Surely You Must be Kidding, PTO?!? “No, and Don’t Call Me Shirley!” – The Seemingly Slapstick (But Yet Unfunny) World of Recent Patent Term Extension Decisions (PART 2)

Earlier this week, we posted Part 1 of our three-part series on U.S. Patent and Trademark Office (“PTO”) Patent Term Extension (“PTE”) decisions under 35 U.S.C. § 156, as added by the 1984 Hatch-Waxman Amendments, for certain FDA-regulated products.  Part 1 focused on both the PTO’s historical and current (180-degree and unsupported change in position) on multiple PTEs.

Today, we move on to Part 2 (or “Part Deux” in homage to the 1993 comedy “Hot Shots! Part Deux,” which starred Lloyd Bridges, who also starred in the 1980 movie “Airplane!” referenced in Part 1 of our series) concerning the PTO’s position and recent decisions on PTE applications for patents covering products approved—and then withdrawn years later—under the Federal Food, Drug, and Cosmetic Act’s (“FDC Act’s”) Accelerated Approval provisions (as well as the Agency’s corresponding regulations, which actually preceded the statutory provisions).  As FDA explains on its website (which includes lists—here and here—of the more than 300 Accelerated Approvals (and withdrawals)):

The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and fill an unmet medical need based on a surrogate endpoint.  A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.

Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug.  If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.

The statutory Accelerated Approval provisions were amended in 2023 as part of the Food and Drug Omnibus Reform Act of 2022 (“FDORA”) to, among other things, give FDA greater authority to expedite the withdrawal of approval of an Accelerated Approval product if clinical benefit is not confirmed post-NDA or -BLA approval.  For more on those amended provisions, see our FDORA Summary here.

Part 2:  Accelerated Approval Withdrawals and the End of the PTE Road

Last week, FDA announced that, for the first time, the Agency flexed its new FDORA-enhanced Accelerated Approval muscle when issuing a final decision to withdraw the approval of Oncopeptides AB’s  (“Oncopeptides’s”) PEPAXTO (melphalan flufenamide) for Injection.  FDA approved PEPAXTO on February 26, 2021 under NDA 214383 for use in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody.

As part of the Accelerated Approval, Oncopeptides was required to conduct “further adequate and well-controlled clinical trials to verify and describe clinical benefit.”  That did not happen.  FDA’s February 23, 2024 decision says that “the grounds for withdrawing approval have been met because: (1) the confirmatory study conducted as a condition of accelerated approval did not confirm Pepaxto’s clinical benefit and (2) the available evidence demonstrates that Pepaxto is not shown to be safe or effective under its conditions of use.

We note all of this FDA law in the context of a patent-related PTE post because FDA’s withdrawal decision has ramifications beyond the FDA world.  You see, Oncopeptides has has pending at the PTO since March 2021 a PTE application for U.S. Patent No. 6,992,207 covering PEPAXTO (Docket No. FDA-2022-E-3124).  And given recent PTO PTE decisions, it may be the end of the road for this PTE application.

Although we don’t know for sure how far back this apparently new effort goes (the precedents we know of are all from 2023), the PTO has—as quiet as a mouse peeing on cotton, as my mother might say—taken the position that once FDA withdraws approval of an NDA or BLA under the Accelerated Approval program (or otherwise!), that action nullifies any pending PTE application.  (Whether withdrawal also nullifies any already-granted PTE is a separate question folks can ponder.)  Consider, for example, the following four PTO decisions we unearthed.

On April 14, 2023, the PTO issued an ORDER TO SHOW CAUSE to Eli Lilly and Company (“Lilly”) “based on the apparent ineligibility of U.S. Patent No. 8,128,929 [] for [PTE] request under 35 U.S.C. § 156.”  The PTE application for U.S. Patent No. 8,128,929 was submitted on December 8, 2016 (Docket No. FDA-2017-E-5106), and concerns FDA’s October 19, 2016 Accelerated Approval of BLA 761038 for LARTRUVO (olaratumab).  The PTO’s ORDER TO SHOW CAUSE points out that:

According to the published Federal Register Notice of July 17, 2020, Lilly requested withdrawal “(revocation)” of its BLA for the human biological product LARTRUVO® (olaratumab).  The Notice, in part, provided that the required clinical data did not meet the required threshold to receive final approval and Lilly waived its opportunity for a hearing.

