For those of us in the Hatch-Waxman Community, June 14, 2018 sowed a lot of confusion. That’s the date on which FDA approved three ANDAs for generic versions of Indivior Inc.’s SUBOXONE (buprenorphine and naloxone) Sublingual Film, 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg (approved under NDA 022410); specifically Dr. Reddy’s Laboratories, Inc. ANDA 205299 (2 mg/0.5 mg and 8 mg/2 mg) and ANDA 205806 (2 mg/0.5 mg and 8 mg/2 mg), and Mylan Technologies Inc. ANDA 207607 (8 mg/2 mg). Noticeably absent from the ANDA approval letters is any discussion of 180-day exclusivity for the 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg strengths approved under the ANDAs. The absense of any discussion in an ANDA approval letter generally means that FDA determined that eligibility for 180-day exclusivity was forfeited by a “first applicant.” But what was FDA’s rationale for making such a determination?? Adding more confusion to the mix was a change in the “Date of Submission” listed on the ANDA Paragraph IV Certifications List for one strength of generic SUBOXONE (12 mg/3 mg), as well as a tentative approval letter FDA issued earlier in the day on June 14, 2018 for Mylan ANDA 207607.
Fast-forward a few weeks and we now have some clarity on the situation. Late on July 20, 2018, FDA finally published a July 13, 2018 Letter Decision explaining the Agency’s rationale for determining that eligibility for 180-day exclusivity was forfeited for each of the 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg strengths of Buprenorphine and Naloxone Sublingual Film. (As to the 2 mg/0.5 mg strength, the ANDA Paragraph IV Certifications List notes that the ANDA submission was withdrawn or that exclusivity was relinquished.) FDA’s 180-day exclusivity forfeiture decisions are pretty significant, particularly for the 4 mg/1 mg and 12 mg/3 mg strengths of SUBOXONE.
But before we get into the meat of FDA’s Letter Decision, let’s set the scene . . . .
FDA initially determined that the first ANDAs for generic SUBOXONE containing a Paragraph IV certification to one or more Orange Book-listed patents – either through an original ANDA submission or an amendment to a substantially complete ANDA – were submitted on October 15, 2012 (2 mg/0.5 mg and 8 mg/2 mg), May 14, 2013 (4 mg/1 mg), and March 26, 2014 (12 mg/3 mg). Presumably those patent certifications were to U.S. Patent Nos. 8,017,150 (“the ‘150 patent”), 8,475,832 (“the ‘832 patent”), and 8,603,514 (“the ‘514 patent”), which were listed in the Orange Book at the time of those initial ANDA submissions. Thus, despite subsequent patent information listings in the Orange Book for SUBOXONE, only the ‘150, ‘832, and ‘514 patents are “exclusivity-bearing” for an ANDA “first applicant.” On June 14, 2018, FDA updated the ANDA Paragraph IV Certifications List to identify that eligibility for 180-day exclusivity as to the 2 mg/0.5 mg strength was forfeited. FDA also changed the March 26, 2014 date initially listed for the 12 mg/3 mg strength to May 14, 2013.
As to the “first applicant” – a term we will get back to shortly – with respect to the 4 mg/1 mg and 12 mg/3 mg strengths of SUBOXONE, FDA says that “[t]he May 14, 2013 First Applicant later withdrew its application for the 4 mg/1 mg and 12 mg/3 mg strengths,” that “[t]he May 14, 2013 First Applicant also informed FDA that it had not given notice to the NDA holder or patent owner for these strengths,” that “FDA’s review of the record confirms that the May 14, 2013 First Applicant did not submit any documentation to its ANDA of providing such notice,” and that “[a]t least one other applicant submitted a substantially complete ANDA (or an amendment to a substantially complete ANDA) for Buprenorphine and Naloxone Sublingual Film, 4 mg/1 mg and 12 mg/3 mg, after May 14, 2013 with a paragraph IV certification and provided notice to the NDA holder and patent holder.”
