Drugmakers hoping to compete with a monoclonal antibody (MAb) granted a seven-year orphan drug exclusivity have final guidance on what they need to do to differentiate their MAbs to get around the exclusivity.

The FDA issued a guidance Tuesday mapping out its current thinking on determining sameness of MAb products under the orphan drug rule. That thinking hasn't changed much in 15 years, despite scientific advances and a better understanding of MAbs.

The final guidance, to be published in Wednesday's Federal Register, tweaks a draft issued in 1999. One of those tweaks is a new paragraph clarifying that the sameness standards in the guidance do not apply to biosimilars.

Drugmakers wanting to take on a drug with orphan exclusivity in a specific indication have two routes – demonstrate superiority or show that their product is a different drug. That means the FDA has to set standards for how it determines if one drug is considered the "same" as another.

Sameness is much simpler for other macromolecules such as proteins, nucleic acids, carbohydrates or live viral vaccines, the FDA said. With those biologics, the agency looks at whether they have the same principal molecular structural features.

It's not so clear with MAbs, given their complexity and variability. "Because of the many processes involved in generating antibody diversity, it is unlikely that independently derived monoclonal antibodies with the same antigen specificity will have identical amino acid sequences," the FDA said in the final guidance.

So how will it determine MAb sameness? Instead of looking at the overall structure of an unmodified MAb, the agency will consider the complementarity-determining regions (CDRs) of the biologic's heavy and light chain variable regions to be its principal molecular structural features. If the CDRs of two MAbs have the same amino acid sequences or only minor amino acid differences, the FDA will likely deem them the same drug.

The agency will make such determinations on a case-by-case basis. The information it will consider includes the sequence of the heavy and light chain variable regions of the MAb, modifications in antibody sequence and particular residues that may have been established as important for antigen binding.

In determining sameness for antibody conjugates, fusion proteins, and bispecific and multispecific antibodies, the FDA will consider the sameness of the MAb element, as well as the sameness of the functional element of the conjugated molecule. "A difference in any one of these elements can result in a determination that the molecules are different," the agency said.

Conversely, two MAb conjugates or fusion proteins would be considered the same drug if the CDR sequences of the antibody and the functional element of the conjugated molecule were both the same.

The FDA also plans to apply the MAb sameness standards to T-cell receptor drugs.

PATENT EXPIRY IS WHAT COUNTS

When it comes to double patenting, the earliest expiration date is the determining factor, the Federal Circuit said in a split decision striking down a Gilead Sciences Inc. patent related to antiviral compounds and methods for their use.

Overturning a lower court, the U.S. Court of Appeals for the Federal Circuit handed down its decision Tuesday, answering the narrow question: "Can a patent that issues after but expires before another patent qualify as a double patenting reference for that other patent?" The majority opinion, written by Judge Raymond Chen, was a resounding yes.

Chief Judge Randall Rader begged to differ. In adopting that opinion, he said, the majority crafted a new judicial rule providing that the expiration dates of patents govern a double patent inquiry irrespective of the filing or issue dates.

"To justify this new rule, the court relies on the flawed assumption that upon the expiration of a patent, the public obtains an absolute right to use the previously claimed subject matter," Rader said.

The majority defended its decision, saying, "If we were to hold that issuance date is the determining factor for double patenting inquiries . . . the terms of such patents could be subject to significant gamesmanship."

In Gilead Sciences Inc. v. Natco Pharma Ltd., Natco claimed Gilead's '483 patent, which has a Dec. 27, 2016, expiration date, was invalid for obviousness-type double patenting over Gilead's '375 patent, which expires early next year.

Since the '483 patent issued first, Foster City, Calif.-based Gilead said the question should be whether the '375 patent was invalid for obviousness. And the answer to that would be no, it maintained.

Gilead filed the '375 patent 10 months before filing the other patent. Although both patents are related to the inhibition of viruses through selective interference with certain enzymes and they contain "very similar and, in substantial parts, identical" written descriptions, Gilead didn't file them as part of the same family of patents, according to court documents. And each patent was handled by a different examiner, neither of whom was apparently told of the other patent.

Rader recognized that condoning Gilead's conduct could lead to some strategizing "to maximize patent term and obtain varying priority dates to hedge against intervening prior art." But he didn't think that was enough reason to "warrant a new judicially created exception to invalidate patents."

Noting that the judicial rule would add to the pressure created by the America Invents Act to file patent applications early, Rader warned that the majority opinion could have unforeseen consequences in the race to the patent office.