On March 31, 2017, Celltrion, Inc. (“Celltrion”) filed three new petition for inter partes review (“IPR”) of two additional patents related to Genentech and Biogen’s Rituxan® (rituximab).  Two of the petitions challenge claims of U.S. Patent No. 7,682,612 (“the ’612 patent”) and the other seeks review of all nine claims of U.S. Patent No.8,206,711 (“the ’711 patent”).  The proceedings are IPR2017-01227 and IPR2017-01230 (both involving the ’612 patent) and IPR2017-01229 (involving the ‘711 patent). The real parties-in-interest identified for Petitioner are Celltrion, Inc., Celltrion Healthcare Co. Ltd., and Teva Pharmaceuticals International GmbH.

Rituximab is an anti-CD20 monoclonal antibody approved for the treatment of non-Hodgkin’s lymphoma, chronic lyphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangitis, and microscopic polyangitis.

The challenged claims of the ’612 patent are directed to methods of treating chronic lymphocytic leukemia (“CLL”) by administering an anti-CD20 antibody to the patient in an amount effective to treat the chronic lymphocytic leukemia, wherein the method does not include treatment with a radiolabeled anti-CD20 antibody (referred to as “single agent” claims).  The challenged claims of the ’711 patent are directed to methods of treating CLL by administering an effective amount of rituximab to the patient at a dosage of 500 mg/m, either alone or in combination with another chemotherapeutic agent.

Earlier this year, the PTAB instituted trial proceedings in IPR2016-01614 based on Celltrion’s petition for review of U.S. Patent No. 7,820,161, which is also related to rituximab (as we reported here).  Last week, Pfizer, Inc. (“Pfizer”) also filed a petition seeking IPR review of the ’161 patent and requested that its case be joined with IPR2016-01614 as discussed in this post.

Celltrion currently has petitions pending for review of three other patents related to rituximab as reported here, and the PTAB denied Celltrion’s petition related to U.S. Patent No. 7,976,838 as reported here.  As discussed in our earlier posts, Boehringer Ingelheim and Celltrion had previously filed petitions at the PTAB for patents related to this same product that were voluntarily dismissed in 2015. A complete list of IPRs related to rituximab and other proposed biosimilars can be found in RFEM’s IPR Dashboard.

Pfizer, Inc. (“Pfizer”) filed a new petition with the Patent Trial and Appeal Board (“PTAB”) on March 24, 2017, for inter partes review (“IPR”) of U.S. Patent No. 7,820,161 (“the ’161 patent”) related to Biogen’s and Genentech’s Rituxan® (rituximab).  The challenged claims of the ’161 patent are directed to a method for treating rheumatoid arthritis by administering more than one intravenous dose of a therapeutically effective amount of rituximab and administering methotrexate.

Rituximab is an anti-CD20 monoclonal antibody approved for the treatment of non-Hodgkin’s lymphoma, chronic lyphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangitis, and microscopic polyangitis.

The proceeding is IPR2017-01115. The only real party-in-interest identified for Petitioner is Pfizer, Inc.  Pfizer reported in January that its proposed biosimilar rituximab (PF 05280586) is in Phase 3 development.  Earlier this month, the PTAB instituted an IPR for certain claims of the ’161 patent on a petition filed by Celltrion (as we reported here), and Pfizer has requested that its petition be joined with that proceeding.

Celltrion currently has petitions pending for review of three other patents related to rituximab as reported here, and the PTAB denied Celltrion’s petition related to U.S. Patent No. 7,976,838 as reported here.  Boehringer Ingelheim and Celltrion had previously filed petitions at the PTAB for patents related to this same product that were voluntarily dismissed in 2015. A complete list of IPRs related to rituximab and other proposed biosimilars can be found in RFEM’s IPR Dashboard.

We will continue to provide updates as these cases progress.

We reported last week that Sanofi-Aventis U.S. LLC, Genzyme Corporation, and Regeneron Pharmaceuticals, Inc. had filed suit in Massachusetts seeking a declaratory judgment that their Dupixent® (dupilumab) product does not infringe Amgen’s U.S. Patent No. 8,679,487 (“the ’487 patent”).  The litigation was filed on March 20, 2017.  In a one-two punch combination, Sanofi and Regeneron filed a petition for inter partes review (“IPR”) of the ‘487 patent with the Patent Trial and Appeal Board (“PTAB”) just three days later on March 23, 2017, and before any substantive activity occurred in the litigation.

