The Federal Circuit has affirmed Bayer’s patent infringement victory related to Baxalta’s biologic product, Adynovate.  Bayer Healthcare LLC v. Baxalta Inc., No. 2019-2418, 2021 WL 771700 (Fed. Cir. Mar. 1, 2021).  At the district court, the jury found the claims of Bayer’s U.S. Patent No. 9,364,520 (“the ’520 patent”) enabled and infringed, and awarded a reasonable royalty of 17.78%.  The appeal raised a variety of issues, including infringement, enablement, damages, and willfulness.  The Federal Circuit affirmed the results of the lower court on all issues.

The ’520 patent is directed to recombinant forms of human factor VIII, a protein useful in the treatment of hemophilia A.  The recombinant forms at issue involve a more specific PEGylation of the protein’s B-domain as compared to the random modifications in the prior art.  The accused product, Adynovate, is a human factor VIII protein with PEGylated amine sites, such as lysine.

Enablement

The question of enablement of the ’520 patent raised an interesting factual scenario.  Baxalta challenged the ’520 patent’s enablement of amine or lysine PEGylation because the specification only provided detailed instructions for practicing the claimed invention using cysteine PEGylation.  In response, Bayer relied on expert testimony to demonstrate that other modifications, such as lysine PEGylation, would have been known at the time of the invention, and the accumulated knowledge of 150 years of protein chemistry would allow one in the field to understand how some amino acids would be more or less amenable to modification.  Despite contrary testimony from Baxalta’s expert, the Federal Circuit held that substantial evidence supported the jury’s verdict.  Baxalta had also challenged the district court’s reliance on the knowledge of a person of ordinary skill as a substitute for the lack of disclosure in the specification.  Both the district court and Federal Circuit rejected this challenge, noting that a specification does not need to disclose each embodiment to enable the full scope of the claims.

Damages

On the issues of damages and the reasonable royalty rate evidence presented at trial, the Federal Circuit found no abuse of discretion in allowing Bayer’s expert testimony on the reasonable royalty rate.  Prior to trial, the district court excluded part of Bayer’s expert testimony on the hypothetical negotiation to determine a reasonable royalty rate.  The district court found that using the midpoint of the bargaining range as a reasonable royalty rate was not tied to the facts of the case, but allowed the expert to testify on his proposed bargaining range of 5.1% to 42.4%.  Ultimately, the jury determined a reasonable royalty rate of 17.78%.  The Federal Circuit found support in the expert report to allow the expert’s discussion of the proposed bargaining range, and noted that Baxalta had the opportunity to fully cross-examine the expert on his theories.  Furthermore, the expert provided ample guidance for the jury to determine the royalty rate, including discussion of the hypothetical negotiation and the Georgia-Pacific factors.  Therefore, the jury could evaluate his opinions and adopt a rate within the proposed range, as it did.

Claim Construction

Baxalta challenged several of the district court’s claim constructions, but the Federal Circuit found adequate support for them.  The court recognized that several of the arguments presented close questions, but the statements in the prosecution history and specification did not rise to the levels of disclaiming certain types of PEGylation as Baxalta had sought.

Infringement

Similarly, the Federal Circuit found substantial evidence to support the jury’s finding that Adynovate met the claim limitations in its infringement analysis.  In particular, the court noted Baxalta’s letter representing to the U.S. Food and Drug Administration that Adynovate includes a controlled and targeted chemical addition of PEG conjugates to the human factor VIII B-Domain.  Combined with supporting expert testimony from Bayer’s expert, there was adequate support for the jury’s determination of infringement.

Additional Issues Raised

The Federal Circuit affirmed the district court’s judgment as to issues raised by the parties regarding supplemental damages and willful infringement.  The district court’s award of supplemental damages was within the court’s discretion and did not constitute an impermissible additur.  Because the jury had determined the royalty rate, applying that rate to the undisputed actual infringing sales base was an appropriate method for the court to award supplemental damages.  Finally, the Federal Circuit agreed that awareness of the ’520 patent was insufficient for a finding of willful infringement, and Bayer failed to present sufficient evidence of the necessary state of mind.  The evidence only showed knowledge of the patents and Baxalta’s direct infringement, but it did not rise to the level of deliberate or intentional infringement required.