Ok . . . so you may be thinking that here the purported “first applicant” was not even a “first applicant” in the first instance because the applicant failed to perfect its Paragraph IV certifications by failing to send notice, and that another applicant that first perfected its Paragraph IV certifications is the one true “first applicant.” After all, courts have affirmed prior FDA rulings that a Paragraph IV certification is not perfected until notice is sent. See Purepac Pharmaceutical Co. v. Thompson, 354 F.3d 877 (D.C. Cir. 2004), aff’g TorPharm, Inc. v. Thompson, 260 F.Supp.2d 69 (D.D.C. 2003). And although both the Purepac and TorPharm decisions were made in the context of the version of the statute that existed prior to the December 2003 enactment of the Medicare Modernization Act (“MMA”), one might reasonably believe that the principle articulated by FDA and affirmed by the courts (i.e., that a Paragraph IV certification becomes effective only when the ANDA applicant ultimately provides notice) applies equally under the post-MMA version of the statute. Indeed, in FDA’s 2015 Proposed Rule to implement certain provisions of the MMA, the Agency proposed an administrative consequence “to address ANDA applicants that fail to timely provide notice of a paragraph IV certification by moving forward the date of submission of the ANDA by the number of days beyond the required time frame that the applicant delayed in sending its notice.” FDA, Proposed Rule, ANDAs and 505(b)(2) Applications, 80 Fed. Reg. 6802, 6840 (Feb. 6, 2015). FDA recognized that, as a result of this consequence, “an ANDA applicant may lose its first applicant status and thus its eligibility for 180-day exclusivity as a result of providing late notice . . . if another applicant submits a substantially complete ANDA containing a paragraph IV certification on the same first day and provides timely notice.” Id. Ultimately, FDA did not adopt this interpretation, but it seems to support the views in both the Purepac and TorPharm decisions.
Well, if you thought the Purepac and TorPharm rationale would come into play, you were correct. . . but not in the way you might have thought. Instead of embracing that law, FDA rejected it and went in a different direction. As FDA notes in the July 13, 2018 Letter Decision, “[t]he withdrawal of the application and the lack of documentation of notice for the (now withdrawn) 4 mg/1 mg and 12 mg/3 mg strengths gave rise to unique questions regarding 180-day exclusivity for these two strengths. . . .” and ultimately resulted in the “first applicant” – the applicant that submitted the first Paragraph IV ANDA on May 14, 2013, but that never perfected its Paragraph IV certifications – forfeiting eligiblity for 180-day exclusivity under the so-called “withdrawal of application” provision at FDC Act § 505(j)(5)(D)(i)(II).
The FDC Act (at § 505(j)(5)(B)(iv)(II)(bb)) defines the term “first applicant” to mean:
an applicant that, on the first day on which a substantially complete application containing a [Paragraph IV certification] is submitted for approval of a drug, submits a substantially complete application that contains and lawfully maintains a [Paragraph IV certification] for the drug.
FDA’s July 13, 2018 Letter Decision breaks this definition down into three prongs:
[1] on the first day on which a substantially complete application containing a [paragraph IV certification] is submitted for approval of a drug [hereinafter the “when” prong],
[2] submits a substantially complete application that contains . . . [a paragraph IV certification for the drug] [hereinafter the “submit” prong] and
[3] lawfully maintains a [paragraph IV certification] for the drug [hereinafter the “lawfully maintains” prong].
Under what FDA terms the “First Effective Approach,” which is the approach affirmed in the Purepac and TorPharm decisions, the Agency says that it creates a problem under the MMA:
When considering the issue prior to enactment of MMA and prior to FDA’s exclusivity determination in this case, FDA has taken an approach to determining eligibility for 180-day exclusivity (termed the “First Effective” approach for purposes of this letter) that when the first paragraph IV certification occurs in an amendment or supplement to an ANDA, the first generic drug applicant that both (1) submits a substantially complete application (amendment or supplement) with a paragraph IV certification and (2) makes it “effective” for the drug by providing notice in a timely fashion, is eligible for 180-day exclusivity.
Under this approach, an applicant who submits an amendment or supplement to a substantially complete application with a paragraph IV certification, but who fails to give timely notice, could lose eligibility for 180-day exclusivity if another applicant submits an amendment or supplement to a substantially complete application with a paragraph IV certification later but gives notice first. Under this approach, the day on which eligibility for 180-day exclusivity is determined would not be fixed; it could change if the first-to-file generic drug applicant submits an amendment or supplement to a substantially complete application with a paragraph IV certification but does not provide notice of that certification before another applicant completed both of those actions. . . .
Presented with questions regarding the meaning of “First Applicant” in this case in the post-MMA context, and upon further review of the relevant statutory and regulatory provisions, FDA has concluded that the “First Effective” approach, which likely grew out of the application of the principles of the pre-MMA statutory framework in the Purepac case, is not consistent with the statutory definition of “First Applicant” as defined by Congress in the MMA. This is so because application of the “First Effective” approach post-MMA effectively writes out of the statutory definition of “First Applicant” the reference to the “first day” in the “when” prong of that definition in cases where notice is not timely given. Thus, . . . in interpreting the MMA statutory language and applying the post-MMA statutory scheme, FDA rejects the “First Effective” approach to determining which applicants are “First Applicants” and is adopting the interpretation explained below to determine “First Applicant” status and eligibility for exclusivity for ANDAs referencing Suboxone 4 mg/1 mg and 12 mg/3 mg strengths. This interpretation is most consistent with the text and structure of the MMA.