The proceeding is IPR2017-01129.  The real parties-in-interest for Petitioner are the same three plaintiffs in the litigation, Sanofi-Aventis U.S. LLC, Genzyme Corp. and Regeneron Pharmaceuticals, Inc.  The ‘487 patent, entitled “Anti-interleukin-4 receptor antibodies,” issued on March 25, 2014, with a total of 17 claims.  Claim 1, the only independent claim, is directed to “an isolated human antibody that competes with a reference antibody for binding to human interleukin-4 (IL-4) receptor.”  The ’487 patent is assigned to Immunex Corporation (“Immunex”), which was acquired by Amgen in 2002.

Dupilumab is a monoclonal antibody intended to inhibit signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13), two key cytokines believed to be the drivers of type 2 helper T-cell (Th2)-mediated inflammation.

As previously reported, Regeneron submitted a biologics license application (“BLA”) for dupilumab to the FDA on July 29, 2016, seeking approval of the product for the treatment of moderate to severe atopic dermatitis in adults.  Atopic dermatitis, the most common form of eczema, is a chronic inflammatory skin disease.  FDA accepted the application for review in September 2016 and granted the dupilumab application priority status, reducing the target goal for approval from the standard ten months after acceptance to just six months.  The PDUFA (FDA goal) date for the dupilumab application was March 29, 2017.  FDA met the target date, granting approval for dupilumab on Tuesday, one day ahead of schedule. Sanofi and Regeneron announced that the product will be available to patients in the U.S. this week.

Amgen’s Amgevita, an adalimumab biosimilar to AbbVie’s Humira®, received approval from the European Commission on March 23, 2017.  Adalimumab is a TNF (tumor necrosis factor) inhibitor that binds to TNF-alpha (TNF-α) preventing it from activating TNF receptors, which cause the inflammatory reactions associated with autoimmune diseases.

Amgevita received approval in all available indications, including the treatment of certain inflammatory diseases in adults, such as moderate-to-severe rheumatoid arthritis; psoriatic arthritis; severe active ankylosing spondylitis (AS); severe axial spondyloarthritis without radiographic evidence of AS; moderate-to-severe chronic plaque psoriasis; moderate-to-severe hidradenitis suppurativa; non-infectious intermediate, posterior and panuveitis; moderate-to-severe Crohn’s disease; and moderate-to-severe ulcerative colitis. According to the announcement, the European Commission also approved Amgevita for the treatment of certain pediatric inflammatory diseases, including moderate-to-severe Crohn’s disease (ages six and older); severe chronic plaque psoriasis (ages four and older); enthesitis-related arthritis (ages six and older); and polyarticular juvenile idiopathic arthritis (ages two and older).

The approval of Amgevita is the first approved biosimilar for Amgen in Europe. Amgen’s adalimumab biosimilar was approved by the FDA in September 2016, and is sold in the United States under the name Amjevita (adalimumab-atto).

On March 21, 2017, Celltrion, Inc. (“Celltrion”) filed two new petitions for inter partes review (“IPR”) of U.S. Patent Nos. 7,846,441 (“the ’441 patent”) and 7,892,549 (“the ’549 patent”). Three days later, on March 24, 2017, Celltrion filed two additional IPR petitions for U.S. Patent Nos. 6,626,196 (“the ‘196 patent”) and 7,371,379 (“the ‘379 patent”).  All four of these patents are related to Genentech’s Herceptin® (trastuzumab). Last month, Celltrion filed a petition with the Patent Trial and Appeal Board (“PTAB”) challenging certain claims of Genentech’s Patent No. 8,591,897, which is also related to Herceptin® as reported in this post.

Celltrion announced that its trastuzumab application had been received for review by the European Medicines Agency (“EMA”) in October of last year, and the company is planning to submit an application to the FDA during the first half of 2017.

Trastuzumab is a monoclonal antibody that interferes with the human epidermal growth factor receptor (HER2)/neu. Herceptin® 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.

The proceedings are IPR2017-01121 (involving the ’441 patent); IPR2017-01122 (involving the ‘549 patent); IPR2017-01139 (involving the ‘196 patent); and IPR2017-01140 (involving the ‘379 patent). The real parties-in-interest identified for Petitioner are Celltrion, Inc., Celltrion Healthcare Co. Ltd., and Teva Pharmaceuticals International GmbH.

