A disappearing Pediatric Exclusivity and other musings about the June 2019 Orange Book supplement

In mid-July the FDA released their June 2019 (Vol. 39, Supp. 6) Orange Book raw data. Here are a few observations about Supplement 6:

There were 47 new patents listed in June. Only four of the newly listed patents had traditional compound claims which does not include new polymorphs, salts or hydrates.

One patent was delisted in June. The patent, 8,759,316, had been listed for KENGREAL®(cangrelor) from Chiesi USA. The claims are directed to a method of transitioning a patient from administration of cangrelor during percutaneous coronary intervention (“PCI”, which is the more modern name for angioplasty with stent) to administration of cangrelor in preparation for surgery, or vice versa. Cangrelor is not in the latest Patent Listing Disputes list, nor is it in the July 16, 2019 “Paragraph IV Patent Certifications” list. The NCE-1 date occurred on June 22.

So why was the patent delisted? One thought that I had was based upon the lack of any mention in the KENGREAL label of the claimed “transitioning” from one dosing regimen for cangrelor to another. Judicial decisions have interpreted the statute (21 USC 355(b)(1)) to require, in part, that a listed patent should claim the drug or an approved method of using the drug. Maybe Chiesi recently noticed the lack of the claimed transitioning method in the KENGREAL label and decided to delist the ‘316 patent in preparation for P. IV filings now that the NCE-1 date had passed. If you know anything more about this, please feel free to add a comment.

10-K for 2010 filed by The Medicines Company (from whom Chiesi acquired KENGREAL in 2016) describes a proposed clinical trial for cangrelor that is in the same vein as the claims (see the “BRIDGE” trial description on p. 11 of the 10-K). So maybe if Chiesi continues to do research along that path the ‘316 patent will have an encore in the future.

Twenty patents for a drug get PED exclusivity, and then sixteen lose it

Novo Nordisk’s XULTOPHY is a fixed-dose combination of insulin degludec and liraglutide for treating Type 2 diabetes. In the Orange Book Companion®’s April 2019 “What’s New” page I noticed that all twenty patents listed in the Orange Book for XULTOPHY had received six months of pediatric exclusivity. There was nothing really special about that since the “What’s New” page often shows that a drug has received pediatric exclusivity.

Now let us fast forward to the June 2019 Orange Book Companion “What’s New” page that was based on the Orange Book Supplement 6 raw data. There I saw that sixteen of the twenty XULTOPHY patents had lost their pediatric exclusivity! That change really raised my curiosity. As it turns out, the FDA was correcting their oversight in showing all twenty patents as having been granted pediatric exclusivity when, in fact, only four should have been. 

The pediatric exclusivity for the XULTOPHY patents was based upon a Written Request from the FDA to Novo Nordisk to conduct pediatric studies on a combination treatment for Type 2 diabetes using injectable liraglutide and oral metformin. Novo Nordisk markets injectable liraglutide monotherapy under the brand name VICTOZA®. The FDA determined that Novo Nordisk had complied with the Written Request as of May 1, 2019, and the pediatric exclusivity was granted. As a result, all of the unexpired patents listed in the Orange Book for VICTOZA were granted the six-month pediatric exclusivity.

The oversight in the XULTOPHY patent listings occurred when the FDA applied the pediatric exclusivity that was earned with pediatric studies on monotherapy VICTOZA to all of the patents listed for the XULTOPHY combination product. The pediatric exclusivity should have instead been applied to only those XULTOPHY patents that were also listed for 
VICTOZA . This is explained in the FDA’s guidance document entitled “Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act” [Sept. 1999 revision] where it states:

if any of the protections covering the monotherapy also apply to a combination product, the pediatric exclusivity appended to the protections for the monotherapy would also apply to the same protections listed for the combination therapy. Guidance at p. 13 (emphasis added).

When I compared the VICTOZA patent listings to the XULTOPHY patent listings only four VICTOZA patents were also listed for XULTOPHY. The FDA’s revision of the XULTOPHY patent listings in June left only those four patents with pediatric exclusivity.


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