We have previously covered various aspects of a legal battle between Genentech and Amgen regarding Amgen’s efforts to market Mvasi, a biosimilar to Genentech’s bevacizumab product, Avastin.  These aspects include Genentech’s quickly-dismissed February 2017 action contending Amgen was in violation of the Biologics Price Competition and Innovation Act (“BPCIA”) (covered here and here), and Amgen’s declaratory judgment action for non-infringement, invalidity, and unenforceability filed in the Central District of California, which was subsequently dismissed in favor of infringement actions brought by Genentech in the District of Delaware (covered here).

With the Delaware cases ongoing, Genentech filed a second patent infringement action in March 2019 spurred on by two Supplemental Biologics License Application (“sBLA”) filed by Amgen that updated certain information related to changes in the manufacturing facility and drug label of its bevacizumab biosimilar.  Genentech then moved to prevent a pending launch of Mvasi under the argument that the sBLA required Amgen to give a new notice of marketing, which would have required Amgen to wait an additional 180 days to launch its biosimilar.  The court denied those motions in July 2019, and Amgen promptly launched its Mvasi product.

Genentech quickly filed an appeal that was accompanied by an emergency motion requesting Amgen be enjoined from selling Mvasi during the appeal.  The emergency motion was denied in August 2019, and the Federal Circuit heard the appeal in June 2020. On July 6, 2020, the Federal Circuit affirmed the lower court’s decision that Amgen’s sBLAs were not new applications that required new notices because the notice statute of the BPCIA requires notice of commercially marketing the biological product, which was not changed in any of Amgen’s supplements.

At this point, Amgen, had essentially overcome all procedural hurdles to marketing Mvasi, and had been marketing the product for nearly a year, while the Delaware infringement cases were pending.

On July 7, 2020, a stipulation of dismissal was filed in the pending Delaware infringement cases, stating that the parties “have entered into a Bevacizumab Settlement Agreement,” voluntarily dismissing all claims with prejudice. A notice of settlement was also provided to the Federal Circuit, indicating that Genentech would not be pursuing further appeal.

While the terms of the settlement are not public, a Q1 2020 earnings presentation by Genentech’s parent company Roche noted “biosimilar erosion in US and Japan” for Avastin. Roche also disclosed efforts to gain approval for Avastin as part of a combination therapy with Genentech’s Tecentriq product for various indications, suggesting that Roche may plan to focus its resources on other therapies rather than continuing to incur legal costs in litigation against Amgen.  Amgen, meanwhile, has reported more than $200 million in U.S. net sales of Mvasi from launch through Q1 2020.

The FDA approved Eli Lilly’s Lyumjev™ (insulin lispro-aabc injection, 100 units/mL and 200 units/mL) last month, which is a new rapid-acting insulin indicated to improve glycemic control in adults with type 1 and type 2 diabetes.  The approval was based on two phase 3 clinical trials based on comparison of Lyumjev and Humalog (insulin lispro injection, 100 units/mL).  Lyumjev demonstrated superior reduction in blood glucose spikes at both one hour and two hours after a test meal as compared to Humalog.  The interactive Multichannel News Release can be found here.

This the second insulin product approved by the FDA in June.

As previously reported, the FDA had yet to approve any biosimilars in 2020 as of June 9, despite a growing pipeline. Since then, the FDA has approved two biosimilar products.

On June 11, Pfizer Inc. announced the FDA’s approval of Nyvepria™ (pegfilgrastim-apgf), a biosimilar of Amgen’s Neulasta™. Nyvepria is indicated “to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.” Pfizer’s news release can be found here. This marks the first approval of a biosimilar in 2020.

Mylan N.V. and Biocon Ltd. also announced on June 11, the approval of Semglee™ (insulin glargine injection) for vial and pre-filled pen presentations to control high blood sugar in adults with type 1 and type 2 diabetes and in adolescents with type 1 diabetes. Semglee is a biosimilar to Sanofi’s Lantus® and is approved for the same indications. Mylan’s news release can be found here.

