PTE Countdown (Or Not?!?): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (Read to a Funky Soundtrack and Vocals by The Pointer Sisters)

For those of us of “a certain age,” the original “Sesame Street” recalls fond memories: Mr. Hooper, Mr. Snuffleupagus (when only Big Bird could see Snuffy), and those catchy songs like “C Is For Cookie” and, of course, “Pinball Countdown” – those animated segments with a funky soundtrack with vocals by The Pointer Sisters that teaches children to count to 12 by following the journey of a pinball through a fanciful pinball machine.

“Pinball Countdown” is quite the earworm, and it rang in this blogger’s mind as I counted the number of Patent Term Extension (“PTE”) requests submitted – and still pending – based on the 2018 NDA approvals for Array Biopharma Inc.’s (“Array’s”) MEKTOVI (binimetinib) Tablets (NDA 210498) and BRAFTOVI (encorafenib) Capsules (NDA 210496).  Array filed six PTE applications in four U.S. Patent Nos. 7,777,050; 8,178,693; 8,193,229; and 8,513,293 based on the approval of MEKTOVI (two PTE applications were filed in each of the ‘050 and ‘229 patents), and six PTE applications in four U.S. Patent Nos. 8,501,758; 9,314,464; 9,593,099; and 9,593,100 based on the approval of BRAFTOVI) (two applications were filed in each of the ‘758 and ‘464 patents).  You can access those PTE applications at FDA-2019-E-3050; FDA-2019-E-3051; FDA-2019-E-3052; FDA-2019-E-3054; FDA-2019-E-3056; FDA-2019-E-3063; FDA-2019-E-3064; and FDA-2019-E-3073.

While it is not unusual for a company to submit multiple PTE applications for multiple patents based on the approval of a marketing application and then make an election as to which patent term to extend based on a single Regulatory Review Period (“RRP”), or for a company to request (and be granted) multiple PTEs based on multiple NDA (or BLA) approvals, the PTE applications for MEKTOVI and BRAFTOVI raise an important matter of first impression: It is Array’s contention that both the BRAFTOVI and MEKTOVI approvals involved four non-same RRPs based on different INDs and NDAs, making four patents eligible for PTE for each approval.

But before we delve into Array’s legal argument, some background on PTEs is in order . . . . because it’s going to be a bumpy ride from here . . .

Under Title II of the Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (1984) (“Hatch-Waxman Amendments”) and 35 U.S.C. § 156, certain patents related to products regulated by FDA are eligible for extension if patent life was lost during a period when the product was undergoing regulatory review.  The “regulatory review period” is composed of a “testing phase” and a “review phase.”  For a drug product, the “testing phase” begins on the effective date of an IND, and ends on the date a NDA is submitted to FDA.  The “review phase” is the period from NDA submission to the date of FDA’s approval of an NDA.  A patent term may be extended for a period of time that is the sum of one-half of the time in the “testing phase” (minus any time before patent issuance), plus all the time in the “review phase” (minus any time before patent issuance), including the time an applicant uses to respond to a Complete Response Letter.  The “regulatory review period” must be reduced by any time that the applicant “did not act with due diligence.”  The total (calculated) regulatory review period may not exceed five years, and the extended patent term may not exceed fourteen years after the date of approval of the marketing application.  In some cases, the term of a patent that is scheduled to expire before the PTO can issue a certificate of extension can be extended on an interim basis.  There are two types of interim PTEs: (1) interim patent extensions available during the “review phase” of the statutory “regulatory review period;” and (2) interim patent extensions available during the PTO’s review of an application for PTE.

The PTE statute states (at 35 U.S.C. § 156(c)(4)) that “in no event shall more than one patent be extended . . . for the same regulatory review period for any product.”  For quite some time now, the PTO has interpreted 35 U.S.C. § 156(c)(4) to permit multiple PTEs under certain circumstances (as well as multiple interim PTEs).  Specifically, for a drug product covered by several patents PTO may extend a different patent for each NDA approved on the same first day (even when multiple NDAs share common “testing phase” and a “review phase” dates).  That is, the PTO considers each NDA “regulatory review period” to be distinct and for which a PTE is available.  We’ve posted on this issue several times over the years – see here, here, and here.

