The Federal Circuit recently held[1] in a 2-1 decision that there was substantial evidence supporting a jury finding that Teva was liable for induced infringement for an indication carved out of its skinny label for its generic version of carvedilol.

The case concerned GSK’s United States Patent No. 4,503,067 (“the ’067 patent”) and Reissue Patent No. RE40,000 (“the ’000 patent”). The ’067 patent covers carvedilol and related compounds, and expired March 5, 2007.  The FDA initially approved carvedilol for hypertension, and GSK marketed it under the brand name Coreg®.  In May 1997, the FDA approved carvedilol for congestive heart failure (“CHF”). The method was patented in the ’000 patent, which reissued in January 2008 and claims a method of decreasing mortality caused by CHF by administering carvedilol together with one or more of an ACE inhibitor, a diuretic, or digoxin.  In 2003, the FDA approved this same combination for use by patients suffering from left ventricular dysfunction following a myocardial infarction.

In March 2002, Teva applied for FDA approval for its generic carvedilol, certifying in its ANDA under Paragraph III of the Hatch-Watch Waxman Act that it would not launch its product until after the ’067 patent expired in March 2007.  Teva received tentative approval in 2004 for its generic for treatment of left ventricular dysfunction following myocardial infarction and hypertension after the expiration of the ’067 patent.  Upon the expiration of the ’067 patent, Teva launched its generic carvdilol with a skinny label indicating only left ventricular dysfunction following myocardial infarction and hypertension.  Teva’s press releases and marketing materials stated that its carvedilol was an AB-rated generic of Coreg® tablets.

In 2011, the FDA required Teva to amend its label to be identical to Coreg®’s labeling, and Teva amended its label to include the indication for treatment of CHF.  In response, GSK filed suit alleging infringement of the ’000 patent during both the 2008-2011 “skinny label” period and during the post-amendment “full label” period.

Teva argued that since it had carved out CHF from its initial 2007 label, citing the carve-out authorization in 21 U.S.C. § 355(j)(2)(A)(viii), it could not be found to induce prescribing physicians to infringe the reissue of the ’069 patent, at least not before Teva amended its label.  However, the jury found that Teva induced infringement of the reissue both before and after amending its label to add CHF as an indication as required by the FDA.

The district court granted Teva’s motion for judgment as a matter of law (JMOL), finding that the jury’s verdict was not supported by substantial evidence for either the skinny- or full-label periods.  The district court found that GSK failed to prove that Teva’s alleged inducement—as opposed to other factors such as information from sources available to physicians (e.g., the American Heart Association, the American College of Cardiology, and various publications) and GSK’s Coreg® Label—actually caused physicians to directly infringe by prescribing generic carvedilol for CHF.  The district court noted that cardiologists had testified that they knew of the various uses of carvedilol before the FDA required Teva to amend its label.  As a result, the district court held that a reasonable factfinder could only have found that these alternative, non-Teva factors were what caused the doctors to prescribe generic carvedilol for an infringing use, during both the skinny- and full-label periods.

The Federal Circuit reversed the JMOL as to both time periods.  The Federal Circuit cited trial evidence, including Teva’s press releases and product catalogs, showing that Teva’s marketing during the skinny label period did not differentiate the uses for which its product was approved compared to Coreg®.  GSK’s experts testified that such marketing would lead doctors to believe that Teva’s carvedilol product was approved for the same uses as GSK’s product, including CHF.

Regarding the district court’s reasoning that “physicians already knew how to use carvedilol for treating CHF” and thus infringement was not “caused” by Teva, the Federal Circuit stated that “[t]he district court applied an incorrect legal standard, for precedent makes clear that when the provider of an identical product knows of and markets the same product for intended direct infringing activity, the criteria of induced infringement are met.”  The Federal Circuit also noted the content of an FDA-approved label can be used to establish inducement to infringe, without clarifying whether its statement referred to the skinny label or the later full label.  The Federal Circuit found, based on the totality of the trial record, that the jury had substantial evidence to support the jury’s conclusion that Teva intended to induce doctors to prescribe Coreg® to treat CHF as claimed in the ’000 patent.  The court remanded the case to the district court for reinstatement of the jury verdicts of infringement and damages.

Chief Judge Prost dissented, stating that the majority’s decision undermined Congress’s purpose for the generic approval system “by allowing a drug marketed for unpatented uses to give rise to liability for inducement and by permitting an award of patent damages where causation has not been shown.”  The dissent emphasizes that “no communication from Teva encouraged doctors to use generic carvedilol to practice the patented method.”