From there, the PTO notes that a PTE “determination is made based on the representations contained in the PTE application,” and that “35 U.S.C. § 156(c) provides ‘[t]he term of a patent eligible for extension under subsection (a) shall be extended by the time equal to the regulatory review period for the approved product which period occurs after the date the patent is issued.’” (Emphasis in original).  Then comes the PTO’s requirement to show cause:

Since there is no longer an approved product, Lilly is required to show cause with regard to its PTE application for LAR TRUVO® ( olaratumab) and establish: (1) why the USPTO should not terminate the PTE application based on the plain language of 35 U.S.C. § 156(c); and (2) why the PTE application for the ‘929 patent should remain under consideration despite Lilly’s express written request of withdrawal (revocation) of BLA-761038 and waiver of the opportunity for a hearing.  In responding to the show cause request, Lilly should identify statutory language in 35 U.S.C. § 156 or case law that would support extension of the ‘929 patent that claims the product despite revocation of the biologics license application. Moreover, Lilly should explain how a PTE application for a withdrawn “revoked” biologics license application is in compliance with requirements of 37 C.F.R. § 1.740.

According to documents in the PTO’s Patent Center, Lilly has not yet filed a response.

Our second example follows the same pattern as the first example above.  On April 20, 2023, the PTO issued an ORDER TO SHOW CAUSE to Glaxo Group Limited (“Glaxo”) “based on the apparent ineligibility of U.S. Patent No. 9,273,141 [] for [PTE] request under 35 U.S.C. § 156.”  The PTE application for U.S. Patent No. 9,273,141 was submitted on September 18, 2020 (Docket No. FDA-2020-E-2275), and concerns FDA’s August 5, 2020 Accelerated Approval of BLA 761158 for BLENREP (belantamab mafodotin-blmf).  The PTO’s ORDER TO SHOW CAUSE points out that:

According to the published Federal Register Notice of March 30, 2023, Glaxo requested withdrawal “(revocation)” of its BLA for the human biological product BLENREP® (belantamab mafodotin-blmf).  The Notice, in part, provided that the required clinical data did not meet the required threshold to receive final approval and Glaxo waived its opportunity for a hearing.

From there, the PTO conveys the same message to Glaxo as it did with Lilly above.  But in this case, there’s a response on file from Glaxo pushing back on the PTO’s position and taking the position that a PTE in this case “is mandatory and not discretionary.”

Our third example also follows the same pattern as the first two examples above.  In addition, it’s playing double duty for us because it’s also one of the pending multiple PTE cases we identified in Part 1 of this series.  On June 27, 2023, the PTO issued two ORDER TO SHOW CAUSE letters (here and here) to Gilead Sciences Inc.  (“Gilead”) “based on the apparent ineligibility of U.S. Patent No. RE 44,599 [and U.S. Patent No. RE 44,638] for [PTE] request under 35 U.S.C. § 156.”  The four PTE applications for U.S. Patent Nos. RE 44,599 and RE 44,638 were submitted nearly ten years ago (a point not lost on Gilead as noted below), on September 17, 2014 (Docket Nos. FDA-2015-E-2602, FDA-2015-E-2604, FDA-2015-E-2619, and FDA-2015-E-2615), and concern FDA’s July 23, 2014 Accelerated Approval of NDA 205858 and NDA 206545 for ZYDELIG (idelalisib) Tablets for different uses.  The PTO’s ORDER TO SHOW CAUSE letters point out that:

According to the published Federal Register Notice of May 26, 2022, Gilead requested withdrawal “(revocation)” of its active ingredient ZYDELIG® (idelalisib).  The Notice, in part, provided that the required clinical data did not meet the required threshold to receive final approval and Gilead waived its opportunity for a hearing.

From there, the PTO conveys the same message to Gilead as it did to Glaxo and Lilly above.  But in this case, as with Lilly, there are responses (here and here) on file from Gilead with respect to each ORDER TO SHOW CAUSE letter.  And Gilead takes the PTO to town(!):

As described below, Applicant believes that the Order rests on a basic factual error regarding the approval status of ZYDELIG (idelalisib) oral tablets (100 and 150 mg). In particular, the Order incorrectly states that [FDA] withdrew approval of ZYDELIG (idelalisib) in May 2022.  In fact, FDA withdrew approval of two of the three indications for which ZYDELIG (idelalisib) had initially been approved. ZYDELIG (idelalisib) remains approved for use “in combination with rituximab, for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.”  On this basis, the pending applications for [PTE] should not be terminated, and Applicant respectfully requests that the USPTO promptly issue a final determination on the pending applications.