  • FDA has not approved any biosimilars in 2020.
  • Two Herceptin® (trastuzumab) biosimilars launch in the U.S. in Q1 2020.
  • EMA approves third Enbrel® (etanercept), eleventh Humira® (adalimumab), seventh Rituxan® (rituximab), and second Humalog® (insulin lispro) biosimilars.
  • FDA has redefined “Biologic Products” to open new pathways for biosimilar and interchangeable approvals of proteins including insulin.

As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years.  Global sales for the top ten branded biologic drugs totaled approximately $81 billion in 2019[1].  In the FDA’s Center for Drug Evaluation and Research’s (CDER) annual report, the FDA highlighted the ten biosimilar approvals in 2019 under the Biologics Price Competition and Innovation Act (BPCIA) of 2009, which was “designed to create competition, increase patient access, and potentially reduce cost of important therapies.”  The FDA’s Biosimilars Action Plan, unveiled in 2018, has been designed to aid the development of a market for biosimilars in order to increase competition for biologic drugs, which make up 40% of U.S. pharmaceutical spending.  Competition in the heavily regulated marketplace for these blockbuster therapeutics is expected to substantially impact the pharmaceutical industry and national health systems.  To date, the U.S. has considerably lagged behind Europe’s expansion of biosimilar drug options.  The RAND Corporation estimates that biosimilar products can save the U.S. health system approximately $54 billion over the next decade, as discussed here.

Since 2005, the biosimilar regulatory framework in Europe has been implemented through the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA).  The CHMP provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by the EMA.  Since Sandoz’s somatotropin biosimilar, Omnitrope®, was first authorized on April 12, 2006, an additional 64 applications have been approved in Europe.  Seven of the authorizations have been withdrawn post-approval (Table 1).

The U.S. did not implement a regulatory framework for biosimilar evaluation until after enactment of the Biologics Price Competition and Innovation Act (BPCIA) of 2009.  Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States.  Sandoz’s filgrastim biosimilar, Zarxio®, received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008.  Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991.  Subsequent to Zarxio®’s approval, 25 other biosimilar drugs have gained U.S. approval to date (Table 2).

As illustrated in the following graph, while the EU’s significant head start led to an imbalance in the number of biosimilar drugs available in the respective markets, the EU’s relatively higher rate of approvals in recent years has widened its lead over the United States, although the U.S. FDA reversed that trend in 2019 with ten approvals.  However, through the first five months of 2020, the FDA has not approved any biosimilar products and the EMA has approved just four products.  The COVID-19 pandemic is likely impacting both regulators and biosimilar applicants.

Currently, twelve biosimilar applications are under review by the EMA for marketing authorization (Table 3).  As an increasing number of patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing.  Biosimilars for more than 26 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).

On February 20, 2020, the FDA redefined the term “biological product” to include all “proteins,” which the rule defines as “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.” Accordingly, the biosimilar and interchangeable pathways are now open to insulin products in the United States.  The EMA already considered insulin a biologic product.  This change by the FDA is expected to lead to additional biosimilar approvals because there are already many biosimilar insulin products approved in Europe, and those biosimilar insulin manufacturers will likely seek to expand into the U.S. market.  In its press release, the FDA explained that it intends “to balance innovation and competition and facilitate the development and approval of biosimilar and interchangeable products. Getting safe and effective biosimilar and interchangeable products approved will help ensure that the market is competitive, and patients may have more affordable access to the treatments they need.”

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated June 5, 2020).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs.

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines compiled on May 7, 2020 and published on May 11, 2020).

Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. and biologics that have biosimilars in the regulatory pipeline.

[1] Based on sales reported by respective manufacturers (1. Humira—Abbvie ($19.17B), 2. Keytruda—Merck ($11.08B), 3. Eylea—Aflibercept ($7.54B), 4. Opdivo—Bristol-Myers-Squibb ($7.20B), 5.  Avastin—Roche ($7.12B), 6. Rituxan—Roche ($6.52B), 7. Stelara—Johnson & Johnson ($6.36B), 8. Herceptin—Roche ($6.08B), 9. Enbrel—Pfizer/Amgen ($5.23B), 10. Remicade—Johnson & Johnson/Merck ($4.38B).