The Standing Committee of the 13th National People’s Congress, China’s top legislature, adopted the Fourth Amendment to the 1984 Chinese Patent Law on October 17, 2020. The Fourth Amendment follows a series of amendments that were last adopted in 2008 and will become effective on June 1, 2021. Among the provisions is Article 76, establishing a new pharmaceutical patent linkage system modeled after the U.S. Hatch-Waxman Act. Article 76 of the Fourth Amendment was implemented in accordance with Article 1.11 of the Economic and Trade Agreement Between the Government of the United States of America and the Government of the People’s Republic of China.[1]

Key provisions of Article 76 of the Fourth Amendment include:

  • Establishment of a platform for registering patent information for marketed drugs (similar to the U.S. FDA’s Orange Book), where a holder of a drug marketing approval or patentee of a chemical drug, biological preparation, or traditional Chinese medicine can register information such as relevant patent number, status, and assignee.
  • A requirement for an applicant seeking market approval for a generic drug to submit a non-infringement statement (Type I-IV), similar to Paragraph I-IV certifications made by ANDA applicants in the United States.
  • A resolution mechanism in which a patentee objecting to the non-infringement statement can file an opposition at the People’s Court or the China National Intellectual Property Administration (CNIPA) within 45 days from when the National Medical Product Administration (NMPA) publishes the drug marketing authorization application, initiating an automatic 9-month stay of the generic drug regulatory approval.
    • For non-infringement statements under Type I-III, the NMPA will make an administrative ruling based on a technical examination of a drug. For non-infringement statements under Type IV, the NMPA will make an administrative ruling based on a technical examination of a drug further in consideration of the decision made by the CNIPA or the People’s Court.
    • The automatic stay period does not stop the NMPA’s technical examination of the drug. The NMPA will issue an administrative ruling when the People’s Court or the CNIPA: 1) determines the drug does not fall within the scope of the patent, 2) declares the patent invalid, 3) finds the parties to have settled and reached an agreement, or 4) fails to reach a verdict within the 9 months.
  • 12-month market exclusivity from the date of marketing authorization for the first generic applicant entrant filing a Type IV non-infringement statement and receiving the marketing authorization.

There are several key differences between the U.S. Hatch-Waxman system and the new Chinese law.  China’s patent linkage system is not limited to small molecules and also includes biologics and traditional Chinese medicine. Further, China provides a much shorter stay period of only 9 months.  This 9-month stay period only applies to small molecules and excludes biologics or traditional Chinese medicine.  The market exclusivity period for first generic entrants (12 months), however, is far longer than that of the United States (180 days).

The patent linkage system for pharmaceutical patents in China is just developing, and the resolution mechanism for patent disputes under Article 76 of the Fourth Amendment currently lacks detail for both generic market entrants and patentees.  One notable piece of information missing in the current legislation is whether there is an obligation for the generic market entrants to notify the patentee of the non-infringement statement.  In this regard, stay tuned for updates on finalized draft rules, which are expected to provide further guidance on China’s new patent linkage system.

[1]The text of the Phase One Trade Agreement with China (2020) is available at: https://ustr.gov/sites/default/files/files/agreements/phase%20one%20agreement/Economic_And_Trade_Agreement_Between_The_United_States_And_China_Text.pdf. Article 1.11 begins on page 1-6 on Chapter 1 (page 7 of the PDF).

Updated March 8, 2021

  • FDA has not approved any biosimilars in 2021 after only approving three in 2020.
  • EMA approves second Novolog® (insulin aspartate), fifth Avastin® (bevacizumab), eighth Neulasta® (pegfilgrastim), and twelfth Humira® (adalimumab) biosimilars, and withdraws approval of an adalimumab biosimilar and a pegfilgrastim biosimilar.
  • Given the increasing number of approved biosimilars in Europe, biosimilar manufacturers are increasingly deciding to not market their products due to commercial reasons.

