Tuesday, October 27, 2015

PTAB Upholds Validity of Herceptin Patent

Today the Patent Trial and Appeal Board issued a unanimous decision in Phigenix, Inc. v. ImmunoGen, Inc., upholding the validity of Immunogen’s US Patent Number 8,337,856.  The petition for inter partes review (IPR) was filed by Phigenix, Inc..  Genentech is a real party-in-interest in the proceedings.

 The ’856 patent claims “[a]n immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, wherein the antibody is [HERCEPTIN].”  Herceptin is a biologic developed by Genentech for the treatment of some forms of breast cancer and gastric cancer.

Phigenix cited several prior art references which allegedly rendered the claims obvious and thus invalid under 35 USC 103.  One of the primary references, Chari 1992, describes immunoconjugates comprising an anti-ErbB2 mouse monoclonal antibody chemically coupled to a maytansinoid toxin (DMI).  The other primary reference was the HERCEPTIN label itself.  A Phigenix expert (Rosenblum) submitted a declaration which, according to Phigenix, established that it would have been obvious to substitute HERCEPTIN for the mouse antibody described in Chari 1192 “based on the teachings of Chari 1992 and HERCEPTIN label, as well as the general knowledge in the art at the time.”

The PTAB rejected petitioner’s argument, however, finding that the patent owner had provided persuasive evidence that at the time the 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.”  The PTAB went on to find persuasive evidence in support of patent owner’s argument 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,” given that “[r]esearchers had targeted tumors with immunoconjugates for about 40 years before the ’856 patent” without success and in view of evidence “indicating that preparing any antibody-toxin immunoconjugate for use in the treatment of human tumors was difficult and unpredictable.”

Previously, the PTAB declined to Institute review in a separate case involving a related patent, US Patent Number 7,575,748.  Phigenix, Inc. v. Genentech, Inc. and ImmunoGen, Inc., Case IPR2014-00842 (PTAB Dec. 9, 2014) (Paper 10).


Monday, October 5, 2015

Apotex Dances the BPCIA Patent Dance with Amgen, But Claims It Does Not Need to Provide 180-Day Notice of Commercial Marketing

The Federal Circuit held in Amgen v. Sandoz that the so-called “patent dance” is optional for applicants  seeking approval of a biosimilar product under the abbreviated BPCIA pathway, as discussed here.  Indeed, biosimilar applicants have in a number of cases chosen not to participate in the “patent dance.”  This occurred, for example, in a recent lawsuit filed by Amgen against Hospira in connection with Hospira’s plan to bring a biosimilar version of Epogen to market, as described in an earlier post.  In fact, until today I was personally unaware of any case in which a biosimilar applicant actually did participate in the patent dance with a reference sponsor, but that has changed with Amgen’s filing of a lawsuit against Apotex on October 2, 2015.

Amgen v. Apotex was filed in the Southern District of Florida, and alleges that Apotex has infringed, or will infringe, US Patent Numbers 8,952,138 and 6,162,427 by seeking approval under the abbreviated BPCIA pathway for a biosimilar version of filgrastim (which is sold by Amgen under the trade name Neupogen).  The complaint is available here.

According to the complaint, Apotex participated in the exchange of information set forth in the BPCIA, i.e., the patent dance, which included providing Amgen with a copy of its abbreviated Biologic License Application (aBLA), and as a result of these exchanges the parties agreed to the inclusion of these two US patents in the lawsuit.  The ‘138 patent “covers improved redox chemistry-based methodologies for efficiently refolding cysteine -containing proteins expressed in non-mammalian cells at high protein frustrations.”  Presumably Amgen believes the patent will be infringed by the processes Apotex will use to manufacture the biosimilar filgrastim.  

The ‘427 patent is directed towards a method that “employs a combination of G-CSF and a chemotherapeutic agent to mobilize stem cells more efficiently from the bone marrow to peripheral blood in a patient in need of a peripheral stem cell transplant.”  Amgen alleges that if FDA approves the Apotex product for the same indications as Amgen’s Neupogen product (which is what FDA did with respect to Zarxio, Sandoz’s biosimilar version of Neupogen), or if FDA requires Apotex’s label to contain the same information as Amgen’s Neupogen, then this will induce infringement of the ‘427 patent.  According to Amgen, “absent a legally cognizable and enforceable commitment by Apotex preventing Apotex from marketing its filgrastim product with a label that includes the same information regarding clinical trials, dosage and standard of care as Neupogen label… an actual controversy exists between the parties.”

The BPCIA also requires that biosimilar applicants “shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the” biosimilar product.  In Amgen v. Sandoz, the Federal Circuit interpreted this language as requiring that a biosimilar applicant “only give effective notice of commercial marketing after FDA has licensed its product.”  According to the complaint, Apotex sent Amgen a letter purporting to be Apotex’s Notice of Commercial Marketing on April 17, 2015.  Amgen seeks a declaratory judgment that the notice provided by Apotex on April 17, 2015 is invalid because at that time Apotex’s product had not been approved for licensure by FDA.
For its part, Apotex has reportedly taken the position, in a letter to Amgen dated August 24, 2015, that “because Apotex followed the pathway and provided Amgen with its application and manufacturing information, providing a notice of commercial marketing is not mandatory.”  Significantly, the Federal Circuit decided Amgen v. Sandoz on July 21, 2015, i.e., prior to Apotex’s letter, and held that notice of commercial marketing after licensure is mandatory.  I do not understand the basis for Apotex’s argument that notice of commercial marketing is not mandatory if the biosimilar applicant has participated in the patent dance, but it will likely be interesting to see how this plays out in the courts.