Recently, the Federal Circuit Court of Appeals dismissed Pfizer Inc.’s (“Pfizer”) appeal for lack of Article III standing. Pfizer had filed an inter partes review (“IPR”) against Chugai Pharmaceutical Co. (“Chugai”) arguing that U.S. Patent Nos. 7,332,289 and 7,927,815 (“the patents-at-issue”) were unpatentable. The patents at issue are directed towards methods of manufacturing rituximab. Specifically, the patents at issue recite purifying proteins by “removing contaminant DNA from a sample containing a physiologically active protein.” The PTAB held that the claims were not invalid and Pfizer appealed.

To establish standing, an appellant must show that it suffered an injury in fact that is traceable to the appellee’s conduct and that is likely to be redressed by a judicial decision in the appellant’s favor.[1] The Federal Circuit explained that when an appellant is not engaging in infringing conduct, in order to demonstrate an actual injury-in-fact in an IPR appeal, the appellant must show that “it has concrete plans for future activity that creates a substantial risk of future infringement or would likely cause the patentee to assert a claim of infringement.”[2]

In support of its argument for standing, Pfizer relied on the FDA’s approval of its product Ruxience® in July 2019, and an announcement in Oct. 2019 that Pfizer would begin selling its product in Jan. 2020.  Ruxience® is a biosimilar to Genentech, Inc.’s rituximab product. Pfizer argued that when it launched its biosimilar product in Jan. 2020, Chugai was likely to file an infringement lawsuit for the patents-at-issue because Pfizer’s Ruxience® concerns purifying the protein using Protein A chromatography.

Pfizer further argued that it had standing because it was “self-evident” that a product existed at the time it filed its appeal. Pfizer relied on the fact that its service email address for the IPR proceedings was rituximabIPR@winston.com. Pfizer also relied on the fact that Chugai listed Genentech, Inc., as a potential real party in interest in the IPR proceedings because Genentech sells a rituximab product and is a subsidiary of F. Hoffmann-La Roche AG, which is an owner of Chugai.

However, the Federal Circuit rejected these arguments and held that Pfizer failed to establish a concrete injury as of the filing of its appeal in Jan. 2019. The Federal Circuit held that any evidence that Pfizer submitted regarding its activities or plans for its biosimilar product occurred after the date of the appeal. The Federal Circuit further held that Pfizer failed to provide sufficient evidence demonstrating its intent to practice the patented methods when manufacturing Ruxience®. As such, because Pfizer failed to establish standing, the Federal Circuit dismissed the appeal.

The Federal Circuit also rejected Pfizer’s argument that the statutory estoppel effect of 35 U.S.C. § 315(e) increases Pfizer’s interest in the outcome of the case. The Federal Circuit held that the statutory estoppel effect does not establish an injury-in-fact when there is no evidence that the appellant engaged in any activity that would lead to an infringement lawsuit.

Conclusions

The Federal Circuit’s dismissal demonstrates the importance of the timing of filing an IPR petition. Any challenger can have standing to file an IPR petition. But in order to appeal an unfavorable decision, the challenger must also have Article III standing, which recent Federal Circuit decisions illustrate may be easier said than done. While the standing requirements are more relaxed when a party is challenging an agency action, the bar remains high.  Generally, parties succeed at establishing an injury in fact when there is a real threat of an infringement suit. The mere fear of future litigation occurring at an undetermined time or the existence of a competitive relationship are not enough. The Federal Circuit has found standing to be satisfied if a party can demonstrate that it intends to engage in infringing activity, it has the capability to do so, and that its product may be infringing.[3] Thus, when a party is not currently faced with litigation, it must collect strong evidence to show it suffered a concrete injury.

However, as this current decision shows, a challenger must not only demonstrate a concrete injury-in-fact, but the injury must have occurred prior to the filing of a notice of appeal. Thus, potential petitioners should carefully consider the opportune time to file the petition and be sure that it aligns with their own activities and product development.

[1] See Op. at 3.

[2] See Op. at 4.

[3] Altaire Pharm., Inc. v. Paragon Bioteck, Inc., 889 F.3d 1274, 1282–83 (Fed. Cir. 2018).

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) held its monthly meeting on March 23-26, 2020. During the meeting, the CHMP reported important updates on the status of the approval process for biosimilars relating to etanercept and rituximab.