The “interpretation explained below to determine ‘First Applicant’ status and eligibility for exclusivity for ANDAs” is referred to as the “First Submitted Interpretation Approach,” and it goes like this:
[U]nder the statute, a “First Applicant” is “an applicant that, on the first day on which a substantially complete application containing a [paragraph IV certification] is submitted for approval of a drug, submits a substantially complete application that contains . . . [a paragraph IV certification for the drug] and lawfully maintains a [paragraph IV certification] for the drug.” Under the “First Submitted” interpretation, the definition of “First Applicant” is read such that the “when” prong (i.e., “on the first day on which a substantially complete application . . .”) refers to a single specific date on which an application was submitted to qualify its sponsor as a “First Applicant”; whereas the “submit” and “lawfully maintain” prongs describe requirements for specific applications submitted on this single fixed date to maintain eligibility for exclusivity. Under this reading of the statute, there can only ever be one “first day on which a substantially complete application containing a paragraph IV certification [or an amendment to a substantially complete application with a paragraph IV certification] is submitted,” regardless of whether the applicant that submits its application (or an amendment or supplement to its application) on that “first day” gives or fails to give timely notice of and/or otherwise lawfully maintains its paragraph IV certification. Thus, while an applicant must meet all three prongs to obtain 180-day exclusivity, the “when” prong refers to a specific, static date determined by the specific first day on which any applicant submits a substantially complete application (or an amendment or supplement to a substantially complete application) containing a paragraph IV certification to a patent listed for that product. This specific date is fixed and does not change because of subsequent events.
According to FDA, the “First Submitted Interpretation” approach “is most consistent with the plain meaning of the ‘First Applicant’ definition because it gives full effect to the ‘when’ prong, including the use of the indefinite article ‘a’ that modifies ‘substantially complete application,’ which suggests that the ‘when’ prong date is set permanently once a substantially complete application (or an amendment or supplement to a substantially complete application) containing a paragraph IV certification is first submitted.” Thus, “[a]ny application, whether an original application, amendment, or supplement, submitted after this ‘first day’ cannot satisfy the ‘when’ prong and cannot be a ‘First Applicant,’ as there can be only one ‘first day on which a substantially complete application containing a paragraph IV certification is submitted.’” FDA goes on to provide other arguments as to why the “First Submitted Interpretation” approach is, according to the Agency, consistent with the plain meaning and structure of the statute and injects some certainty and predictability into the 180-day exclusivity landscape.
Applying this approach to a 180-day exclusivity analysis for the 4 mg/1 mg and 12 mg/3 mg strengths of generic SUBOXONE, FDA concluded as follows:
[T]he May 14, 2013 First Applicant qualified as the “First Applicant” for both the 4 mg/1 mg and 12 mg/3 mg strengths. The first day on which a substantially complete ANDA application (or an amendment or supplement to a substantially complete application) containing a paragraph IV certification was submitted for Buprenorphine and Naloxone Sublingual Film, 4 mg/1 mg and 12 mg/3 mg, was May 14, 2013, the day on which the May 14, 2013 First Applicant submitted its application or amendment. Thus, the “first day” under the definition of “First Applicant” is May 14, 2013 as there was no applicant that submitted a substantially complete ANDA with a paragraph IV certification (or amended its substantially complete application with a paragraph IV certification) prior to that date. Because the May 14, 2013 First Applicant withdrew its application for the 4 mg/1 mg and 12 mg/3 mg strengths, it forfeited 180-day exclusivity under section 505(j)(5)(D)(i)(II). Its forfeiture means there were no barriers to approval of subsequent applicants for those strengths.
Moving on to FDA’s 180-day exclusivity analysis for the 8 mg/2 mg strength of generic SUBOXONE, we see for the first time FDA’s application of an interpretation the Agency discussed in a January 2017 draft guidance document on 180-day exclusivity. As we previously posted, that interpretation concerned the so-called “failure-to-market” forfeiture provision at FDC Act § 505(j)(5)(D)(i)(I).
