As previously reported, earlier this year Celltrion, Inc. (“Celltrion”) filed petitions seeking inter partes review (“IPR”) of certain Genentech patents covering Herceptin® (trastuzumab).  In particular, Celltrion challenged the patentability of certain claims of U.S. Patent Nos. 7,846,441 (“the ʼ441 patent”); 7,892,549 (“the ʼ549 patent”); 6,626,196 (“the ʼ196 patent”); 7,371,379 (“the ʼ379 patent”).  Earlier this month, the PTAB issued decisions instituting trial on all four patents.

The ʼ441 patent is the subject of IPR2017-01121.  The claims of the ʼ441 patent are directed to a method of treating cancers linked to the overexpression of the human ErbB2 protein by administering an anti-ErbB2 antibody and a taxoid chemotherapeutic agent in the absence of an anthracycline derivative.  The claims further require that the combination be administered “in an amount effective to extend the time to disease progression in said human patient, without increase in overall severe adverse events.”

In the institution decision, the PTAB interpreted only the term “extend the time to disease progression in said human patient, without increase in overall severe adverse events.”  Relying heavily on “unequivocal” statements made during prosecution, the PTAB determined that the term requires a comparison of the claimed combination therapy to no treatment.  Interestingly, the PTAB’s construction differs from the construction advanced by Celltrion – a construction that Genentech did not challenge.  Celltrion had proposed that the term be construed to require a comparison of the combination of Taxol® and Herceptin® to Taxol® alone.

Applying its adopted construction, the PTAB found that the record contained sufficient evidence that “compared to no treatment, anti-ErbB2 antibodies alone would extend the time to disease progression in patients with breast cancer.”   The PTAB also agreed with Petitioner’s view that “the combination therapy satisfies the limitation of clinical efficacy, because each of trastuzumab and paclitaxel extends time to disease progression relative to no treatment, and an ordinary artisan ‘would not have expected the combination to change this.’”  With respect to the “without increase in overall severe adverse events” portion of the claim, the PTAB again reiterated that the proper comparison is to no treatment, and accepted the testimony of Petitioner’s expert that “a patient with untreated HER2-positive cancer will experience more overall severe adverse events due to the underlying disease itself, compared to severe adverse events experienced due to treatment.”  Finally, the PTAB concluded that it would have been obvious to avoid anthracyclines because they were known to cause irreversible cardiotoxicity, and “many patients would have been previously treated with, and become resistant to, first-line anthracycline chemotherapeutics.”

The PTAB addressed Genentech’s argument that the prior art taught away from combining a taxoid with an anti-ErbB2 antibody, but concluded that “we are not persuaded that prior art as a whole teaches away from combining paclitaxel and an anti-ErbB2 antibody in treating HER2-positive cancers.”  In reaching this conclusion, the PTAB referenced Petitioner-cited references that show “paclitaxel is effective in treating HER2-positive cancers, demonstrates ‘strong synergy’ of paclitaxel and an anti-ErbB2 antibody…and suggests clinical trials of the combination therapy.”  The PTAB also acknowledged evidence of secondary considerations that was submitted by Genentech, but noted that Petitioner had not been given an opportunity to respond to that evidence.  Accordingly, the PTAB concluded that it would not weigh that evidence until the record has been fully developed during trial.

The ʼ549 patent is the subject of IPR2017-01122.  The ʼ549 patent is a continuation of the application that issued as the ʼ441 patent discussed above. The claims of the ʼ549 patent are directed to a method of treating cancers characterized by the overexpression of ErbB2 by administering a combination of an anti-ErbB2 antibody, a taxoid chemotherapeutic agent, and another growth inhibitory agent.  The claims further require that administration be “in an amount effective to extend the time to disease progression in the human patient.”