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 76 applications have been approved in Europe.  Ten of the authorizations have been withdrawn post-approval (Table 1).  Most recently, market authorization holders for Halimatoz® (adalimumab) and Udenyca® (pegfilgrastim) requested that their marketing authorizations be withdrawn due to commercial reasons.  There are eleven other approved adalimumab biosimilars and seven other approved pegfilgrastim biosimilars.

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, 28 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 2020 and the first two months of 2021, however, the FDA has only approved three biosimilar products, whereas the EMA has approved fourteen biosimilar products.  The COVID-19 pandemic has likely shifted regulatory and industry focus to vaccines and therapeutics, thereby causing delays in biosimilar approvals.  Moreover, given the difficult patent litigation and competitive landscapes, there appear to be fewer biosimilar BLAs than in 2017-2019.

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, 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 28 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 March 8, 2021).

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, 2021 and published on January 7, 2021).

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).

On February 23, 2021, a Federal Circuit panel of Chief Judge Prost, Judge Newman, and Judge Moore reheard oral argument in GlaxoSmithKline LLC v. Teva Pharms. USA, Inc. As discussed in our previous post, on February 9, 2021, the panel issued an order granting Teva’s petition for rehearing, vacating the prior October 2, 2020 judgment and withdrawing the October 2, 2020 opinion. The panel limited the oral argument to the issue of whether there is substantial evidence to support the jury’s verdict of induced infringement during Teva’s “skinny label” period from January 8, 2008 through April 30, 2011.

As we previously reported, in its original opinion the Federal Circuit held that based on the entire trial record there was substantial evidence to support the jury’s finding that Teva induced infringement throughout the term of the patent-at-issue, including during its “skinny label” period. In the vacated opinion, the Federal Circuit noted that “[p]recedent has recognized that the content of the product label is evidence of inducement to infringe” and cited “the FDA labels” as supporting the jury’s infringement verdict, but did not clarify whether those statements referred to Teva’s label during the skinny label period, the period when the label expressly included the patented indication, or both. See GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 976 F.3d 1347, 1355 (Fed. Cir. 2020). Following the Federal Circuit’s original opinion, Teva and several amici expressed concerns that the opinion could have monumental impacts in threatening the viability of Congress’s “carve out” statute (21 U.S.C. § 355(j)(2)(A)(viii)) and exposing generic companies to infringement liability despite the use of skinny labels.

During the oral argument on rehearing, the panel focused its attention on the specific facts of the case rather than the broader legal issues.  The panel geared its questions towards the labels, the accessibility of Teva’s press releases, and the trial testimony of the parties’ experts. The panel appeared to remain aligned as it did in its original opinion. Chief Judge Prost, who dissented from the majority’s original opinion, focused much of her attention during the oral argument on questioning GSK’s attorney about the wording of the indications in GSK’s label and its declarations to the FDA, while Judge Moore, who joined in the original majority opinion, pressed Teva’s attorney on the accessibility of Teva’s press releases. Judge Newman remained silent throughout much of the rehearing, but questioned Teva’s attorney about how to address the amici’s concerns without discouraging the research and development of new methods of use for older drugs.

In light of the panel’s questions during the oral argument and the concerns expressed by Teva and the amici, it appears that the panel is inclined to issue a more narrowly tailored opinion reaching the same conclusions, but revising its reasoning to focus on the specific facts of the case.

We will provide additional updates on this important case once the Federal Circuit issues its opinion.

In a precedential opinion in Amgen Inc. et al. v. Sanofi, Aventisub LLC, et al., No. 20-1074 (Fed. Cir. 2021) issued on February 11, 2021, the Federal Circuit affirmed the decision of the United States District Court for the District of Delaware granting JMOL that Amgen’s Repatha® patents (U.S. Patent Nos. 8,829,165 and 8,859,741) were invalid for lack of enablement.  The district court’s grant of JMOL overturned a jury verdict finding Amgen’s claims were not invalid for lack of enablement.

