The Great Delisting! Companies delist patents in response to FTC notices.

The FTC sent letters dated November 7, 2023 to nine pharmaceutical companies stating that the FTC believes:

certain patents have been improperly or inaccurately listed in the Orange Book with regard to [name of pharmaceutical company] products and that we have availed ourselves of the FDA’s regulatory process and submitted patent listing dispute communications to the FDA regarding the patents.

Below, I discuss products for which the NDA holder delisted some, but not necessarily all, patents as a result of receiving the FTC letters.

ARNUITY ELLIPTA, ANORO ELLIPTA

ARNUITY ELLIPTA is an inhaled drug indicated for the once-daily maintenance treatment of asthma as prophylactic therapy. The FTC letter for ARNUITY ELLIPTA mentions four patents, but only mentions one strength of the drug. Strengths of a drug are identified in the Orange Book by “Product Number” (“Prod. No.”). For example, in the Orange Book, there are three product numbers for ARNUITY ELLIPTA (fluticasone furoate). Those product numbers, 001, 002 and 003, represent the following strengths of ARNUITY ELLIPTA in milligrams per inhalation (mg/inh):

Prod. No. 001 = 0.1mg/inh

Prod. No. 002 = 0.2mg/inh

Prod. No. 003 =  0.05mg/inh

However, since the FTC letter for ARNUITY ELLIPTA only mentioned “Product Number 1”, Glaxosmithkline (“GSK”) apparently took that identification literally and only reviewed patents that had been listed for ARNUITY ELLIPTA’s Prod. No. 001 strength even though all three strengths of ARNUITY ELLIPTA had the same six patents listed. Moreover, none of the claims of those six patents had any limitations that involved the strength of the drug.

GSK delisted three of the patents listed in the Orange Book for ARNUITY ELLIPTA Prod. No. 001 (8,113,199, 8,161,968, and 8,534,281). Those three patents were identified in the FTC letter along with 8,746,242 which was not delisted. The ‘199 patent claims a dose counter doohickey for which there should be very little doubt about its lack of eligibility for listing in the Orange Book. While there might be arguments that could be made towards the eligibility of the ‘281 and ‘968 patents, GSK nonetheless delisted them. That left three patents remaining listed for ARNUITY ELLIPTA Prod. No. 001.Despite there being no limitations in any of the patnet involving the strength of the drug, GSK left all of the original six patents listed for each of the other two ARNUITY ELLIPTA strengths, Prod. Nos. 002 and 003. 

Since GSK concluded that three of the patents listed for Prod. No. 001 should be delisted, there could definitely be a question as to why those same patents were not delisted for Prod. Nos. 002 and 003. 

GSK did not delist 8,746,242 which was the fourth patent for ARNUITY ELLIPTA Prod. No. 001 that the FTC had included in their letter. Independent claim 1 of the ‘242 patent is directed to a “medicament dispenser” that could include the ARNUITY ELLIPTA inhaler device. The claim also requires “at least one medicament carrier carrying multiple distinct medicament portions . . .”  That limitation could include the “foil blister strip of powder” described in the ARNUITY ELLIPTA label as containing the active ingredient. Together, those two elements could be interpreted to meet the two elements of the “drug product” definition of 21 CFR 210.3(4), (generally summarized as “a finished dosage form . . . that contains an active drug ingredient”). Such an interpretation would make the ‘242 patent eligible for listing in the Orange Book, and so could support Glaxo’s decision to retain the ‘242 patent in the Orange Book.

In a letter to Senator Elizabeth Warren and Representative Pramila Jayapal dated January 12, 2024, GSK confirmed that they were delisting three of the four patents that the FTC had included in their letter for ARNUITY ELLIPTA Prod. No. 001. However, GSK came to the same conclusion as I did, above, and informed Senator Warren and Representative Jayapal that they were keeping the ‘242 patent listed.

Orange Book Vol. 44, Supp. 2 shows that GSK additionally delisted the ‘199 dose counter doohickey patent from the patent listing for another GSK drug called ANORO ELLIPTA (umeclidinium bromide and vilanterol trifenatate), NDA 205624 Prod. 001. ANORO ELLIPTA is an inhaled drug that was approved on December 18, 2013 for maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). ANORO ELLIPTA was not mentioned in any letter that the FTC sent to Glaxo.

AUVI-Q

The FTC’s letter to Kaleo Inc. questioned the eligibility of eight of the thirty patents that Kaleo had listed in the Orange Book for Kaleo’s AUVI-Q epinephrine autoinjector product (NDA 201739, Prod. No. 002). None of the claims of those eight patents mentioned the active ingredient of the AUVI-Q product, epinephrine. In an FDA Law Blog entry, Sara Koblitz described the FTC’s position as being that a claim of a patent must mention the specific active ingredient of the approved drug in order to be eligible for listing in the Orange Book. None of the eight patents identified by the FTC mentioned epinephrine as being in the claimed device.