  • Nepexto® (Etanercept)

At the meeting, the CHMP adopted a positive opinion that recommended the grant of a marketing authorization for Mylan IRE Healthcare Ltd.’s Nepexto® product. The CHMP approved Nepexto®, a biosimilar of Enbrel®, for all of the same indications as Enbrel® including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis, non-radiographic axial spondyloarthritis), plaque psoriasis, and pediatric plaque psoriasis. Enbrel® was previously approved for use in the European Union (EU) on February 3, 2000. The CHMP concluded that Nepexto® “is highly similar to the reference product Enbrel (etanercept)” and “[d]ata show that Nepexto has comparable quality, safety and efficacy to Enbrel.”[1] The CHMP adopted this opinion after completing an assessment of the biosimilarity between Nepexto® and Enbrel® based on preclinical and clinical studies demonstrating bioequivalence to the reference product.

The European Commission will now consider the CHMP’s positive opinion and determine whether to approve Nepexto®. If approved, the European Commission will grant authorization allowing Nepexto® to be marketed by the member countries of the EU. The EC’s decision on approval is expected in May 2020.

  • Rituximab

At the meeting, the CHMP also reported that on March 16, 2020, Mabion S.A. (Mabion) withdrew its applications for initial marketing authorization for two rituximab biosimilars. Rituximab Mabion was intended for the treatment of certain blood cancers (non-Hodgkin’s lymphoma and chronic lymphocytic leukemia) and certain inflammatory diseases (severe rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis).

Initially, to support its applications, Mabion submitted laboratory studies to demonstrate that Rituximab Mabion’s structure, purity, and biological activity were highly similar to the reference product, MabThera. Mabion also presented a primary study of 629 rheumatoid arthritis patients that compared the effectiveness of Rituximab Mabion to MabThera.

Mabion withdrew its applications after the European Medicines Agency (EMA) evaluated the submitted information and prepared questions for the company. At the time of the withdrawal, the EMA held the provisional opinion that Rituximab Mabion could not be authorized for the requested indications. The CHMP reported that the EMA “was concerned that biosimilarity between Rituximab Mabion and the reference medicine MabThera had not been established” and “had concerns about the manufacturing process and the system for ensuring reliable quality of the medicine.”[2]

Following the release of the meeting highlights, Mabion issued a report on March 30, 2020, explaining that the reason for the withdrawal was a change in its regulatory strategy. Mabion explained that its applications were initially based on “a two-step strategy (obtaining small-scale marketing authorization, followed by a subsequent submission of a variation application relating to a large-scale manufacturing process).”[3] However, in view of its “goal to register a product based on a commercially attractive large-scale quality process”, Mabion decided to withdraw the application for the small-scale process. Mabion is preparing a new marketing authorization application for Rituximab.

In February, the U.S. Food and Drug Administration (“FDA”) and the Federal Trade Commission (“FTC”) published a joint statement regarding collaborative efforts to promote competition in the marketplace for biological products – including biosimilars and interchangeable products – by identifying joint goals both agencies will work to achieve, as well as measures to be taken to achieve those goals. While the joint statement reiterated the importance of promoting competition in the biologics market to benefit consumers and innovation, it also addressed the need to take action to discourage false or misleading statements and promotional communications by biological product manufacturers. The statement discussed the utility and benefits of biologics; and identified some of the federal government’s actions to develop a competitive biologics industry, starting with the 2010 Biologics Price Competition and Innovation Act (“BPCIA”) and ending with the FDA’s 2018 Biosimilars Action Plan (“BAP”), which outlined strategies to accelerate biosimilar competition. As one of the goals mentioned in the BAP was to support market competition by reducing “gaming” and other methods to unfairly delay biosimilar competition, the recent joint statement appears to be the next step towards achieving that goal.