The claims at issue cover a genus of monoclonal antibodies that bind a certain epitope of PCSK9 and block binding of PCSK9 to the LDL receptor.  The Federal Circuit ultimately concluded that practicing the full scope of the claims would require undue experimentation given the breadth of the functional claim limitations, the limited guidance and examples provided in the specification, and the unpredictability of antibody generation.

The Federal Circuit applied the Wands factors in its analysis, stating that Wands “did not proclaim that all broad claims to antibodies are necessarily enabled.” The Court found the facts were more akin to those in Wyeth, Enzo, and Idenix, in which the claims at issue—drawn to small molecules, rather than antibodies—had both structural and functional limitations, and in which the specifications failed to teach whether the many embodiments of the broad claims would exhibit the required functionality.[i]

Summarizing the body of enablement law, the Court stated “[w]hat emerges from our case law is that the enablement inquiry for claims that include functional requirements can be particularly focused on the breadth of those requirements, especially where predictability and guidance fall short. In particular, it is important to consider the quantity of experimentation that would be required to make and use, not only the limited number of embodiments that the patent discloses, but also the full scope of the claim.”  While the Court stated that its holding is not that “the effort required to exhaust a genus is dispositive,” it held that “[i]t is appropriate … to look at the amount of effort needed to obtain embodiments outside the scope of the disclosed examples and guidance.”  Thus, while a claim that includes functional language may be enabled, broad functional limitations create “high hurdles” for fulfilling the enablement requirement.

According to the Court, Amgen’s patent disclosures failed to satisfy this heightened bar. As the Court reasoned, making the full scope of the claimed embodiments in the Repatha patents would require “substantial time and effort.” The only ways to discover the undisclosed claimed embodiments would be either through trial and error (i.e., making structural modifications to the disclosed antibodies and then screening the new antibodies for the desired binding and blocking properties), or by discovering the antibodies de novo according to the randomization-and-screening “roadmap” described in the specification. The Federal Circuit agreed with the district court that the small subset of examples of antibodies provided in the specification did not provide sufficient guidance as to how to obtain the full range of working embodiments within the claims.

Impact

The Federal Circuit’s conclusion here was not unexpected, especially after the panel judges made clear during the oral arguments held in December that Amgen faced an “uphill battle” in defending the validity of their antibody genus claims. But how does this decision impact the biologics market and the future of antibody claims? Significantly.

First, it’s now open season not only on antibody patents, but also on patents covering a large genus of molecules in general, particularly those reciting functional limitations. Armed with this decision, patent challengers may now more easily invalidate antibody claims through post-grant review or ex parte reexamination, as well as during litigation.  A search of USPTO records reveals that there may be nearly 25,000 patents granted in the past 20 years that claim antibodies based on the functions of “binding” or “blocking” susceptible to invalidation for lack of enablement.[ii]  And at least some of those patents may cover highly profitable drugs with significant market share or be currently blocking or deterring market entry of other molecules into the pharmaceutical market.  In fact, of the top ten global best-selling drugs forecasted for 2021, five are antibody drugs or antibody fragment drugs, with tens of billions of dollars in annual sales.[iii] By putting broad functionally defined patent claims at serious jeopardy, competing companies may be able to enter the market with molecules that will emerge from under the shadow of such claims.

Second, while the Federal Circuit’s opinion does not provide guidance as to how patent owners should claim a novel genus of antibodies, the decision strongly suggests that purely functional language likely will not suffice. Patent drafters seeking to claim an antibody genus using functional limitations will need to pay close attention to the requisite analysis to enable one of ordinary skill in the art to make and use the claimed scope, e.g., by disclosing sufficient structural features and limitations, a substantial number of examples of antibodies that fall within the genus relative to the genus as a whole, and a crystal clear roadmap that can be used to identify antibodies within the scope of the claim without undue experimentation.  Whenever possible, patent drafters should primarily focus on structural claiming as the first line of defense, e.g., by drafting claims reciting specific complementary determining region (CDR) sequences, or perhaps a high percentage of identity to a specific disclosed amino acid sequence. Functional claiming may still have value as a second line of defense in patent claims, particularly if the drafter carefully considers the breadth of the claims, provides a sufficient amount of direction and guidance, and provides a number of specific working examples demonstrating that species spanning the full scope of the claims achieve the claimed function.