The  claims did, in fact, identify the claimed device to be a “medicament delivery device configured to deliver a medicament into a body.” That broad type of statement, in my opinion, could reasonably support the listing of the patent in the Orange Book. Indeed, when a patent attorney drafts claims for a drug delivery device they do not necessarily know the names of all of the drugs, presently existing or to be discovered in the future, that could be delivered using the claimed device. Therefore, why must a drug delivery device patent be limited to specific known drugs for Orange Book listing purposes when a broader term such as “medicament” would serve just as well?

In Vol. 43, Supp.12 of the Orange Book, Kaleo delisted all eight patents that the FTC had identified in their letter. Each of the remaining patents listed for AUVI-Q did, in fact, contain at least one claim that identified epinephrine as the medicament being delivered by the claimed device.

Unlike GSK’s inaction with ARNUITY ELLIPTA, Kaleo delisted all of the patents identified by the FTC from the Orange Book listings for the other two approved strengths of AUVI-Q, NDA 201739, Prod. Nos. 001 and 003, even though the FTC letter had only identified Prod. No. 002. 

Possibly as a result of Kaleo’s further review of their Orange Book listings for AUVI-Q, Orange Book Vol. 44, Supp. 1 showed that Kaleo delisted an additional four patents (7,918,823, 9,056,170, 9,259,539, and 9,278,182) from the listings for all three strengths of AUVI-Q. Three of those four patents did, in fact, contain claims that included epinephrine as the active ingredient being delivered by the device. So there might be other differences known to Kaleo that distinguished all of those additional four delisted patents from the approved AUVI-Q device.

RESTASIS MULTIDOSE

RESTASIS MULTIDOSE has a complicated history. The first-approved version of RESTASIS (hereinafter “original RESTASIS”) was a product of Allergan, and was approved on Dec 23, 2002 under NDA 021023. Original RESTASIS was packaged in single-use vials containing 0.4ml of the approved 0.05% cyclosporine ophthalmic emulsion. The product was supplied in trays containing 30 or 60 of the single-use vials. Each vial could deliver two drops of emulsion.

RESTASIS MULTIDOSE was approved on October 27, 2016 and is supplied in a white opaque LDPE squeeze bottle containing 5.5ml of emulsion. The bottle has a white opaque polypropylene top containing a unidirectional valve and air filter. The bottle is topped with a protective olive green polypropylene cap.

The emulsion from one single-use vial of original RESTASIS was to be used immediately after opening, and the remainder was to be discarded immediately after administration. So if the patient only needed treatment in one eye, there would be sufficient emulsion remaining in the vial for a second drop to be applied later to the same eye that needed the treatment. Since original RESTASIS was to be administered twice daily approximately 12 hours apart, there was concern on the part of FDA reviewers that a patient might save the opened vial and use it to make the second administration for that day in the same eye even though the labeling instructs the patient to immediately discard the unused contents of the opened vial.

 Allergan was acquired by Abbvie in May 2020. So, both versions of RESTASIS (original and MULTIDOSE) are currently shown in the electronic Orange Book as Abbvie products. However, the Vol. 23 (2003), Supp. 3 PDF version of the Orange Book shows that the NDA number and product number for the original RESTASIS was changed to NDA 050790, Prod. No. 001. Since the NDA number was now in the 50,000 series, the active ingredient, cyclosporine, would have been considered to be a so-called “old antibiotic.” As a result, there could be no patent listings under Hatch-Waxman for original RESTASIS since old antibiotics such as Prod. No. 001 were not covered by Hatch-Waxman until the enactment of the Qualified Individual (“QI”) Act on Oct. 8, 2008. The QI Act provided for patent listings for old antibiotics.

The first patent listings for original RESTASIS appeared in Vol. 28 (2008), Supp. 11 of the Orange Book Supp. 11 was published the month following the enactment of the QI Act. By the time RESTASIS MULTIDOSE was approved on October 27, 2016 there remained six patents listed in the Orange Book for original RESTASIS, as the first two patents that had been listed for original RESTASIS following the enactment of the QI Act had expired.

RESTASIS MULTIDOSE was approved on October 27, 2016 under the same 50,000-series NDA number, 050790, as original RESTASIS, but was designated as Prod. No. 002. As the name implies, RESTASIS MULTIDOSE is a drug product that contains multiple doses of the 0.05% RESTASIS emulsion in a container that was apparently designed to reduce evaporation from the emulsion during storage. See Orange Book-listed patent 8,292,129 starting at column 1, line 28 where it states: 

What is problematic here [referring to the generic dispensing devices known in the prior art] is that the inlet opening and the connection of the inlet opening to the medium reservoir permit an escape of the medium in gaseous form. 

Following the approval of RESTASIS MULTIDOSE on October 27, 2016, Allergan listed the six original RESTASIS patents for the newly approved RESTASIS MULTIDOSE (see Orange Book Vol. 36 (2016), Supp. 11). Allergan later added four additional patents to the RESTASIS MULTIDOSE listings (Orange Book Vol. 37 (2017) Supp. 6). That later listing gave RESTASIS MULTIDOSE a total of ten patents in the Orange Book.