Array presents a new twist on the multiple PTE argument.  The following is taken from one of the BRAFTOVI PTE applications, but the argument is the same for the MEKTOVI PTE applications:

For many drug products, clinical testing and FDA approval involve a single IND and NDA. In these situations, only one RRP will exist and only one patent will be eligible for term extension. In other cases, however, due to the complexity of the clinical trials or for FDA’s “administrative convenience,” multiple INDs or NDAs may be required for FDA approval. For drug products reviewed under multiple INDs or NDAs, multiple RRPs will exist and multiple patents will be eligible for term extension.

For example, if multiple NDAs for the same new drug product are approved simultaneously (to meet the statutory “first permitted commercial marketing” requirement discussed further below), non-same RRPs have been found to exist and multiple patent terms have been extended.  This has occurred where the NDAs reference the same underlying IND and even when the NDA and IND reviews occur over identical time frames.  Each IND/NDA combination was determined as not being the “same” RRP under§ 156(c)(4) and each provided the legal basis for a patent term extension.

For this to happen, the Patent Office had to interpret “same regulatory review period” in 156(c)(4) as not referring to a same time period but rather, referring to a same substantive regulatory activities and review undertaken by FDA.  In other words, if the regulatory information produced and reviewed by FDA during any RRP is different from the regulatory information of any other RRP, they would be considered not to be the “same” even if the underlying IND and NDA time periods overlap or are identical.

Under the Patent Office’s interpretation of the statute, non-same RRPs can be found to exist for the same product approval whether they are due to multiple NDAs and/or multiple INDs, as long as the underlying information reviews are different. Indeed, the statutory purpose of an RRP is to compensate a patentee for lost term associated with FDA review.  It should not matter, therefore, whether that term is lost due to multiple NDAs or multiple INDs as the outcome will be the same lost term due to regulatory delays in either event.

In the case of BRAFTOVI™, four separate INDs were required for the clinical studies and investigations that went into FDA drug product approval.  Accordingly, each IND contributed to a regulatory delay represented by the following non-same RRPs:

• RRP#l: IND 111003 + NDA 210496
• RRP#2: IND 117085 + NDA 210496
• RRP#3: IND 113850 + NDA 210496
• RRP#4: IND 120738 + NDA 210496

Based on these non-same RRPs for BRAFTOVI™, four separate patents are eligible for term extension.

The PTO is already putting up a fight on the legal argument Array has raised.  In a letter to FDA, the PTO comments: “It would appear that contrary to there being four separate ‘non-same’ regulatory review periods which gave rise to the single approval, it is the combination of the information from the four INDs that provided sufficient data to support the approval of the single NDA for BRAFTOVI® (NDA 210496).”  To that end, the PTO requests that FDA confirm “that the product identified in the application, BRAFTOVI® (encorafenib), has been subject to a SINGLE regulatory review period within the meaning of 35 U.S.C. § 156(g) before its first commercial marketing or use as the term ‘regulatory review period’ has been interpreted and implemented by FDA.”

Array responded to the PTO back in May 2019 in a 14-page letter stating, in part:

In previous cases where a product approval involved multiple RRPs, FDA determined that two RRPs would not be considered the “same” if the first product approval involved separate NDA review periods, even if the NDAs relied on the same investigational new drug (IND) review period (see e.g., OMNICEF®, ADCETRIS®, MYCAMINE®).  Moreover, two RRPs were not considered to be the “same” even where the combined IND and NDA review periods were identical in time (see e.g. LYRICA®).  However, the only way to square these non-sameness determinations with Section 156(c)(4) is for FDA to construe the term “same” to mean the same information undergoing regulatory review and not the same period of time under which the regulatory review takes place.  Thus, FDA appears to consider multiple RRPs not to be the “same” as long as they involve the review of different regulatory information for product approval, even if some or all of the IND and/or NDA periods overlap.

Consistent with this FDA precedent, the four RRPs identified in each of the Array PTE applications must also be determined as not being the “same” under Section 156(c)(4), because each involves the review of regulatory information that is different from the information under review in every other RRP. Accordingly, FDA must reject the recommendations in the USPTO’s advisory letter and make the determination that four non­same RRPs exist for each of the BRAFTOVI® and MEKTOVI® approvals.

The Array PTE requests and dockets have been on our radar for some time.  Moreover, the same legal argument was raised for a second time in the context of PTE applications for VITRAKVI (larotrectinib) Capsules (NDA 210861) and Oral Solution (NDA 211710) (see Docket Nos. FDA-2019-E-5681; FDA-2019-E-5682; FDA-2019-E-5663; and FDA-2019-E-5662), and for a third time in the context of PTE applications for patents covering a medical device, TherOx Downstream System, with multiple Investigational Device Exemptions and a single Premarket Approval (see the patent image file wrapper for each of U.S. Patent Nos. 8,246,564; 7,820,102; and 6,582,387).  So why are we blogging on the issue now?