Notably, this decision diverges from European practice, where broad patents to antibodies against a new epitope are the norm, and follow-on applications claiming particular sequences are often rejected as lacking inventive step over the broad patent’s functional disclosures.

Given the cascading repercussions of this decision, Amgen will likely file a petition for writ of certiorari. It  will be interesting to see if a petition is granted in this case, particularly after the Supreme Court refused in January 2021 to consider whether a genus claim is not enabled “as a matter of law” if it encompasses a large number of compounds in Idenix.[iv]

[i] See Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 1385–86 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340, 1345–48 (Fed. Cir. 2019), cert. denied 140 S.Ct. 2634 (2020); Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 1160–63, 1165 (Fed. Cir. 2019), cert. denied 2021 WL 161021 (Jan. 19, 2021).

[ii] Based on PTO Patent Full-Text and Image Database searches (http://patft.uspto.gov/netahtml/PTO/search-adv.htm) conducted on February 23, 2021 using the query: ACLM/antibody AND (ACLM/bind$ OR ACLM/block$) AND ISD/20000223->20210223.

[iii] https://www.echemi.com/cms/132623.html

[iv] 941 F.3d 1149, 1160–63, 1165 (Fed. Cir. 2019), cert. denied 2021 WL 161021 (Jan. 19, 2021).

A panel of the Federal Circuit agreed on February 9, 2021, to rehear arguments in a case between GlaxoSmithKline LLC (“GSK”) and Teva Pharmaceuticals USA, Inc (“Teva”) regarding Teva’s generic to GSK’s carvedilol product, Coreg®. As discussed below and in our previous post, the three-judge panel previously held in a 2-1 decision in October 2020 that Teva’s carvedilol product induced infringement of a patent covering the treatment of congestive heart failure even during a period in which Teva’s label had “carved out” that indication, resulting in a so-called “skinny label.” The Panel (Judges Prost, Newman, and Moore) is scheduled to rehear arguments on February 23.

Whenever an Abbreviated New Drug Application (“ANDA”) is filed, among the many requirements the Applicant must address are whatever patents the reference drug application holder has registered with the FDA to protect its exclusivity in marketing the drug. For ANDA Applicants, this usually requires filing a certification that I) the application holder did not register patents covering the drug, II) the patent or patents have expired, III) the Applicant does not seek to market the drug until a patent has expired, or IV) the registered patent is invalid or will not be infringed. A certification under the fourth provision—a “Paragraph IV” Certification—typically results in patent litigation.

However, when an Orange Book listed patent covers only certain methods of use, ANDA Applicants may file a “Section viii Statement” asserting that “method of use patent does not claim … a use for which the applicant is seeking approval.” In other words, if a drug is approved for multiple indications, an ANDA Applicant can overcome patents that cover less than all of the approved indications as a regulatory hurdle by submitting a Section viii Statement (potentially avoiding patent litigation under the Hatch-Waxman Act).

Before Teva received approval for its carvedilol product, there were three indications listed for Coreg®: one had no patent protection, one was covered by a soon-expiring patent which Teva opted to wait out, and the third—for congestive heart failure (CHF)—had active patent protection. Teva omitted the CHF indication from its proposed label rather than challenge the CHF patents, creating a skinny label with two indications rather than three. However, Teva eventually reinserted the missing indication after its generic product had been on the market for several years.

The case was tried by a jury, which found that Teva had induced infringement of the CHF patent claims even during the several years that that indication was omitted from Teva’s label. The district court granted Teva’s Motion for Judgment as a Matter of Law, finding no inducement during any time period—including when Teva’s label included the CHF indication.  The split Federal Circuit panel reversed, restoring the jury finding of infringement during all time periods, holding that evidence, including Teva’s marketing of its drug as equivalent to the existing Coreg® and physicians’ knowledge that Coreg® could be used to treat CHF, was sufficient to support the verdict regardless of the label’s stated indications.