The challenged claims of the ’441 patent are directed to a method of treating cancers linked to the overexpression of the human ErbB2 protein by administering an anti-ErbB2 antibody that binds to epitope 4D5 and a taxoid chemotherapeutic agent in the absence of an anthracycline derivative.  The challenged claims of the ’549 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 therapeutic agent which may be another antibody, a growth inhibitory agent, or a cytokine.  The challenged claims of the ’196 and ’379 patents are generally directed to methods of treating cancers characterized by the overexpression of ErbB2 by administering an effective amount of an anti-ErbB2 antibody using a dosage regimen that provides a large initial dose, followed by the subsequent administration of additional dosages in amounts that are the same as or less than the initial dosage spaced two to three weeks apart (referred to in the specification as “front loading”).  Hospira has also filed IPR petitions challenging claims of the ’441, ’549, ‘196 and ‘379 patents, as we reported here in January 2017.

Hospira  filed a petition on which trial has been instituted at the PTAB on a fifth patent related to Herceptin® (as reported here). A complete list of IPRs related to trastuzumab and other proposed biosimilar products can be found in RFEM’s IPR Dashboard.

Mylan is also seeking approval of a trastuzumab biosimilar. Mylan recently withdrew two IPR petitions and announced that Mylan and Biocon have reached a global settlement and licensing agreement with Genentech and Roche regarding Mylan’s trastuzmab biosimilar as discussed in this post.

Sanofi-Aventis U.S. LLC, Genzyme Corporation, and Regeneron Pharmaceuticals, Inc. (collectively “Plaintiffs”) filed a Complaint in the United States District Court for the District of Massachusetts seeking a declaratory judgment from the Court that the development, manufacturing, sale, and promotion of Dupixent® (dupilumab) does not infringe U.S. Patent No. 8,679,487 (“the ’487 patent”).  The ‘487 patent, entitled “Anti-interleukin-4 receptor antibodies,” issued on March 25, 2014, with a total of 17 claims.  The ’487 patent is assigned to Immunex Corporation (“Immunex”), which was acquired by Amgen in 2002.

Dupilumab is a monoclonal antibody intended to inhibit signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13), two key cytokines believed to be the drivers of type 2 helper T-cell (Th2)-mediated inflammation.  Regeneron submitted a biologics license application (“BLA”) for dupilumab to the FDA on July 29, 2016, seeking approval of the product for the treatment of moderate to severe atopic dermatitis in adults.  Atopic dermatitis, the most common form of eczema, is a chronic inflammatory skin disease.  FDA accepted the application for review in September 2016 and granted the dupilumab application priority status, reducing the target goal for approval from the standard ten months after acceptance to just six months.  The PDUFA (FDA goal) date for the dupilumab application is March 29, 2017.

Plaintiffs state in the Complaint that Amgen had previously attempted to develop a monoclonal antibody treatment for asthma (AMG-317) that inhibited the activity of interleukin 4 (IL-4) and interleukin 13 (IL-13) and further allege that Amgen “abandoned” its development efforts after the product showed “disappointing” results in Phase II clinical trials.  The Complaint acknowledges that Amgen’s development efforts resulted in a number of patents, including the ’487 patent.  According to the Complaint, counsel for Regeneron and Sanofi learned just days ago that “Amgen has hired litigation counsel to prosecute a patent infringement litigation related to Amgen’s work on antibodies to the IL-4 receptor and is in the process of retaining experts.”  The Complaint further states that Amgen “has a long history of aggressively enforcing its patents against competitors” and notes that Amgen is “currently engaged in an unrelated patent litigation concerning Sanofi and Regeneron’s product Praluent®”.

The case is Civ. No. 17-cv-10465 and has been assigned to Judge Woodlock.  Amgen has not yet filed an Answer to the Complaint, and Amgen and has not filed a suit accusing Sanofi and Regeneron of infringing the ’487 patent.  A threshold question for the Court to consider will likely be whether the Complaint sets forth facts sufficient to establish the existence of an “actual controversy” between the parties regarding infringement of the ’487 patent.

Federal Courts are prohibited from issuing advisory opinions.  To establish jurisdiction under the Declaratory Judgment Act, it is necessary for the Plaintiff to demonstrate “that there is a substantial controversy, between parties having adverse legal interests, of sufficient immediacy and reality to warrant” relief.  See Medimmune, Inc. v. Genentech, 549 U.S. 118 (2007); see also 28 U.S.C. §§ 2201-2202.

We will continue to provide updates as the litigation continues.

Hospira, Inc. (“Hospira”) filed a petition with the Patent Trial and Appeal Board (“PTAB”) on September 9, 2016, for inter partes review (“IPR”) of U.S. Patent No. 7,622,115 (“the ’115 patent”) related to Genentech’s Avastin® (bevacizumab).  Interestingly, Genentech elected not to file a preliminary response.  On March 16, 2017, the PTAB issued a decision instituting review of claims 1-5 of the ’115 patent.  The claims of the ’115 patent are generally directed to methods of treating cancer in a patient by administering an effective amount of bevacizumab and assessing the patient for gastrointestinal perforation during treatment.