The joint statement identified four “joint goals” to help the effort to deter false or misleading statements about biosimilars and other anticompetitive behaviors in the industry. First, the agencies will coordinate to promote greater competition in biologic markets to the extent possible. This goal will be achieved by the FDA developing materials to educate consumers and providers about biosimilars, and both agencies collaborating on future public outreach efforts, such as sponsoring a public meeting to discuss competition for biologics. The second goal identified is that the FDA and FTC will work together to deter behavior that impedes access to samples needed for the development of biologics. To this end, both agencies will collaborate to identify and deter tactics used to prevent or impede access to samples of the reference product that a prospective biosimilar applicant needs for testing in order to be licensed as a biosimilar or interchangeable biosimilar, as well as consider additional information sharing arrangements between each other. The third goal is to take the appropriate action against false or misleading communications about biologics, including biosimilars within their respective authorities. The joint statement expressed both agencies’ intent to use their statutory authority to the fullest extent to take action against communications that misrepresent the safety or efficacy of biosimilars, deceives consumers, deters competition, or have the potential to impact public health. The FDA also stated its plans to publish draft guidance outlining considerations for FDA-regulated advertisements and promotional labeling that contains information about biologic products. It has since published that guidance, in which it discusses its position on topics such as the general content requirements for FDA-regulated promotional materials for reference products and biosimilar products, how to identify reference products and biosimilar products in such materials, what firms should consider before presenting data or information from the studies conducted to support licensure of the reference product, and what to consider when comparing reference products and biosimilar products. As a final goal, the FTC will review patent settlement agreements involving biologics, including biosimilars, for antitrust violations, pursuant to its authority via the Patient Right to Know Drug Prices Act.

In addition to the agencies’ efforts, a number of pending legislation hope to address the biosimilar market. The Purple Book Continuity Act (HR1520) would require the publication of patents disclosed during the BPCIA patent dance, the legislative process to get biosimilars approved to market. The Affordable Prescriptions for Patients Act of 2019 (S 1416) and Affordable Prescriptions for Patients Through Improvements to Patent Litigation Act of 2019 (HR 3991) aim to diminish anticompetitive behavior during the patent dance by prohibiting the act of “product hopping” by reference product owners, and limiting the number of late-filed or late-issued patents that could be asserted during the dance, respectively. The first two have reached the Senate, and the third is still in the reporting phase.

These actions clearly illustrate the federal government’s intent to improve the current condition of the biosimilars market. Time will determine, however, whether their actions are as strong as their intentions.

A white paper released in 2019 by The Biosimilars Forum and Medicines for Europe shows the United States and Europe accounting for more than a combined 80% of sales of biologic medicines, and more than a combined 90% of biosimilars.[1] This, of course, has led to a focus on these markets for the biopharmaceutical industry.  However, as many in the industry are already aware, biopharmaceutical markets in East Asia are rapidly developing and represent a massive potential for growth for biosimilars.

For example, China is the second largest pharmaceutical market in the world,[2] but the China National Medical Products Administration (NMPA) only approved its first biosimilar in February 2019, Shanghai Henlius Biotech’s 汉利康® (pronounced “Han-li-kang”), which references Genentech and Biogen’s Rituxan (rituximab).[3] A second biosimilar, Bio-Thera’s QLELTLI®, which references Abbvie’s Humira® (adalimumab), was not approved by the NMPA until November 2019.[4] Despite this seemingly late start, it has been reported that China has approved more than 200 clinical trials for biosimilars,[5] and this is reflected by an increasing pace of approvals and other activity starting in the later part of 2019.

Beyond China, this increasing pace is reflected elsewhere in East Asia as discussed below, with approvals and other activity in South Korea and Japan.

This activity should signal not only an opportunity for expansion within these growing markets, but also a potential growth in competition that those in the industry, whether creating originator molecules or biosimilars, should be monitoring closely.

Biosimilar Development Activity:

Beyond the events described above, several major deals have been announced regarding the planned expansion of biosimilar activity into East Asian markets.

For example, on November 6, 2019, Samsung Bioepis and Biogen announced a commercialization agreement for two of Samsung Bioepis’s biosimilar candidates referencing Genentech’s Lucentis (ranibizumab) and Regenron’s Eylea (aflibercept) into several markets, including Japan.[15] This agreement also included an option for Biogen to commercialize three of Samsung Bioepis’s existing biosimilar products, Benepali (etanercept), Flixabi (infliximab), and Imraldi (adalimumab) in China.