Following the panel’s opinion, Teva filed a Petition for Rehearing En Banc arguing generally that the panel’s decision essentially nullified the utility of a Section viii Statement and harmed the doctrine of induced infringement by removing a causation element.  Eight amicus briefs were filed supporting rehearing—seven of which explicitly supported Teva.

On February 9, 2021, the panel issued an order vacating its October 2020 judgment and scheduling a rehearing of the appeal on the merits. The oral argument is scheduled for Tuesday, February 23, and is limited to the question of whether there is substantial evidence supporting induced infringement during the time period that the CHF indication was not present on Teva’s label.

Additional coverage of this case will follow as it develops, including coverage of the oral argument scheduled to take place next week.

On December 9, 2020, the Federal Circuit heard oral arguments on the validity of Amgen’s patents (U.S. Patent Nos. 8,829,165 and 8,859,741) on cholesterol-lowering drug Repatha. Specifically, the question came down to whether the patents, claiming a genus of antibodies by their functional properties, are enabled under 35 U.S.C § 112. The panel consisted of Judges Sharon Prost, Alan D. Lourie, and Todd M. Hughes.  While we are still awaiting the Court’s decision, the oral argument strongly suggested that the Federal Circuit is likely to continue its trend of holding functional genus claims invalid under Section 112.

Claim 1 of Amgen’s ’165 patent, which is representative, recites “an isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of [certain listed amino acid residues], and wherein the monoclonal antibody blocks binding of PCSK9 to LDLR.”  Amgen explains that its claims cover antibodies that bind a certain epitope on the PSK9 protein, and that its inventors discovered that antibodies that bind this “sweet spot” will block PSK9 from binding to LDL receptors, ultimately lowering cholesterol.

Within seconds after counsel for Amgen began his argument, Judge Lourie stepped in and pointed out that the patent claims are composition of matter claims defined by function (in fact, two separate functions – “binding” and “blocking”) rather than structure. Given the breadth of this functional language, and the district court’s finding that “a substantial amount of time and effort” would be required to determine the scope of the claims, Judge Lourie stated that “that sounds like undue experimentation,” making it a “pretty uphill battle” for Amgen to overcome.

Amgen’s counsel responded that the claim is directed to a specific structure, namely the specific arrangement of “sweet spot” binding sites in the form of a 3D structure, which results in the functional “blocking.”  However, Judge Lourie seemed unconvinced that the claims were not purely based on function.

Judge Prost then addressed the issue of “roadmap predictability,” referring to Amgen’s argument that the specification provides a roadmap enabling those skilled in the art to make and use the full scope of antibodies within the claim.  Judge Prost asserted that there was no direction or guidance as to whether a specific antibody will bind, or exactly how to make the 400 distinct antibodies that Amgen argues fall within the claimed genus.  She stated that only 26 of the antibodies were described in the specification, with only nine of those antibodies exhibiting successful binding to the “sweet spot.”  As to the other 384 antibodies, she noted that there was simply no evidence of what those antibodies may be, and that they may very likely cover competitor antibodies whose structures are quite different from those described in the specification.

Counsel for Sanofi continued with this “numbers” argument, questioning whether 400 antibodies was even an accurate scope of the claimed genus. Citing the testimony of a lead inventor and an expert who stated that they didn’t know how many antibodies the genus would cover, and noting the many different permutations based on the dual functionality and the effects of a change of just a single amino acid, he argued that the number is more likely in the millions, or “astronomical.”  Using an analogy to the California gold rush (“the fact that you knew that there were gold in the hills and that you knew you had a pan to find it, doesn’t mean that you’re entitled to gold on every square mile of the California countryside”), he argued that determining the scope of the claims in this case is a classic example of undue experimentation.

