanding into in the eastern and midwestern United States.  Some metropolitan areas observed an increase in heroin overdose deaths.  Reports reveal that many prescription opioid users have turned to heroin as a cheaper and/or more easily obtained alternative to prescription drugs.
• The trend of lower cocaine availability in the United States that began in 2007 continued through 2012.
• Methamphetamine availability is likely increasing because of sustained production in Mexico (the primary foreign source for the United States market) and continuing small-scale domestic production.
• Marijuana availability appears to be increasing because of sustained high levels of production in Mexico (the primary foreign source of United States supply) and increased domestic cultivation.
• The abuse of synthetic designer drugs has emerged as a serious problem in the United States.  The abuse of synthetic cannabinoids, such as “K2” and “Spice,” and synthetic cathinones, like “bath salts,” increased over the past few years, and “abusers have suffered severe consequences.”  Both state legislation and national scheduling of these drugs have helped to “mitigate the threat.”  DEA noted that the threat posed by synthetics most likely will continue to increase, in part because the chemical make-up of these drugs often differs by only one compound.  Thus as DEA exercises its scheduling authority to control certain substances, producers quickly change the chemical component of the newly banned substance to create a new one
• MDMA (ecstasy) is available in markets throughout the United States.  However, data suggest availability and abuse of the drug may have peaked.

By Karla L. Palmer – 

As reported here yesterday on the track and trace provisions, after many months of legislative maneuvering and various iterations emanating from both the House and Senate, the Senate passed without amendment and by voice vote H.R. 3204 – the “Drug Quality and Security Act.”  The Act removes the unconstitutional advertising and promotion provisions that for years plagued Section 503A of the Federal Food, Drug and Cosmetic Act; thus clarifying long-standing confusion concerning whether and where FDA could enforce Section 503A.  The law is effective upon enactment, and Section 503A will be enforceable nationwide. 

The Act’s Section 503B creates a new category of FDA registrant called “outsourcing facilities.”  Distinguished from compounders engaged in more traditional compounding for individual patients based on individual prescriptions, outsourcing facilities will be permitted to compound and ship interstate large volumes of sterile drugs without first obtaining individual prescriptions.  These hybrid compounders can pay a registration fee and voluntarily register with FDA, while those compounders that remain more “traditional” pharmacies will continue to be primarily regulated by state boards of pharmacy.

Outsourcing facilities will be subject to FDA oversight similar to drug manufacturers, including compliance with current good manufacturing practices.  In addition to registering with the Agency, these facilities must report to FDA every six months products that they compound, and must report adverse events.  Section 503B also provides FDA the resources and authority to conduct risk-based inspections.  In addition, the law requires FDA to list FDA-regulated outsourcing facilities on FDA’s website, requires detailed labeling on compounded drugs, and prohibits false and misleading advertising.  We have prepared a detailed cheat sheet on the provisions of Sections 503A and 503B. 

Hyman, Phelps & McNamara, P.C. is very pleased to announce that Larry K. Houck and Riëtte van Laack, PhD have been named Directors of the firm.  Mr. Houck’s practice area encompasses controlled substances and regulated chemicals as well as state licensing and registration compliance issues.  Mr. Houck worked in the Drug Enforcement Administration’s Office of Diversion Control for 15 years as both a Diversion Investigator and as a Coordinator in the Office of Diversion Control’s Liaison and Policy Section prior to joining the firm in 2001. 

Dr. van Laack focuses her practice primarily in the area of food regulation and OTC products.  She also has extensive field experience in the food science and technology industry, working as a researcher abroad and in the United States.  Prior to joining the firm, Dr.. van Laack worked, among other things, as a researcher with the Agricultural Research Service of the USDA and as a professor at the Department of Food Science and Technology at the University of Tennessee.

The American Conference Institute will be holding its inaugural forum on
current Good Manufacturing Practices (“cGMPs”) in Washington, D.C. from Thursday, January 23 to Friday, January 24, 2014.  A copy of the conference program can be obtained here.  Hyman, Phelps & McNamara, P.C.’s Douglas B. Farquhar will be presenting at the conference in a session titled “International Inspections: Preparing For Inspection of Overseas Manufacturing Facilities by FDA and Comparable Foreign Regulatory Authorities.”

The conference will include presentations from regulatory and legal experts on myriad topics, including presentations from several key government officials.  Howard R. Sklamberg, Director of FDA’s Office of Compliance in the Center for Drug Evaluation and Research, will discuss the Agency’s “Case for Quality” Initiative.   Annamarie Kempic, Deputy Chief Counsel for Litigation in FDA’s Office of Chief Counsel, will discuss cGMP Complaints, Consent Decrees, and Corporate Integrity Agreements.  In addition, Jeffrey Steger, the Assistant Director in the Consumer Protection Branch, Civil Division of the U.S. Department of Justice, will give a rundown of notable cGMP actions.

FDA Law Blog is a conference media partner.  As such, we can offer FDA Law Blog readers a special $200 discount off the current price tier.  The discount code is: FLB200.  We look forward to seeing you at the conference.

By Jessica A. Ritsick & William T. Koustas –

Over 25 years ago, the Prescription Drug Marketing Act ("PDMA") was passed.  The PDMA called for implementation of a national system to follow prescription drugs through the supply chain.  After years of talking about it (see here), and months of kicking the can down the road in Congress, it’s finally here: H.R. 3204, the Drug Quality and Security Act, which mandates a federal, interoperable electronic track-and-trace system, has arrived! 