January 12, 2020, saw Samsung Bioepis enter another commercialization agreement, this time with Mundipharma, for four of Samsung Bioepis’s biosimilar candidates into Hong Kong and Taiwan.[16]

Finally, on January 21, 2020, Celltrion announced that it planned to build a $500 million factory in China to begin manufacturing its biologics to supply the Chinese market.[17] However, Celltrion had chosen Wuhan as the location for its new facilities, and given that the Chinese city is at the center of the recent  coronavirus outbreak, it has recently been reported that these plans may be on hold.[18]

[1] http://biosimilarsforum.org/PDF/BIosimilars_WhitePaper-final.pdf

[2] https://pharmaceuticalcommerce.com/business-and-finance/global-pharma-spending-will-hit-1-5-trillion-in-2023-says-iqvia/

[3] https://www.fosunpharma.com/en/news/news-details-3749.html

[4] https://www.bio-thera.com/EN/ShowNews.asp?id=60

[5] https://www.parexel.com/news-events-resources/blog/biosimilars-china

[6] http://www.koreabiomed.com/news/articleView.html?idxno=6738

[7] http://www.mochida.co.jp/english/news/docs/2019/191127_teriparatideBS.pdf

[8] https://www.businesswire.com/news/home/20191204005310/en/

[9] http://www.gabionline.net/Biosimilars/News/China-approves-bevacizumab-copy-biological-Ankada

[10] https://www.globenewswire.com/news-release/2019/12/10/1958295/0/en/AffaMed-Therapeutics-Receives-NMPA-Approval-to-Initiate-Phase-III-Clinical-Trial-in-China-with-Herceptin-Trastuzumab-Biosimilar-Candidate-AMT901.html

[11] https://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/007086.html

[12] https://www.businesswire.com/news/home/20191230005088/en/Clover-Biopharmaceuticals-Initiates-Phase-III-Study-Etanercept

[13] https://www.globenewswire.com/news-release/2020/01/06/1966350/0/en/Sorrento-Announces-Filing-for-Approval-of-Infliximab-Biobetter-Antibody-by-Its-Partner-Mabpharm-in-China.html

[14] https://www.samsungbioepis.com/en/newsroom/newsroomView.do?idx=145&currentPage=1

[15] https://www.samsungbioepis.com/en/newsroom/newsroomView.do?idx=138&currentPage=1

[16] https://www.biospace.com/article/releases/mundipharma-enters-partnership-with-samsung-bioepis-to-expand-biosimilars-into-hong-kong-and-taiwan/

[17] https://pharmaintelligence.informa.com/resources/product-content/2020/01/27/10/58/celltrion-sets-out-strategy-for-china; https://asia.nikkei.com/Business/Companies/Celltrion-plans-500m-factory-in-Wuhan-to-tap-China-drug-market

[18] https://www.centerforbiosimilars.com/news/celltrions-wuhan-plans-on-hold-amid-coronavirus-outbreak

On January 15, 2020, Hospira filed a petition for rehearing en banc asking the full Federal Circuit to reconsider a prior panel’s analysis of the Safe Harbor provision and reverse the finding of infringement. In December 2019, the Federal Circuit affirmed the District of Delaware’s decision denying Hospira’s motion for judgment as a matter of law and upholding the jury’s verdict that Hospira infringed Amgen’s patent and that some batches of drug substance for Hospira’s erythropoietin biosimilar drug product were not covered by the Safe Harbor provision of 35 U.S.C. § 271(e)(1).

35 U.S.C. § 271(e)(1), also known as the Safe Harbor provision, provides that it shall not be an act of infringement to make use, offer to sell, sell, or import into the United States a patent invention “solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.”

During its initial appeal, Hospira argued that the jury instructions regarding the Safe Harbor provision improperly focused the jury on the reasons why each batch of EPO was made instead of how each batch was used or whether the use was reasonably related to the development and submission of information in Hospira’s BLA. The jury instructions read, “[i]f Hospira has proved that the manufacture of a particular batch was reasonably related to developing and submitting information to the FDA in order to obtain FDA approval, Hospira’s additional underlying purposes for the manufacture and use of that batch do not remove that batch from the Safe Harbor defense.” Op. at 13-14. Hospira argued that it only had to prove the use was reasonably related to the submission of the BLA, not the manufacture.