Judge Hughes poised an interesting question about why the number of experiments matters if the test being conducted is the same across all samples and is not qualitatively difficult. He also stated that he was having difficulty distinguishing the Wands case from the facts at issue here. Counsel for Sanofi responded that repeated testing, regardless of whether that test is the same each time, is just labor intensive, to such a degree that no scientist would consider doing it. He also argued that the “hit rate” (or amount of antibodies found to be within the genus) was of particular importance – in Wands, the hit rate was nearly 50%, whereas here, he argued, it’s searching for a needle in a haystack.

Overall, the oral arguments provide insight into the Judges’ views and shed some light on the future of antibody genus claims.  The Court seems likely to follow its decisions in Idenix and Wyeth, where functionally-defined claims to a genus of small molecules were held invalid under Section 112, extending this precedent into the antibody field.[1]  The USPTO has already made it difficult for patent owners to obtain claims to a functionally defined genus of antibodies.  We expect that patent owners claiming a novel genus of antibodies will need to recite structural features such as specific complementary determining region (CDR) sequences, or perhaps a percentage of identity to a given amino acid sequence.  Hopefully, the Federal Circuit’s opinion will offer some guidance to this effect, but biotech companies should not expect new support from the Federal Circuit for functional genus claims. Given that the breadth of acceptable claims for antibodies is narrowing, patent attorneys will need to explore other options for drafting enforceable claims to continue to motivate innovation in the field.

[1] Idenix Pharm. LLC v. Gilead Scis. Inc., 941 F.3d 1149 (Fed. Cir. 2019), cert denied 2021 WL 161021 (Jan. 19, 2021); Wyeth & Cordis Corp. v. Abbott Labs., 720 F.3d 1380 (Fed. Cir. 2013).

On January 28, 2021, Bio-Thera Solutions, Ltd., a biopharmaceutical company based in China, announced that the U.S. Food and Drug Administration (FDA) accepted its Biologics License Application (BLA) for BAT1706, a proposed biosimilar to bevacizumab, referencing Genentech’s Avastin®, but excluding indications under orphan drug exclusivity protection.  The FDA has set November 27, 2021, as the decision date for the application.

Bevacizumab is an angiogenesis inhibitor, which suppresses new blood vessel growth in tumors by inhibiting vascular endothelial growth factor A.  Bio-Thera’s BLA seeks approval of BAT1706 for the treatment of metastatic colorectal cancer in combination with fluorouracil-based chemotherapy, non-squamous non–small cell lung cancer, recurrent glioblastoma, metastatic renal cell carcinoma in combination with interferon α, and persistent, recurrent, or metastatic cervical cancer.

Bio-Thera also filed for regulatory approval for BAT1706 in China and the European Union.  In December 2020, Bio-Thera announced a partnership with Brazil-based Biomm for the commercialization of BAT1706 in Brazil.  Bio-Thera has also commercialized a biosimilar of adalimumab, referencing Abbvie’s Humira®, and received marketing authorization in China.  Bio-Thera is also developing additional biosimilar products including tocilizumab, golimumab, ustekinumab and secukinumab, and mepolizumab.

“The FDA’s acceptance of our BLA is a significant achievement that brings Bio-Thera closer to providing cancer patients in the USA with a high-quality, low-cost treatment option,” said Dr. Shengfeng Li, Founder and CEO of Bio-Thera Solutions. “Regulatory filings for BAT1706 have now been accepted by the China National Medical Products Administration (NMPA), European Medicines Agency (EMA) and FDA, demonstrating Bio-Thera’s commitment to developing BAT1706 to global standards so that BAT1706 can be made available to the global cancer patient community.”

In the U.S., two bevacizumab biosimilars have been approved: Mvasi launched by Amgen in July 2019 and Zirabev by Pfizer in January 2020.  The FDA’s acceptance of the BLA added Bio-Thera to a list of biosimilar developers, including Amgen, Pfizer, Samsung Bioepis, Centus, and Mylan, to report the filing of a BLA for a bevacizumab biosimilar.