Bills on both sides of Congress started getting traction back in April (see our previous post here).  As Spring turned to Summer, there was speculation that a bill could be passed by summer recess. Summer turned to Fall, and by this point, a bi-cameral, bi-partisan version of the bill emerged (see our previous post here).  The bill was passed by voice vote in the House at the end of September, and there was hope that the Senate would pass it by the end of the fiscal year.  Then, the government shutdown happened, and the bill took a back seat.  However, at long last, here we are: a federal law mandating an interoperable electronic track-and-trace system is now a reality!  The fully interoperable electronic track-and-trace system is set to become a reality in 10 years, but in the interim, there are deadlines to get all players in the supply chain up to speed so that in a decade, the interoperable system is ready to go.

From a brief review, it appears that the bill has passed in identical form to the bill we blogged about and outlined in September (see our summary here, and a U.S. Senate press release here).  It’s hard to believe, after years of haranguing, that this has become a reality, and it appears likely this bill will soon be signed into law.  As Fall gets colder, we’re warmed by knowing that if anything is frozen this Winter, for once, it won’t be track-and-trace. 

By Riëtte van Laack –

On November 7, 2013, the Food Safety and Inspection Service (FSIS) amended its prior label approval system regulations to expand the circumstances in which certain types of labels and labeling are generically approved and do not need specific FSIS approval. 

Under the final rule, companies need not submit the label for approval if the label bears all required mandatory labeling features and includes only claims that are defined in FSIS’s regulations, the Food Standards and Policy Book (with the exception of natural and negative claims), and allergen statements in compliance with the Food Allergen Labeling and Consumer Protection Act.

Labels that cannot be generically approved include temporary approvals, labels for export only that bear labeling deviations, religious exemption (e.g., Buddhist exemption), and labels bearing special statements and claims.  With the exception of the child-nutrition box, which is reviewed by the Agricultural Marketing Service, claims that have been reviewed by other Government agencies (e.g., organic claims and health claims) are considered special statements and claims. 

FSIS issued a guidance providing additional information regarding the final rule. The guidance includes a long list of examples of statements that are not eligible for generic approval  and a list of examples of claims that are eligible.

The final rule is intended to reduce the time for approval of labels that do not qualify for generic approval.  Although the Agency will continue to review all label applications, labels that do not qualify for generic approval will receive first priority for review.  Applications for labels that qualify for generic approval will receive lower priority and may take longer to be reviewed.

The final rule also consolidates the regulations regarding approval of labels for meat and poultry (9 C.F.R. §§ 317.4, 317.5, 381.132, 381.133) into a new single part, 9 C.F.R. Part 412.

The rule will become effective on January 6, 2014, and, unfortunately, will not provide any relief to those affected by the backlog that resulted from the government furlough in October 2013.

By Jessica A. Ritsick & William T. Koustas –

At this year’s Health Care Distribution Management Association (HDMA) annual track-and-trace conference, most minds were focused on one thing: the potential passage of H.R. 3204, the Drug Quality and Security Act, which would mandate a uniform, national, interoperable electronic track-and-trace system.  We’ve been following the evolution of this bill, which has seen more definitive traction in Congress in the past year than it has in the 25+ years since the passage of the Prescription Drug Marketing Act (PDMA), which requires a drug pedigree system be put in place (see our previous posts here, here, here, and here.)  Luckily, we haven’t been holding our breath, and neither were the conference attendees, because when the conference closed on November 13, 2013, H.R. 3204 was taken up, yet again, by the Senate, only to be again delayed by an unrelated amendment from Senator David Vitter (R-LA).

The conference provided a thorough overview of what all players in the prescription drug supply chain could expect should the bill become law.  It also provided food for thought about potential hiccups in the law’s implementation over the next 10 years.  Unlike Congress, however, at HDMA, it seemed like everyone was on the same page.  The general tenor in the room was that a national track-and-trace system was welcomed.  Virginia Herold, Executive Director of the California Board of Pharmacy, expressed to the group that California found the bill satisfactory, although the 10 year timeline was longer than it preferred.  Connie Jung, Acting Associate Director of Policy and Communications for FDA’s Office of Drug Security, Integrity, and Recalls, also expressed satisfaction with the bill, but also acknowledged that the work was just getting started.  Dr. Jung conveyed to the group that FDA has been actively ramping up its efforts and looking ahead to the new track-and-trace world, and acknowledged that the Agency is not in this alone; working with other players in the game is both welcomed and necessary to success. 

With fingers crossed, attendees looked ahead to the future of track-and-trace.  Panelists expressed that the national system will hopefully make it harder for bad actors to corrupt the integrity of the supply chain, as the current patchwork of state pedigree laws allows bad actors to shop around for more lenient states.  It is hoped that this bill will put everyone on a level playing field and reduce loopholes.  Moreover, once implemented, panelists expressed hope that the systems created under the bill could be leveraged in other prescription drug problem areas, such as with prescription pain medication abuse (e.g., pill mills, doctor shopping).  While many expressed that some of the deadlines in the bill might be unrealistic, there was general consensus that supply chain partners were ready to get to work making this long-held dream a reality.