HUMIRA DOSING PATENT FALLS BUT NOT BASED ON HUMIRA'S HALF-LIFE

On May 16, 2017, the PTAB issued a Final Written Decision in IPR2016-00172, filed by Coherus, finding Abbvie’s U.S. Patent 8,889,135 unpatentable as obvious over two prior art references. 

Claims 1, 3 and 4 of the ‘135 Patent

1. A method for treating rheumatoid arthritis in a human subject, comprising administering subcutaneously to a human subject having rheumatoid arthritis a total body dose of 40 mg of a human anti-TNFα antibody once every 13 -15 days for a time period sufficient to treat the rheumatoid arthritis, wherein the anti-TNFα antibody comprises an IgG1 heavy chain constant region; a variable light ("V.sub.L") chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:7, a CDR2 having the amino acid sequence of SEQ ID NO:5, and a CDR3 having the amino acid sequence of SEQ ID NO:3; and a variable heavy ("VH") chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:8, a CDR2 having the amino acid sequence of SEQ ID NO:6 and a CDR3 having the amino acid sequence of SEQ ID NO:4.

3. The method of claim 2, wherein the anti-TNFα antibody is administered for a period of at least 24 weeks.

4. The method of claim 1, wherein the anti-TNFα antibody is administered for a period of at least 24 weeks.

The combination of two prior art references taught all the limitations of the claims of the ‘135 Patent.

‘135 patent	van de Putte
subcutaneous 40 mg once every 13–15 day	subcutaneous 40 mg weekly
24 weeks	3 months (12 weeks),
	Kempeni
	biweekly intravenous 0.5 mg/kg= 40 mg fixed subcutaneous dose
	24 weeks

The PTAB found the ‘135 Patent to be obvious since “Kempeni expressly discloses a dose that is equivalent to the recited subcutaneous 40 mg dose. Kempeni also teaches biweekly administration. (D2E7 was administered every two weeks in the dose range from 0.5 to 10 mg/kg). Accordingly, Kempeni explicitly provides a motivation for converting van de Putte’s weekly dosing regimen into a biweekly dosing regimen. Kempeni also suggests that the person of ordinary skill would have expected success in treating RA with such a dosing regimen.”

The PTAB, however, rejected Coherus’ argument that the ‘135 Patent was obvious since the claimed biweekly dose corresponded to the half-life of Humira (11.6–13.7 days):  “Petitioner asserts in the Petition that the ordinary artisan would have doubled van de Putte’s 20 mg dose to 40 mg and weekly dosing interval to biweekly based on the single PK parameter of half-life.  Neither Petitioner nor Dr. Baughman direct us to a drug with a dosing interval that corresponds to its half-life, or to other evidence supporting the assertion that skilled artisans routinely use half-lives to develop a dosing schedule.  Moreover, we note that Patent Owner identifies several prior art therapeutic antibodies that were not dosed according at a frequency equal to a single half-life, including: (1) REMICADE®, which is dosed only once every 3–6 half-lives; (2) RITUXAN®, which is dosed once every 2.8 halflives; (3) MYLOTARG®, which is dosed once every 5 half-lives; and (4) ZENAPAX®, which is dosed once every 0.6 half-lives.  Patent Owner argues persuasively that half-life is not the only factor the skilled artisan would have considered in modeling a dosing regimen.”

This is not the only biosimilar IPR where antibody half-life has become an issue.  To obtain Herceptin dosing patents (US Patent 6,627,196 and 7,371,379), Genentech successfully argued during prosecution that a POSA would not have wanted to increase the interval between doses beyond trastuzumab’s known half-life (i.e., either 5.8, 8.3, or 9.1 days) for fear that insufficient levels of drug would remain in the patient to treat cancer.  In its IPR petitions (IPR2017-01139 and IPR2017-01140), Celltrion argued that “half-life is only one piece of the relevant information. . . Rather, when determining whether a less frequent regimen was likely to be effective, a POSA would have considered half-life together with initial serum concentration and target trough serum concentration.”   The PTAB has not yet ruled on Celltrion’s IPR petitions.  It would be interesting to see whether the PTAB dismisses Genentech’s half-life argument as well.