The COVID-19 relief and spending bill signed into law on December 27, 2020, includes a provision – Division BB, Title III, Subtitle C, Section 325[1] – that adds a new paragraph 9 to 42 U.S.C. §262(k) requiring the U.S. Food & Drug Administration (“FDA”) to provide more information to the public about patented biological products. This information includes:

  1. a list of each biological product, by nonproprietary name, for which a biologics license is in effect;
  2. the date of licensure and the application number;
  3. the licensure status and, as available, the marketing status; and
  4. exclusivity periods.

The FDA has 180 days from the enactment of the paragraph to make this information available to the public in its Database of Licensed Biological Products, or “Purple Book,” and the FDA is required to revise the list every 30 days.  Prior to enactment of this provision, the Purple Book, unlike the Orange Book for small molecules, did not contain any patent information.

As part of the “patent dance” for biosimilar approval, a reference biologic product sponsor provides a biosimilar applicant with patent information regarding the reference product. The new paragraph now requires that the sponsor provide this information to the FDA within 30 days of the date the information is provided to the biosimilar applicant. The FDA is required to include this patent information when it revises the Purple Book every 30 days. The FDA is also required to publish any subsequent or supplemental list of patents provided to a biosimilar applicant.

Notably missing are any consequences for reference sponsors for failure to provide this information to the FDA.  Stay tuned for updates on how FDA implements these new requirements and whether the FDA promulgates any new regulations for providing the information.

 

[1] The text of the bill is available at: https://rules.house.gov/sites/democrats.rules.house.gov/files/BILLS-116HR133SA-RCP-116-68.pdf.  Section 325 begins on page 2125 of Division BB (page 4592 of the PDF).

On December 2, 2020, Boehringer Ingelheim Pharmaceuticals, Inc. (“Boehringer Ingelheim”) submitted a Citizen Petition requesting a change in the FDA’s interpretation of “strength” of biological products under the Biologics Price Competition and Innovation Act (“BPCIA”).  The Citizen Petition is available on regulations.gov under docket number: FDA-2020-P-2247.  Boehringer Ingelheim seeks an interpretation of “strength” to mean total drug content, without regard to concentration.  The Citizen Petition further requests the FDA update its guidance documents to incorporate the new definition, and apply the updated definition to pending and approved applications before the agency.

The proposed change would primarily impact the approval of “interchangeable” biological products.  An “interchangeable” biological product “means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” 42 U.S.C. § 262(i)(3). One requirement for the FDA to approve such a product is that the proposed biological product has the same “strength” as the reference product: “the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; . . .” Id. § 262(k)(2)(i)(IV).  According to Boehringer Ingelheim, the FDA currently interprets “strength” as encompassing both total drug content and concentration.

In the petition, Boehringer Ingelheim presents three arguments as to why the concentration should not be included when evaluating the strength of the biological product.  First, Boehringer Ingelheim states that the FDA’s interpretation of “strength” conflicts with the BPCIA.  Second, it unnecessarily and unreasonably facilitates anticompetitive practices, such as patent “evergreening” tactics designed to prevent or delay competition from biosimilar and interchangeable products seeking approval.  And third, the interpretation is arbitrary and capricious in violation of the Administrative Procedure Act because it treats injectable solutions differently than similarly situated parenteral products without any reasonable basis.

Boehringer Ingelheim markets Cyltezo® in 20 mg and 40 mg doses, each administered at a 50 mg/mL concentration.  Cyltezo is an approved biosimilar of Humira® at the same concentration.  In addition to the original 50 mg/mL dosage, Humira was later approved for use in a 100 mg/mL formulation.  Boehringer Ingelheim argues that when FDA interprets “strength” to mean concentration, it allows brand manufacturers to manipulate the concentration of their reference products at strategic times during the extended eight to ten-year development period for biosimilars, which unfairly creates a “moving target” for sponsors seeking approval via the 351(k) pathway.  If the FDA modifies its interpretation of “strength” as Boehringer Ingelheim has requested, Boehringer Ingelheim can seek an interchangeability determination of Cyltezo that would apply to Humira’s higher concentration formulation.