The November 7, 2023 letter that the FTC sent to Abbvie was directed to RESTASIS MULTIDOSE, and not to original RESTASIS. The letter recited four patents that were being questioned. Those were the additional patents mentioned above that Abbvie had added to the RESTASIS MULTIDOSE patent listings in Vol. 37, Supp. 6 of the Orange Book. However rather than delisting the four patents that the FTC was questioning, Abbvie filed delisting requests with the FDA to delist the six patents listed for RESTASIS MULTIDOSE that had first been listed for original RESTASIS.

Abbvie’s decision to request delisting of the six original RESTASIS patents was a logical one since four of those patents had been found to be invalid for obviousness in a trial in the Eastern District of Texas (Allergan, Inc. v. Teva Pharmaceuticals USA, Inc. et al, Case No. 2:15-cv-1455-WCB (EDTX October 16, 2017 Order)(aff’d Fed. Cir. Nov.13, 2018), and the remaining two patents were found to be invalid for obviousness in a challenge at the PTAB (Sept. 27, 2019). That would leave RESTASIS MULTIDOSE with only the four patents being questioned by the FTC: 8,292,129, 8,561,859, 9,676,525, and 9,669,974.

All of the patents questioned by the FTC are in separate patent families. The claims of the ’129 and ‘859 patents are directed to dispensing devices for dispensing liquid media. The technology recited for the claimed devices is basically tied to dispensing the media contained in the device’s reservoir through an “outlet opening” and replacing the volume of dispensed media with air through an “inlet opening” so as to effect volume equalization in the reservoir.

The claims of the ’129 and ‘859 patents increase in complexity as they are read from the first to last. Yet at no point is an “active drug ingredient” recited or even tangentially referred to in any claim that might allow an argument that a claim meets the “drug product” definition of 21 CFR 210.3(4) that requires an “active drug ingredient.” Indeed, as the device is illustrated in the drug label, the RESTASIS MULTIDOSE product for which the ’129 and ‘859 patents were listed seems like nothing more than an ordinary squeezable eye drop dispenser with a complicated plumbing.

That leaves the ‘525 and ‘974 patents. The claims of the ’974 patent listed for RESTASIS MULTIDOSE vacillate between “a protective cap for a dispenser for discharging a pharmaceutical and/or cosmetical liquid,” (claims 1-4 and 9-10) and a “discharge device comprising: a dispenser for discharging a pharmaceutical and/or cosmetical liquid.” (claims 5-8). The “cap” claims would not make the ‘974 patent eligible for listing in the Orange Book since a claim to a mere cap on the device would not be a claim to a “finished dosage form” as is required by 21 CFR 210.3(4). However, claims 5-8 of the ‘974 patent that are directed to the “discharge device”, itself, may well make the patent eligible for listing, especially when the claims recite that the device is used to dispense a “pharmaceutical” liquid.

The claims of the ‘525 and ‘974 patents both include the element of a dispenser for discharging a “pharmaceutical and/or cosmetical liquid.” So the use of the claimed invention with some kind of pharmaceutical (e.g., cyclosporine) at least gives support for listing the patent in the Orange Book. However, the FDA Law Blog entry authored by Sara Koblitz mentioned previously describes the FTC’s position as being that a claim of a patent must mention the active ingredient of the approved drug in order to be eligible for listing in the Orange Book. With cyclosporine not being mentioned in any claim of the ‘525 ‘or ‘974 patents the FTC might argue that those patents would not be eligible for listing. But can’t a drug product be claimed using a broad genus term such as “pharmaceutical” as well as by using species terms such as the specific active ingredient? As such, in my opinion, a genus term such the “pharmaceutical” liquid of the ‘974 and ‘525 patents could be considered to an encompass an “active drug ingredient” as required by 21 CFR 210.3(4). That would then support an argument that the ‘974 and ‘525 patents would be eligible for listing in the Orange Book.

ADVAIR HFA, FLOVENT HFA, VENTOLIN HFA

All of the above products are products of “Glaxo” (Glaxo Group Ltd and GlaxoSmithKline). Patent No. 7,500,444 was listed in the Orange Book for each of those products, and the FTC questioned the eligibility of the ‘444 patent for listing in the Orange Book. All of the products are administered via inhalation. ADVAIR HFA and FLOVENT HFA are used for asthma, while VENTOLIN HFA is used for bronchospasm.

The claims of the ‘444 patent are directed to an “actuation indicator” such as a dose counting device for the inhaled products. The actuation indicator is merely a part of the overall inhaler device, and so would be unlikely to be considered to meet the Drug Product definition of 21 CFR 210.3(4) that requires a drug product to be a finished dosage form that contains an active drug ingredient.

Since the FTC letter only identified FLOVENT HFA Prod. No. 003, Glaxo only delisted the ‘444 patent for the FLOVENT HFA 0.044mg/inh. strength (Prod. No. 003). The ‘444 patent remains listed for the remaining two strengths of FLOVENT HFA (Prod. Nos. 001 and 002).

Glaxo delisted the ‘444 patent for the sole approved strength of VENTOLIN HFA and for all three strengths ADVAIR HFA. 



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