Much like in IPR2017-01121, and again relying on “applicant’s unequivocal statement” during prosecution, the PTAB interpreted the “…extend the time to disease progression…” term to require a comparison to no treatment.  The PTAB also interpreted the term “effective amount” in independent claim 5 to encompass “an amount effective to extend the time to disease in the human patient.”  The PTAB declined to construe any other proposed terms, although it did adopt the construction of “administering a combination” that was previously advanced by Genentech in the earlier IPR2017-00737, which was filed by Hospira.  Trial was not instituted on the Hospira ʼ549 patent IPR.

Based on these constructions, the PTAB applied the same reasoning regarding clinical efficacy of the claimed combination, and the avoidance of anthracyclines (in claim 16) as in the ʼ441 patent IPR.  Consequently, the PTAB determined that Celltrion had established the required reasonable likelihood that it would prevail in showing the challenged claims are unpatentable.

The ʼ196 patent is the subject of IPR2017-1139, and the ʼ379 patent is the subject of IPR2017-1140.  The ʼ196 patent and the ʼ379 patent originate from the same patent family, which is a different family from the ʼ441 or ʼ549 patents discussed above.

The ʼ196 patent is directed to methods for treating cancer characterized by overexpression of ErbB2 receptors by administering an initial dose of an anti-ErbB2 antibody followed by administration of subsequent doses spaced at least two weeks apart that are equal to or less than the initial dose.  The ʼ379 patent is directed to similar methods, but also requires the administration of an effective amount of a chemotherapeutic agent to the patient.  Notably, the ʼ196 patent and the ʼ379 patent are the subjects of IPR2017-00804 and IPR2017-00805, respectively.  Those IPRs were both filed by Hospira, and the PTAB has instituted trial on both patents.

The institution decisions for the ʼ196 patent and the ʼ379 patent are virtually identical.  In both cases, the PTAB declined to construe any claim terms despite both Celltrion and Genentech proposing constructions for various terms.  Turning to the asserted grounds, the PTAB recognized that the “prior art only explicitly described weekly dosing intervals,” but accepted Celltrion’s contention – supported by expert testimony – that “the skilled artisan would have been motivated to use a three week dosing interval in order to align both the antibody and chemotherapy infusion treatments on the same schedule.”  With respect to the initial dose, the PTAB accepted Celltrion’s calculations that an ordinary skilled artisan “would have administered an 8 mg/kg loading dose…followed by 6 mg/kg maintenance doses…each administered three weeks apart.”  The PTAB found this dosing schedule would have been clinically effective because it would have maintained a target serum concentration above the concentration taught by the prior art to be required for efficacy.

Genentech challenged Celltrion’s reliance on a reference on the basis that it had already been before the Examiner during prosecution.  Under 35 U.S.C. § 325(d), the PTAB can “reject the petition or request because, the same or substantially the same prior art or arguments previously were presented to the Office.”  However, here the PTAB declined to deny institution because it concluded that Celltrion had presented the disputed reference in a “new light” by using an expert declaration to explain its significance.  In particular, the PTAB found “there is no basis to suggest that the Examiner considered the calculations set forth by [Celltrion’s expert] showing that a tri-weekly dosing regimen would have resulted in an acceptable trough serum concentration…”

The PTAB also rejected various other arguments made by Genentech in its Preliminary Patent Owner Response.  For example, Genentech asserted that a skilled artisan would not use the chemotherapy dosing strategy of maintaining dose intensity to adjust antibody dose, and further asserted that the increasing dose amount and lengthening the dosing interval was known to cause higher peak and lower trough concentrations as opposed to smaller doses administered more frequently.  Genentech also asserted that Celltrion had failed to establish a reasonable expectation of success with respect to efficacy due to the non-linear pharmacokinetics of the antibody.  But, in each instance, the PTAB pointed out that Genentech had not submitted expert testimony with its response, and so the PTAB would “decline to give [Celltrion’s] arguments, which are based on expert testimony, less weight in comparison to [Genentech’s] attorney arguments.”

Herceptin® is a monoclonal antibody that interferes with human epidermal growth factor receptor (HER2)/neu.  The produce is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease.

We will continue to keep you updated on future developments.