In its opinion, the Federal Circuit panel disagreed and held that the jury instructions were proper because Section 271(e)(1) “extends to all uses of patented inventions  that are reasonably related to the development and submission of any information under the FDCA” and that each accused activity must be evaluated separately to see if the exemption applies. Op. at 14 (quoting Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193, 202 (2005)). The Federal Circuit concluded that Amgen’s patented invention was the methods of manufacture and Hospira’s accused activity was the use of those methods of manufacture. The Federal Circuit reasoned that the correct inquiry is whether each act of manufacture was for uses reasonably related to the submission of information to the FDA. The Federal Circuit then held that substantial evidence supported the jury’s finding that some of the batches were not manufactured for the sole purpose of use reasonably related to the development and submission of information to the FDA.

In its recent petition for rehearing en banc, Hospira made two primary arguments: (1) the panel ignored binding legal precedent in its decision; and (2) the panel incorrectly applied a different rule for manufacturing process than the rule for other types of patents.

First, relying on the Supreme Court’s decision in Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193, 206 (2005), Hospira argued that the panel’s analysis ignores the Supreme Court’s admonition that “all uses” reasonably related to obtaining FDA approval are exempted and that the Safe Harbor provision’s application is broader than just information required for approval. According to Hospira, it is not reasonable to expect an applicant to submit the minimum amount of data required to the FDA. Hospira argued that its accused batches were all used to generate data for the FDA as data from every accused batch was used to revise release specifications in response to the CRL.

Second, Hospira argued that the panel erred when it ruled that “because the patents-in-suit claim methods of manufacture, subsequent uses that are objectively related to obtaining FDA approval cannot bring the making of the EPO within the Safe Harbor if the manufacture itself was not ‘required,’ at the time of manufacture, for seeking FDA approval.” Pet. at 10. Hospira argued that the panel substituted the well-established test regarding the uses of the patented invention with an analysis of the underlying purpose for why each match was made. Hospira argued that the panel erred by applying a different analysis for manufacturing process patents than for other patents.

Hospira emphasized that the previous panel’s decision “threatens to eviscerate the protections Congress intended to provide under the Safe Harbor, particularly in the BPCIA context” and that this issue is of vital importance as manufacturing patents are the focus of many BPCIA cases. Pet. at 15.

We will continue to provide updates as the case continues.

  • Since November 2019, biosimilar versions of pegfilgrastim, rituximab, bevacizumab, and trastuzumab have launched in the United States.
  • FDA approved fifth Humira® (adalimumab) biosimilar, but it will not launch until 2023.
  • FDA approved third Neulasta® (pegfilgrastim) biosimilar and all three have launched.
  • FDA approved fourth Remicade® (infliximab) biosimilar.

As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years.  Global sales for the top ten branded biologic drugs totaled approximately $81 billion in 2018[1].  In the FDA’s Center for Drug Evaluation and Research’s (CDER) annual report, the FDA highlighted the ten biosimilar approvals in 2019 under the Biologics Price Competition and Innovation Act (BPCIA) of 2009, which was “designed to create competition, increase patient access, and potentially reduce cost of important therapies.”  The FDA’s Biosimilars Action Plan, unveiled in 2018, has been designed to aid the development of a market for biosimilars in order to increase competition for biologic drugs, which make up 40% of U.S. pharmaceutical spending.  Competition in the heavily regulated marketplace for these blockbuster therapeutics is expected to substantially impact the pharmaceutical industry and national health systems.  To date, the U.S. has considerably lagged behind Europe’s expansion of biosimilar drug options.  The RAND Corporation estimates that biosimilar products can save the U.S. health system approximately $54 billion over the next decade, as discussed here.

Since 2005, the biosimilar regulatory framework in Europe has been implemented through the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA).  The CHMP provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by the EMA.  Since Sandoz’s somatotropin biosimilar, Omnitrope®, was first authorized on April 12, 2006, an additional 59 applications have been approved in Europe.  Seven of the authorizations have been withdrawn post-approval (Table 1).

The U.S. did not implement a regulatory framework for biosimilar evaluation until after enactment of the Biologics Price Competition and Innovation Act (BPCIA) of 2009.  Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States.  Sandoz’s filgrastim biosimilar, Zarxio®, received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008.  Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991.  Subsequent to Zarxio®’s approval, 25 other biosimilar drugs have gained U.S. approval to date (Table 2).

