On October 27, the PTAB issued a Final Written Decision in an IPR challenging claims 1-8 of US Patent 8,337,856, directed to immunoconjugates comprising an anti-ErbB antibody, such as the humanized anti-ErbB2 antibody known as HERCEPTIN® (huMAb4D5-8), linked to a maytansinoid toxin. Petitioner had argued that claims 1-8 were obvious over a 1992 reference (Chari) in view of the HERCEPTIN label, and further in view of two additional references (Rosenblum 1999 and Pegram 1999).

Generally, the Petitioner contented that “Chari 1992 teaches all limitations recited in claims 1–8 of the ’856 patent, except that it does not disclose huMAB4D5-8 (as recited in independent claim 1) or a pharmaceutically acceptable carrier (as recited in claim 5).”  Additionally, the Petitioner asserted that “relying on the Rosenblum Declaration … it would have been obvious to the ordinarily skilled artisan, at the time the ’856 patent was filed, to substitute the mouse monoclonal TA.1 antibody in the immunoconjugate of Chari 1992 with the humanized mAb huMAB4D5-8 to produce the claim-recited immunoconjugates ‘based on the teachings of Chari 1992 and HERCEPTIN® Label, as well as the general knowledge in the art at that time.”   In an attempt to provide motivation for the substitution of the mouse Ab of Chari with the humanized Ab, Petitioner argued thathumanized mAbs, such as huMAB4D5-8, were preferred over their mouse-derived counterparts for clinical applications, as indicated in Chari 1992 (Ex. 1012, 130, 1st col.);

  1. humanized mAbs, such as huMAB4D5-8, were preferred over their mouse-derived counterparts for clinical applications, as indicated in Chari 1992 (Ex. 1012, 130, 1st col.);
  2. huMAB4D5-8 selectively bound with high affinity to HER2 and had been approved for use to treat breast tumors in humans, as indicated in the HERCEPTIN® Label; and
  3. clinical studies indicated that huMAB4D5-8 worked well in combination with microtubule-directed chemotherapy agents for the treatment of breast cancer, as indicated in the HERCEPTIN® Label (Ex. 1008, 1, 1st col.)

Petitioner also contended that a reasonable expectation of success was present because “it was known that: (1) huMAB4D5-8 was more effective in treating breast cancer when used in combination with the microtubule targeting drug paclitaxel, as described in the HERCEPTIN® Label; (2) Chari 1992’s maytansinoid conjugates targeted the same cells as huMAB4D5-8; and (3) an immunoconjugate containing a humanized antibody was less immunogenic, and therefore more effective in humans, than an immunoconjugate containing a mouse antibody.”

In response Patent Owner provided “persuasive evidence [according to the PTAB] … that in March 2000, at the time the ’856 patent was filed, prior art indicated that HERCEPTIN®-maytansinoid immunoconjugates would have been expected to exhibit unacceptable levels of antigen-dependent toxicity in normal human liver tissue in patients. PO Resp. 1–13. For example, Patent Owner points to Pai-Scherf 1999 (Ex. 2029), which describes a Phase I clinical study of human patients receiving an immunoconjugate (erb-38) comprising a portion of the anti-HER2 monoclonal antibody e23 fused to a truncated form of Pseudomonas exotoxin A.  As stated by Patent Owner, although the Pai-Scherf group “initiated the study in humans based on ‘excellent antitumor activity and acceptable animal toxicities,’” it nonetheless observed unacceptable hepatotoxicity in all patients in the treatment group.” (emphasis added).

Further, the PTAB held that the Patent Owner had provided:

Persuasive evidence that ordinary artisans would not have had a reasonable expectation that any immunoconjugate, much less the claimed Herceptin®-maytansinoid immunoconjugate in particular, would be useful to treat solid tumors in humans. PO Resp. 18–22 (describing prior failures in developing immunoconjugates for treating solid tumors), 47–51 (discussing long-felt need). As noted by Patent Owner, “[r]esearchers had targeted tumors with immunoconjugates for about 40 years before the ’856 patent” without success. Id. at 21–22 (citing numerous exhibits). Patent Owner sufficiently points to evidence of record indicating that preparing any antibody-toxin immunoconjugate for use in the treatment of human tumors was difficult and unpredictable.

Accordingly, the PTAB decided that “Petitioner does not persuade us that a preponderance of the evidence establishes that a skilled artisan would have had a reasonable expectation of success in 2000 that a Herceptin®-maytansinoid immunoconjugate would be useful in the treatment of breast tumors in humans, as Petitioner asserts.”

Objective indicia of non-obviousness

The PTAB also commented on Patent Owner’s used of objective indicia of non-obviousness regarding claim 8.  Specifically, the PTAB agreed that Patent Owner had provided evidence showing “unexpected superior results as compared to closest prior art compositions, fulfilling a long-felt and unmet need, praise in the field, and commercial success”, including evidence that T-DM1/Kadcyla®, the product encompassed by the claim, “fulfilled a long-felt, unmet need for an immunoconjugate capable of targeting a solid tumor in patients without excessive toxicity”.  Additionally, the PTAB held that Patent Owner’s evidence relating to the commercial success of the product thru its expert Mr. Jarosz (analyzed sales and prescription data, and marketing and promotional efforts relating to the product) was compelling.  The PTAB agreed that the Patent Owner’s secondary consideration evidence was not expected, and that the unexpected results were commensurate in scope with claim 8.