PTAB Splits on Instituting Challenges to Herceptin® Patents

By: Casey Kraning, Ph.D. and Jenny Shmuel

On July 27th, the PTAB issued institution decisions in five IPRs brought by Hospira challenging four Genentech patents related to Herceptin® (trastuzumab). The patents are directed to various methods of treating cancer patients with combination therapies incorporating anti-ErbB2 antibodies. Three challenges were instituted (IPR2017-00737, -00804, and -00805), and two were denied (IPR2017-00731 and -00739). These decisions mark a new point in the challenge to Herceptin® patents, which have been challenged in IPRs more than any other biologic drug seventeen times in 2017 alone.

Human ErbB2 receptor (also known as HER2 or HER2/neu) is overexpressed in ~25-30% of human breast cancers, and is associated with particularly aggressive forms of breast cancer, as well as increased resistance to traditional chemotherapeutics. A recombinant humanized anti-ErbB2 monoclonal antibody, trastuzumab (marketed by Genentech under the tradename Herceptin®), was approved by the FDA in 1998 to treat patients with ErbB2-overexpressing metastatic breast cancers. One of the top ten best-selling drugs, worldwide Herceptin® sales continue to grow, surpassing $6.7 billion in 2016.

The four patents at issue in Hospira's IPRs specifically target methods of treating patients with ErbB2-overexpressing cancers. Two of the patents, U.S. Pat. Nos. 7,892,549 and 7,846,441, are directed to specific combination therapies wherean anti-ErbB2 antibody is combined with two chemotherapeutic agents, in the absence of an anthracycline derivative (e.g. doxorubicin or epirubicin). The other two patents, U.S. Pat. Nos. 6,627,196 and 7,371,379, are directed to dosing strategies for anti-ErbB2 antibodies consisting of a higher initial "loading dose" followed by lower "maintenance doses," which are given in at least two week intervals, with concurrent chemotherapy. The last of these patents does not expire until February of 2022.

In IPR2017-00737, the PTAB instituted all six 103 grounds challenging the '549 patent. The PTAB found that Hospira sufficiently showed that it was known that anti-ErbB2 antibodies were effective in treating HER2-positive breast cancer, and their synergy with other chemotherapeutics was obvious to one of skill in the art. Moreover, the PTAB found that two- and three-drug combinations were routinely used to treat cancer, and were generally considered in the art to be superior to single agent therapies.

However, Hospira was not successful in IPR2017-00739, which also challenged the '549 patent, but on 102(a) and (b) anticipation grounds. The PTAB found unpersuasive Hospira's argument that the '549 patent was not entitled to the priority date of its provisional application, given that the Examiner had fully considered the same arguments underlying the patent applicant's claim to priority during prosecution, and Petitioners had presented no new evidence or argument. Therefore, the three references Hospira asserted against the '549 patent post-dated its priority date and were not considered prior art.

In IPR2017-00731, Hospira unsuccessfully challenged U.S. Pat. No. 7,846,441 on two separate 103 grounds, based on three references which were also asserted in IPR2017-00737. The PTAB dismissed one reference because during prosecution of the '441 patent, the inventors submitted declarations to antedate the reference and disqualify it as prior art. On the remaining 103 ground, the PTAB found that Petitioners had not made a sufficient showing that a person of ordinary skill in the art would have avoided anthracyclines. Noting that they had found otherwise in IPR2017-00737, the Board stated that the additional disclosures of the antedated reference and a second prior-art reference disclosed in the IPR2017-00737 proceeding, combined with persuasive expert testimony, led to a dispositive difference in the record.

Finally, the PTAB instituted IPR2017-00804 and -00805 on the '196 and '379 patents. Hospira asserted the same combination of three prior art references in both petitions, arguing successfully that the references taught an initial loading dose of at least 5 mg/kg of the anti-ErbB2 antibody followed by weekly doses of a lower maintenance dose. Even though only a weekly treatment was explicitly taught, "an ordinary artisan would nonetheless have been motivated to decrease the frequency of [anti-ErbB2] injections to once every three weeks" for practical reasons, namely increased patient compliance and convenience. The PTAB particularly credited the testimony of Hospira's two experts, who described the pharmacokinetic and clinical implications of the prior art.

These three instituted IPRs join a fourth previously filed by Hospira, instituted in March of 2017 on yet another Herceptin® patent (U.S. Pat. No. 7,807,799). Pfizer, named as a real party in interest in Hospira's IPRs, has also filed four of its own petitions challenging two additional patents. Finally, Celltrion Inc. has filed seven petitions challenging six Herceptin® patents, including the four discussed here, as well as a newer patent that does not expire until March of 2030.

Institution decisions on these additional IPRs will be forthcoming in the next several months, and we will continue to monitor and report on new developments as they arise.