Bevacizumab is an anti-vascular endothelial growth factor A (Anti-VEGF) specific monoclonal antibody that inhibits formation of new blood vessels and is used to slow the growth of tumors related to several types of cancers.  Avastin® is indicated for treatment of conditions related to metastatic colon cancer, lung cancer, glioblastoma, ovarian cancer, and cervical cancer.

The proceeding is IPR2016-01771. The real party-in-interest identified for Petitioner is Hospira. Petitioner also identified Pfizer Inc. as a real party-in-interest who, going forward, may have control or an interest in the outcome of the proceeding. The only real party-in-interest identified for Patent Owner is Genentech, Inc. (“Genentech”).

Hospira and Genentech are also involved in several IPR proceedings concerning Genentech’s patents for trastuzumab (Herceptin®). The PTAB has instituted one of those proceedings as reported in this post and Institution decisions on Hospira’s other trastuzumab patent petitions are expected in July and August of this year.  A complete list of IPRs related to trastuzumab and other proposed biosimilars can be found in RFEM’s IPR Dashboard.

Earlier this year, Genentech filed litigation against Amgen in the United States District Court for the District of Delaware accusing Amgen of failing to comply with the disclosure requirements of section (l)(2)(A) of the BPCIA during the first step of the “patent dance” for Amgen’s proposed bevacizumab biosimilar as discussed in this post.   Judge Sleet dismissed that complaint exactly two weeks after it was filed, as reported here, but the dismissal was without prejudice, permitting Genetech to file an Amended Complaint.

Celltrion, Inc. (“Celltrion”) filed three new petitions with the Patent Trial and Appeal Board (“PTAB”) on March 15, 2017 for inter partes review (“IPR”) of Biogen’s U.S. Patent Nos. 8,329,172 (“the ’172 patent”), 8,557,244 (“the ’244 patent”), and 9,296,821 (“the ’821 patent”) related to rituximab.

Rituximab is an anti-CD20 monoclonal antibody approved for the treatment of non-Hodgkin’s lymphoma, chronic lyphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangitis, and microscopic polyangitis.

The proceedings are IPR2017-01093 (the ’172 patent), IPR2017-1094 (the’244 patent), and IPR2017-1095 (the ’821 patent). The real parties-in-interest identified for Petitioner are Celltrion, Inc., Celltrion Healthcare Co. Ltd., and Teva Pharmaceuticals International GmbH.

The sole claim of the ’172 patent is directed to a method of treating low-grade B-cell non-Hodgkin’s lymphoma (“NHL”) by administering a well-known chemotherapy regimen of cyclophosphamide, vincristine, and prednisone (“CVP”), followed by rituximab maintenance therapy administered in four weekly doses of 375 mg/m2 every six months for two years.  The ’244 patent has two claims.  Claim 1 of the ’244 patent is directed to a method of treating a patient with diffuse large cell lymphoma (a subset of Non-Hodgkin’s Lymphoma) by administering a combination of an unlabeled chimeric anti-CD20 antibody and chemotherapy (the chemotherapy consisting of cyclophosphamide, hydroxydaunorubicin/doxorubicin, vincristine, and prednisone/prednisolonew).  The treatment claimed in the ’244 patent is specific to a patient who is greater than 60 years old, has bulky disease, and has a tumor greater than 10 cm in diameter. Claim 2 of the ’244 patent further limits the chimeric anti-CD20 antibody to rituximab.  The ’821 patent has six claim which are generally directed to methods for treating low-grade or follicular NHL by administering rituximab during a chemotherapy regimen of CVP.

The PTAB recently issued institution decisions on two other patents related to rituximab.  On February 24, 2017, the PTAB instituted review of certain claims of U.S. Patent No. 7,820,161 (“the ’161 patent”) based on a petition filed by Celltrion in IPR2016-01614 as we reported here, and on March 2, 2017, the PTAB denied Celltrion’s request for inter partes review of U.S. Patent No. 7,976,838 in IPR2016-01667 as we reported here.

A complete list of IPRs related to rituximab and other proposed biosimilars can be found in RFEM’s IPR Dashboard.  We will continue to provide updates as these cases progress.