In addition, Applicant would like to take this opportunity to address several issues raised by the Order.  First, the Order repeatedly characterizes the Accelerated Approval pathway as “conditional” or otherwise short of final approval.  This characterization represents an incorrect interpretation of the eligibility requirements for patent term extension under 35 USC 156.

Finally, Applicant respectfully requests that the USPTO promptly issue a final determination on the pending PTE applications related to ZYDELIG (idelalisib).  These applications have been pending for more than nine years. There is no apparent justification for such delay, particularly where the USPTO has granted dozens of patent term extensions based on products approved – and PTE applications submitted- more recently than ZYDELIG (idelalisib).

Ouch!  Since then, there’s no record of the PTO responding.  As Lt. Frank Drebin of Police Squad once said: “The truth hurts, doesn’t it, Hapsburg?  Oh sure, maybe not as much as landing on a bicycle with the seat missing, but it hurts!”

Our fourth example ties in our Part 1 post and the references to BELVIQ (lorcaserin HCl) Tablets (NDA 022529; approved on June 27, 2012) and the Improving Regulatory Transparency for New Medical Therapies Act (“IRTNMTA”), with the PTO’s December 21, 2023 ORDER TO SHOW CAUSE “based on the apparent ineligibility of U.S. Patent No. 6,953,787 [] for [PTE] request under 35 U.S.C. § 156.”  That PTE application was submitted to the PTO on July 26, 2012.  While that’s quite a while ago, the file was complicated by a fight over the IRTNMTA (see our previous post here).

In any case, the PTO’s December 21, 2023 ORDER TO SHOW CAUSE, unlike the two cases above, goes outside of the Accelerated Approval withdrawal context.  It follows a February 13, 2020 request from the sponsor of BELVIQ that FDA withdraw approval of BELVIQ, a September 17, 2020 FDA Federal Register Notice withdrawing approval of BELVIQ (effective September 17, 2020), and a March 4, 2021 Federal Register Notice in which FDA determined that BELVIQ was withdrawn from sale for safety or effectiveness reasons.  According to the PTO:

Since there is no longer an approved product, Eisai as authorized entity acting on behalf of the PTE Applicant, Arena, is required to show cause with regard to its PTE application for BELVIQ® (lorcaserin hydrochloride) and establish: (1) why the USPTO should not terminate the PTE application based on the plain language of 35 U.S.C. § 156(c); and (2) why the PTE application for the ’787 patent should remain under consideration despite the express written request of withdrawal (revocation) of the active ingredient BELVIQ® (lorcaserin hydrochloride) and waiver of the opportunity for a hearing. In responding to the show cause request, Eisai should identify statutory language in 35 U.S.C. § 156 or case law that would support extension of the ’787 patent that claims the product despite revocation of the active ingredient. Moreover, Eisai should explain how PTE application for a withdrawn “revoked” of active ingredient BELVIQ® (lorcaserin hydrochloride) is in compliance with requirements of 37 C.F.R. § 1.740.

In a February 16, 2024 response to the PTO’s ORDER TO SHOW CAUSE, “Applicant submits that the PTE statute (35 U.S.C. § 156) does not condition the right to an extension on the continued approval of a drug product during pendency of a PTE application,” and that the “patent should remain under consideration for PTE, and Applicant’s second interim extension request should be granted, despite the fact that FDA’s approval for BELVIQ has been withdrawn.”

Based on the above documents, the PTO is in for a fight on negating PTE for products withdrawn under the Accelerated Approval withdrawal procedures, and where FDA determines that a product is withdrawn for safety or effectiveness reasons.  But one must wonder whether or not the PTO—absent failing in its current efforts—will go one step farther and seek to negate PTE applications when approval of a product is withdrawn outside of the Accelerated Approval or safety/effective circumstances above.  That is, when the application holder voluntarily requests withdrawal of approval for no particular reason.  After all, as Mama Karst is fond of saying: “Why do a job half-assed when you can do it whole-assed?”  To that end, one can almost picture someone at the PTO sitting back in his/her office poring over FDA Federal Register notices withdrawing application approvals and comparing them to long-pending PTE application files.  And with the unbelievable lag-time from PTE application submission to PTE grant, there may be a lot of candidates to choose from.