This case raises issues over the extent to which generic manufacturers can rely on a skinny label to avoid a finding of induced infringement.  The holding indicates that mere marketing of a generic drug as “AB-rated” or equivalent to a branded product may lead to a finding of inducement where the branded drug is approved for a patented use that has been carved out of the generic/biosimilar’s label.  Generic and biosimilar manufacturers may wish to consider taking affirmative steps to inform physicians that their product is not approved for the patented use in order to reduce the likelihood of finding inducement.

[1] http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/18-1976.OPINION.10-2-2020_1663180.pdf

Updated October 12, 2020

  • FDA has only approved two biosimilars in 2020.
  • No biosimilars have launched in the U.S. since April 2020.
  • EMA approves first Novolog® (insulin aspartate), third and fourth Avastin® (bevacizumab), and sixth Herceptin® (trastuzumab) biosimilars.

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 a September 2020 report, the IQVIA Institute for Human Data Science estimated biosimilar sales totaling $80 billion over the next five years compared to $14 billion during the previous five years (2015-2019), and that the availability and use of biosimilar medicines would reduce U.S. drug costs by $100 billion through 2024.

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.

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 69 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, 27 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.  Through the first nine months of 2020, however, the FDA has only approved two biosimilar products, whereas the EMA has approved eight biosimilar products.  The COVID-19 pandemic has likely shifted regulatory and industry focus to vaccines and therapeutics, thereby causing delays in biosimilar approvals.

A recent study of U.S. biosimilar approvals found that most comparative efficacy trials conducted to obtain FDA approval for a biosimilar had a tendency to be larger, longer, and more costly than clinical trials required for originator products. Moreover, the FDA requires animal studies whereas the EMA does not require animal studies to approve a biologic product.  Thus, in addition to the patent litigation landscape, there are regulatory hurdles and costs faced by biosimilar applicants that deter or delay biosimilar products from reaching the U.S. market.

Currently, eleven 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.”  The FDA approved Mylan’s insulin glargine product SemgleeTM on June 11, 2020, as an equivalent to Sanofi’s Lantus® although it is not considered a biosimilar because approval was under 351(a) of the Public Health Service (PHS) Act (42 U.S.C.. 55. 262(k)).  “We are proud to be the first company, following the reference product, to receive FDA approval on and launch both the vial and pen presentations of an insulin glargine treatment with an identical amino acid sequence to Sanofi’s Lantus,” said Mylan CEO Heather Bresch. She estimated the potential market to be more than 30 million Americans.  In its press release, Mylan stated that it has submitted all necessary documentation to request FDA approval as a biosimilar to Lantus under the 351(k) pathway and “remains confident in seeking an interchangeability designation.”

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated October 11, 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 September 4, 2020 and published on September 9, 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).

Last week, the Federal Circuit denied Sandoz’s petition for an en banc rehearing of its precedential July 1st panel decision upholding two of Immunex’s patents covering Enbrel®.

As explained in the petition, Immunex was the first to make etanercept, the tumor necrosis factor (TNF) receptor fusion protein that is the active ingredient in Enbrel® (used to treat chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis). Immunex launched Enbrel® in 1998 and its original patents shielded the drug from competition through 2019. At the same time, Hoffmann-La Roche Inc. (“Roche”) was also developing TNF receptor fusion proteins. When Roche filed its applications in 1995, the resulting patents still qualified for a term of 17 years from issuance. In 2004, Roche and Immunex entered into an exclusive license agreement giving Immunex the sole right to prosecute Roche’s applications, which were amended to cover etanercept and methods of making etanercept. The applications ultimately issued as the patents-in-suit, U.S. Patent Nos. 8,063,182 (“the ’182 Patent”) and 8,163,522 (“the ’522 Patent”), in 2011 and 2012, respectively. The ’182 Patent expires in November 2028 and the ’522 Patent expires in April 2029 – 10 and 15 years after the expiry of Immunex’s own patents covering Enbrel® (U.S. Patent Nos. 7,915,225 and 5,605,690), respectively.

After Sandoz filed an abbreviated Biologics License Application (“aBLA”) seeking approval to market Erelzi, a biosimilar of Enbrel®, Immunex filed suit for patent infringement. Sandoz stipulated to infringement, but argued that the patents-in-suit are invalid for obviousness-type double patenting (“OTDP”), asserting that they are “commonly owned” by Roche and Immunex, and that the new patents improperly extended Immunex’s protection for Enbrel®.