Well, there’s been a development that could not only throw Array’s arguments into . . . um . . . “disarray” . . . but that could call into question any multiple PTEs granted by the PTO.

Earlier this week, when the non-Beta version of Regulations.gov was operational (because the new, and not too user-friendly, Beta version currently operates only on Tuesday and Thursday – see our previous post here – and searching is a pain), several new PTE dockets popped up in which Nabriva Therapeutics GMBH (“Nabriva”) requests multiple PTEs for different patents based on FDA’s August 19, 2019 approval of two NDAs for XENLETA: NDA 211672 for XENLETA (lefamulin) Tablets, and NDA 211673 for XENLETA (lefamulin) Injection.  You can access those PTE requests at Docket Nos. FDA-2020-E-1839; FDA-2020-E-1840; FDA-2020-E-1841; FDA-2020-E-1842; and FDA-2020-E-1843.

OK . . . so a request for multiple PTEs based on different NDA approvals is nothing new.  But what’s shocking is a July 13, 2020 letter from the PTO to FDA contained in each XENLETA PTE docket.

Styled as a “REQUIREMENT FOR INFORMATION PURSUANT TO 37 C.F.R. §1.750,” the PTO does an about-face on the availability of multiple PTEs:

The issue is whether 35 U.S.C. § 156 permits a patent owner who owns more than one patent to obtain more than one patent term extension for the same FDA approved product.  Applicant has filed multiple PTE applications directed to the same product (lefamulin). If applicant contends that more than one patent may be extended based on the approval of lefamulin, then applicant is required to provide legal support pursuant to 35 U.S.C. § 156, expressly demonstrating that the statute permits multiple term extensions based on the same product.  Absent a convincing showing, the Office plans to issue only one PTE directed to XENLETA® (lefamulin), provided that the requirements of 35 U.S.C. § 156 are met. . . .

Although both FDA approvals received the same date, they cannot both be considered as “first” approved under § 156(a)(5)(A) and they cannot both constitute distinct regulatory review periods under§ 156(a)(4).  These interpretations go against the plain statutory language, which states:

“the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred.”  There cannot be more than one “first permitted commercial marketing or use” of the product or more than “a” (single) regulatory review period of the product, subject to patent term extension.  Id.  Additionally,§ 156(c)(4) states that “in no event shall more than one patent be extended under subsection (e)(l) for the same regulatory review period for any product.”  Hence, subsection (c)(4) limits the right of a patent owner to obtain more than one extension based on time lost for the “same” regulatory review period for “any product.” See, 35 U.S.C. § 156(c)(4) and 37 C.F.R. § 1.785(b).

The PTO goes on to cite Novartis AG v. Ezra Ventures LLC, 909 F.3d 1367 (Fed. Cir. 2018), Arnold Partnership v. Rogan, 246 F. Supp.2d 460 (E.D. Va. 2003), and even (curiously) Biogen lnt’l v. Banner Life Sciences LLC, 956 F.3d 1351 (Fed. Cir. 2020) as supposed legal support for its position.  PTO then concludes the letter with the following paragraph and footnote acknowledging a change in position:

Section 156 does not allow for multiple extensions of patents beyond the one patent per one approved product.  The regulatory review period of XENLETA® (lefamulin) can be used as a basis for extension of only one patent.  See 35 U.S.C. § 156(c)(4) and 37 C.F.R. § 1.785(b).  Therefore, the Office plans to limit applicant to extending only one patent for the approved product (lefamulin).¹

¹The Office acknowledges that in the past it has permitted more than one extension when multiple forms of administration of the same drug product were applied for and approved by the FDA on the same day.  However, the Office believes that the proper interpretation of the statute, especially in light of recent court decisions discussed in this requirement for information, mandates that only a single patent be extended for any given drug product, regardless of the number of forms of administration approved by the FDA.

This is quite a bombshell!  We suspect the PTO will find itself in court trying to defend any final determination on multiple PTEs (maybe in the context of multiple PTE requests that were on the verge of being granted, such as for BAXDELA and BRIVIACT, but are now subject to letters like this).  And if the PTO is ultimately successful, then that decision could spawn litigation to invalidate previously-granted PTEs.  What a mess this could be!