Hospira, Inc. (“Hospira”) filed a petition with the Patent Trial and Appeal Board (“PTAB”) on September 16, 2016 for inter partes review (“IPR”) of U.S. Patent No. 7,807,799 (“the ’799 patent”) related to Genentech’s Herceptin® (trastuzumab).  On March 15, 2017, the PTAB issued a decision instituting review of claims 1–3 and 5–11 of the ’799 patent.  The ’799 patent is generally directed to methods for reducing leaching of protein A during protein A affinity chromatography by reducing temperature or pH, or by adding protease inhibitors.  The challenged claims are specific to a method of purifying a protein that comprises a CH2/CH3 region, including an antibody, and certain claims specify a method of purifying trastuzumab.

Trastuzumab is a monoclonal antibody that interferes with the human epidermal growth factor receptor (HER2)/neu. Herceptin® 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.

The proceeding is IPR2016-01837. The real party-in-interest identified for Petitioner is Hospira. Petitioner also identified Pfizer Inc. as a real party-in-interest who, going forward, may have control or an interest in the outcome of the proceeding. The real party-in-interest identified for Patent Owner is Genentech, Inc. (“Genentech”). Hospira has several petitions for IPR pending for other patents related to trastuzumab.  Institution decision on Hospira’s other petitions are expected in July and August.  A complete list of IPRs related to trastuzumab and other proposed biosimilars can be found in IPR Dashboard. We will continue to provide updates as these cases progress.

In related news, Mylan announced earlier this week that it reached a global settlement agreement with Roche and Genentech that will provide Mylan with global licenses for its trastuzumab biosimilar as reported in an update to this post on Monday.  According to the press release, Mylan has exclusive commercialization rights for the proposed biosimilar trastuzumab in the U.S., Canada, Japan, Australia, New Zealand, and in the European Free Trade Association countries, and Biocon has co-exclusive commercialization rights with Mylan for the product in the rest of the world.  Mylan and Biocon announced in November 2016 that Mylan had submitted an application for a trastuzumab biosimilar to the FDA. The BSUFA date (FDA’s target goal) for Mylan’s trastuzumab application is September 3, 2017.

On March 10, 2017, the PTAB published a decision terminating the proceedings in IPR2016-1693 and IPR2016-1694 because the parties have reached a settlement.  Mylan filed two petitions requesting inter partes review (“IPR”) of certain claims (1, 2, 4, 12, 25, 29-31, 33, 42, 60, 62-67, 69 and 71-81) of U.S. Patent No. 6,407,213 (“the ’213 patent”) issued to Carter, et al., entitled “Method for Making Humanized Antibodies.” Although the ’213 does not claim a specific product, Genentech has publicly stated that the technology claimed by the ’213 was used in the development of Herceptin® (trastuzumab), as well as several other products.

Mylan and Biocon announced in November 2016 that Mylan had submitted an application for a trastuzumab biosimilar product to the FDA.  Trastuzumab is a monoclonal antibody that interferes with the human epidermal growth factor receptor (HER2)/neu. Herceptin® 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.

The settlement was reached shortly before a decision on institution was expected from the PTAB.  Mylan filed both petitions on the ’213 patent on August 30, 2016.  The patent owner filed its preliminary responses on December 16, 2016, and the PTAB would have issued a decision on institution no later than March 16, 2017.

The real parties-in-interest identified for Petitioner are Mylan Pharmaceuticals Inc.,

Mylan Inc., Mylan GmbH and Biocon Ltd. Petitioner also identified Mylan N.V. out of an abundance of caution, but made no admission that Mylan N.V. is a real party-in-interest.  The only real party-in-interest identified for Patent Owner is Genentech, Inc.  Although these two IPRs have been terminated, there are several petitions pending on other patents related to Herceptin® (trastuzumab).  A complete list of IPRs related to rituximab and other proposed biosimilars can be found in RFEM’s IPR Dashboard.

3-13-17 UPDATE:  Mylan announced on March 13, 2017 that the settlement of the ‘213 patent dispute is part of a broader settlement agreement with Roche and Genenetech that will provide Mylan with global licenses for its trastuzumab product.  As part of the settlement, Mylan will also withdraw its IPR challenge to U.S. Patent No. 6,331,415.

According to the press release, Mylan has exclusive commercialization rights for the proposed biosimilar trastuzumab in the U.S., Canada, Japan, Australia, New Zealand and in the European Union and European Free Trade Association countries, and Biocon has co-exclusive commercialization rights with Mylan for the product in the rest of the world.  The BSUFA date (FDA’s target goal ) for Mylan’s trastuzumab application is September 3, 2017.