In its July 1, 2020 panel decision, the Federal Circuit affirmed a decision from the District of New Jersey, finding that Roche and Immunex did not “commonly own” the patents-in-suit, and thus Immunex’s patents could not serve as an OTDP reference against the Roche patents.  The issue ultimately came down to whether the agreement entered into by Roche and Immunex was a licensing agreement or an effective assignment of “all substantial rights.” Under the terms of the agreement, Immunex has the sole right to grant sublicenses, to make, have made, use, sell, offer for sale and import products covered by the patent family. But because the agreement accorded Roche a secondary right to sue for infringement if Immunex fails to do so (even though Immunex can convert the license into a formal assignment for a $50,000 payment), the panel found that Immunex doesn’t have “all substantial rights.” Therefore, the decision concluded that the patents are not commonly owned and the issue of OTDP isn’t triggered.

Sandoz’s petition for rehearing asked the following question:  “May a party… avoid becoming an effective owner under the all-substantial-rights test, and thereby evade double-patenting scrutiny, merely by leaving the nominal owner with a theoretical secondary right to sue, which the licensee can prevent from ever ripening by issuing a royalty-free sublicense?”

As the FDA approved Sandoz’s Erelzi in 2016, the company is eager to launch and is reportedly looking at its options for moving forward.  Presumably, those options include a petition for a writ of certiorari to the Supreme Court.  We will report on future developments.

Pharmaceutical companies Biocon Biologics and Mylan announced at the end of last month the U.S. launch of their long-acting insulin glargine product Semglee.  Semglee was approved in June as an equivalent to Sanofi’s reference product insulin glargine, Lantus.

The companies are launching Semglee at a “65% discounted list price,” calling it the lowest wholesale acquisition cost for any long-acting insulin glargine on the market. Mylan, the distribution partner, is offering Semglee at the wholesale acquisition cost of $147.98 per package of five 3mL pens and $98.65 per 10mL vial.  For reference, the individual vial cost of Lantus was $431 in 2019 according to a Senate Finance Committee letter.  It should be noted, however, that wholesale acquisition cost does not necessarily reflect the actual cost to consumers or healthcare providers.

Both companies expressed the intention to have Semglee formally approved as a biosimilar to Lantus, and were confident that Semglee would receive interchangeability designation.  Both designations would accelerate the competition in the insulin market.  Mylan stated that all necessary documentation to request approval of Semglee as a biosimilar to Lantus has already been submitted to the FDA.

Kiran Mazumdar-Shaw, Executive Chairperson of Biocon, commented that the launch “represents another milestone achievement for Biocon in making insulin-based therapy increasingly accessible for people with diabetes globally.  We are confident that along with our long-standing partner Mylan, we will be able to address the needs of millions of patients living with diabetes in the U.S.”

Pharmaceutical companies Teva Pharmaceutical Industries Ltd. and Alvotech announced on Wednesday, August 5, 2020, that they will be entering into an exclusive partnership for the commercialization of biosimilar products in the United States.  This partnership aims to combine Teva’s long-standing commercial presence and extensive infrastructure in the U.S. market with Alvotech’s scientific experience and state-of-the-art biologics manufacturing.

Under the agreement, Alvotech will be responsible for the development, registration, and supply of the biosimilars, while Teva will be exclusively commercializing the products in the U.S.  Teva and Alvotech will share the profits of the partnership.  Press releases from the two companies state that five biosimilar product candidates will be commercialized under the partnership, addressing multiple therapeutic areas.  While the announcements did not specify which biosimilars would be candidates or what indications would be addressed under the partnership, both companies’ press releases stated that the combined sales of the originator products of the five candidate biosimilars generate around $35 billion in U.S. sales.

Brendan O’Grady, executive vice president and head of North America commercial at Teva, was quoted stating “[t]his commercial partnership with Alvotech will enable Teva to lend its technical expertise in working with the FDA to bring products to the U.S. market while broadening its growing biosimilar portfolio and continuing to leverage its unique cross-functional expertise across both specialty and generic medicines.”

More information may be found at both companies’ websites.  Teva’s announcement may be found at: https://www.tevapharm.com/news-and-media/latest-news/teva-and-alvotech-announce-strategic-partnership-to-collaborate-in-the-u.s.-biosimilar-market/.  Alvotech’s announcement may be found at: https://www.alvotech.com/newsroom/alvotech-and-teva-announce-strategic-partnership-to.

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).