By way of background, the FDC Act provides that a first applicant’s eligibility for 180-day exclusivity may be forfeited if the first applicant fails to market the drug by the later of two “bookend” dates. The first date is the earlier of 75 days after final approval of the first applicant’s ANDA and 30 months after the date of submission of the first applicant’s ANDA. The second date is calculated 75 days after a final court decision. Specifically, the statute provides:
(bb) with respect to the first applicant or any other applicant (which other applicant has received tentative approval), the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a certification qualifying the first applicant for the 180-day exclusivity period under subparagraph (B)(iv), at least 1 of the following has occurred:
(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.
(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.
(CC) The patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under subsection (b).
FDA interprets FDC Act § 505(j)(5)(D)(i)(I)(bb) to require an “all-in-one” approach instead of a “mix-and-match” approach. Under the “all-in-one” approach, the parenthetical “(which other applicant has received tentative approval)” provides that the 75-day period is triggered when the same subsequent applicant has both tentative approval and a final court decision that the relevant patent is invalid or not infringed. Under the “mix-and-match” approach, the parenthetical allows different subsequent ANDA applicants to have tentative approval and a final court decision.
FDA’s draft guidance also addresses FDC Act § 505(j)(5)(D)(i)(I)(bb) with respect to whether or not the order in which an “other applicant” obtains a court decision and tentative approval counts. In a hypothetical situation described in the draft guidance, FDA clarifies that a relevant court decision triggers the 75-day period once tentative approval is obtained, even if that tentative approval is later obtained by the same applicant. Thus, it is not the completion of the two events – tentative approval and a court decision – that triggers the 75-day countdown (unless the tentative approval comes before the court decision), but the court decision that is solely relevant. So, a later-obtained tentative approval makes a previously-obtained court decision (by the same applicant) operative, such that if tentative approval is obtained one year after the court decision, 180-day exclusivity is forfeited retroactively (absent any commercial marketing by the first applicant). (We will leave for another day whether or not this interpretation is consistent with the intent of this forfeiture provision. After all, the Chairman of the Federal trade Commission (“FTC”) testified in 2003 as the forfeiture provisions were being discussed by Congress that “if a subsequent generic applicant is ‘ready to go,’ the first applicant’s exclusivity should not block its entry. . . provided the first applicant [has] a reasonable period for which to begin commercial marketing.” Examining The Senate And House Versions Of “The Greater Access To Affordable Pharmaceuticals Act,” Hearing Before The Sen. Jud. Comm., at 116 (Aug. 1, 2003) (prepared statement of the Hon. Timothy Muris, Chairman of the FTC) (emphasis added).)
With that background in place, here are the facts as provided by FDA:
- “One or more first applicants submitted a substantially complete ANDA (or an amendment to a substantially complete ANDA) for a generic Buprenorphine and Naloxone Sublingual Film, 8 mg/2 mg containing a paragraph IV certification on October 15, 2012.” This is likely ANDA 204383, which FDA tentatively approved on October 24, 2017.
- “The October 15, 2012 First Applicant qualified as a ‘First Applicant’ and therefore was eligible for 180-day exclusivity for its generic Buprenorphine and Naloxone Sublingual Film, 8 mg/2 mg absent forfeiture.”
- “A subsequent applicant submitted an ANDA after October 15, 2012 and provided notice to the NDA holder and patent owner. This subsequent applicant was sued for patent infringement, and the suit included the patent or patents qualifying the October 15, 2012 First Applicant for 180-day exclusivity. More than 75 days prior to FDA’s exclusivity determination on June 14, 2018, a federal district court entered a consent decree and final judgment in favor of the subsequent applicant on the Qualifying Patent. The consent decree and final judgment included a finding that the Qualifying Patent was not infringed. The subsequent applicant was tentatively approved on June 14, 2018.” Ahha! That explains the July 14, 2018 tentative approval of Mylan ANDA 207607. It made the forfeiture of 180-day exclusivity effective.
Given these facts, FDA posits that an “earlier of” (aa) bookend date occurred (i.e., “30 months after the date of submission of the application of the first applicant”), as well as a (bb) bookend date that was later than (aa). The (bb) bookend date, which is based on a (bb) subitem (BB) court decision, “transpired more than 75 days before FDA’s exclusivity determination on June 14, 2018,” when FDA tentatively approved Mylan ANDA 207607. Thus, according to FDA, “[t]he October 15, 2012 First Applicant did not market its product by the later of the item (aa) date and the item (bb) date. Accordingly, it forfeited its eligibility for 180-day exclusivity for Buprenorphine and Naloxone Sublingual Film, 8 mg/2 mg, under the failure to market forfeiture provision.”