As illustrated in the following graph, while the EU’s significant head start led to an imbalance in the number of biosimilar drugs available in the respective markets, the EU’s relatively higher rate of approvals in recent years has widened its lead over the United States, although the U.S. FDA reversed that trend in 2019 with ten approvals.

Currently, nine biosimilar applications are under review by the EMA for marketing authorization (Table 3).  As an increasing number of patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing.  Biosimilars for at least 24 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).

On November 5, 2019, Sandoz announced the approval of its pegfilgrastim biosimilar ZiextenzoTM.  “When a cancer patient with febrile neutropenia gets an infection, it can have serious consequences such as delays or dose reductions of chemotherapy,” said Carol Lynch, President of Sandoz Inc. “The approval of Ziextenzo expands our oncology portfolio, providing physicians with a long-acting supportive oncology biosimilar option. It builds on the foundation of trust and experience we developed with our short-acting filgrastim Zarxio® – the leading filgrastim by market share in the US – including consistent product supply and reliable patient services.”

On November 18, 2019, Pfizer announced the approval of its adalimumab biosimilar AbriladaTM.  “Biosimilars like ABRILADA represent an opportunity to help improve access to important treatment options for patients living with chronic, and often debilitating, inflammatory conditions,” said Richard Blackburn, Global President, Pfizer Inflammation and Immunology. “Our current portfolio of approved biosimilar products is one of the broadest in the industry and we are proud to offer additional treatment options for patients.”

On December 6, 2019, Amgen announced the approval of its infliximab biosimilar AvsolaTM.  “The approval of AVSOLA represents an important milestone across our biosimilar and inflammation portfolios,” said Murdo Gordon, executive vice president of Global Commercial Operations at Amgen. “Following July’s exciting launches of our two biosimilars in oncology, AVSOLA highlights Amgen’s long-term commitment to providing more affordable biological treatment options to patients across critical disease states, including chronic inflammatory conditions.”

In addition to these biosimilar approvals, on December 23, 2019, AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) announced the approval of EnhertuTM, which is a HER2 directed antibody drug conjugate (ADC) designed to delivery cytotoxic chemotherapy to cancer cells via a human epidermal receptor 2 (HER2) antibody (trastuzumab) attached to a novel topoisomerase I inhibitor payload and a tetrapeptide-based linker.  José Baselga, Executive Vice President, Oncology R&D, said: “Enhertu has shown impressive results in women with HER2-positive metastatic breast cancer, with the majority of women benefiting from treatment and the median duration of the response exceeding 14 months. With this first approval, we are proud to bring Enhertu to patients with high unmet need and we look forward to further exploring its potential in additional settings.” Antoine Yver, Executive Vice President and Global Head, Oncology R&D, Daiichi Sankyo said: “The approval of Enhertu underscores that this specifically engineered HER2-directed antibody-drug conjugate is delivering on its intent to establish an important new treatment for patients with HER2-positive metastatic breast cancer. Since the beginning of our clinical trial programme four years ago, we have focused on the opportunity to transform the treatment landscape for patients with HER2-positive metastatic breast cancer, and we are extremely proud of how quickly we delivered Enhertu to patients in the US, as Enhertu represents one of the fastest-developed biologics in oncology.”

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated January 24, 2020).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs.

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines compiled on January 6 2020 and published on January 7, 2020).

Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. and biologics that have biosimilars in the regulatory pipeline.

 

[1] Based on sales reported by respective manufacturers (1. Humira—Abbvie ($19.94B), 2. Opdivo—Bristol-Myers-Squibb ($7.57B), 3. Keytruda—Merck ($7.17B), 4. Enbrel—Pfizer/Amgen ($7.126B), 5. Herceptin—Roche ($6.981B), 6.  Avastin—Roche ($6.847B), 7. Rituxan—Roche ($6.75B), 8. Eylea—Aflibercept ($6.551B), 9. Remicade—Johnson & Johnson/Merck ($5.908B), 10. Stelara—Johnson & Johnson ($5.156B)).