Patents related to Regeneron’s EYLEA (aflibercept) were recently added to the Purple Book.  Under the Biological Product Patent Transparency Act, signed into law December 27, 2020 and codified at 42 U.S.C. § 262(k)(9), patents must be submitted to the FDA for listing in the Purple Book during the “Patent Dance” under the BPCIA. Specifically, within thirty (30) days after the reference product sponsor (RPS) has submitted a list of patents that could reasonably be asserted against the biosimilar manufacturer under § 262(l)(3)(A), the RPS must provide the list of patents and their expiry dates to FDA.

Regeneron listed twenty-nine patents in connection with EYLEA, four of which do not expire until 08/18/2040 (U.S. Nos. 11,053,280, 11,104,715, 11,174,283, and 11,186,625). Although there are multiple aflibercept biosimilars currently under development, all have yet to receive FDA approval. Regeneron’s recent Purple Book listing presumably comes as part of a Patent Dance with Viatris (formerly Mylan), which filed an aBLA for its aflibercept biosimilar MYL-1701P in late 2021. At least six other aflibercept biosimilars are in, or have completed, phase 3 clinical trials. These include SB-15 (Samsung Bioepis), ABP 938 (Amgen), FYB203 (Formycon and Bioeq), SOK583A19 (Sandoz), CT-P42 (Celltrion), and OT-702 (Ocumension Theraputics and Shandong Boan Biological Technology).

On April 18, 2022, the Supreme Court invited the Solicitor General to file a brief expressing the views of the United States in the Amgen, Inc. v. Sanofi, Inc. case, which involves important questions of enablement for genus claims. We have previously covered the Federal Circuit’s decision, Amgen’s petition for a writ of certiorari, and the multiple amicus curiae briefs submitted in this case. Additionally, on March 14, 2022, Sanofi filed its Opposition to Amgen’s cert petition, and on March 22, 2022, Amgen filed its Reply Brief. The Supreme Court’s Call for the Views of the Solicitor General (“CVSG”) signals the Court’s interest in this case. This post provides a summary of Sanofi and Amgen’s latest briefing. We will continue to provide updates as this case evolves.

The introduction of Sanofi’s Opposition is direct, arguing that Amgen “attempt[ed] to corner the market on PCSK9 inhibitors—and after Respondents developed Praluent—Amgen obtained additional patents that broadly claim all antibodies that bind to certain amino acids on PCSK9 and clock its binding to receptors.” Sanofi argues that the Federal Circuit’s decision “rightly rejected this gambit, holding that Amgen’s broad functional claims are not enabled and thereby invalid under 35 U.S.C. § 112.” It further tried to persuade the Court that the decision does not need to be reviewed, as “in its unanimous decision, the [Federal Circuit] panel merely applied well-established law to the undisputed relevant facts and determined that Amgen’s broad functional claims require undue experimentation and thus are not enabled by the particular specification.”

In response to Amgen’s first argument that the Federal Circuit treated the enablement issue as a question of law while the Supreme Court has treated it as a question of fact, Sanofi alleges that the Supreme Court has consistently held that patent validity issues like enablement are questions of law involving subsidiary findings of fact. Sanofi cites Supreme Court cases framing the issue of patent validity as a question of law, and cites Federal Circuit cases that have followed suit. It argues that Amgen “cites a handful of this Court’s decision predating the Civil War.” Sanofi discusses parts of Amgen’s cited cases to argue that these cases do not actually contradict the Federal Circuit’s decision. While Sanofi acknowledges that some of the cases Amgen cites included factual issues for the jury, it argues the issues related to the capabilities of the person skilled in the art. Sanofi thus argues that there is no reason for the Supreme Court to hear this case because it is consistent with precedent. Sanofi even asserts that “Amgen also vastly overstates the importance of this issue,” which is interesting given the multiple amicus briefs submitted encouraging the Supreme Court to take up the case.

As to Amgen’s second argument that the Federal Circuit’s decision created a special test applicable to functional genus claims, Sanofi states this is simply not true; the Federal Circuit repeatedly disclaimed any bright-line rule, and its holding was only a result of applying the same factors that the Federal Circuit has used in the past. Sanofi insists that Amgen’s second argument “is nothing more than a request for factbound error correction dressed up as a supposed legal dispute.” It notes that the Federal Circuit repeatedly stated its decision was not a bright-line rule, and that the Federal Circuit decided Amgen’s claims required undue experimentation after considering the Wands factors in this specific case.[1] Sanofi argues that Amgen neither challenged the use of the Wands factors nor the breadth of its claims. It contends that the Federal Circuit created no new test for enablement, but the claims were not enabled to allow one of ordinary skill to make and use the full scope of the invention.

Amgen’s Reply Brief is consistent with the arguments made in its petition. First, Amgen states that “Sanofi-Regeneron cannot dispute that this Court has repeatedly declared that enablement is a ‘question of fact’ for ‘the jury.’”[2] Amgen cites cases concluding that enablement is a question of fact for the jury, and argues that the determination of whether a jury or a judge should decide if a patent is enabled is extremely important for patent infringement cases. Second, Amgen argues that the Federal Circuit’s holding that the specification must enable skilled artisans “to reach the full scope of claimed embodiments” without “substantial time and effort” was unnecessary, as the evidence shows that the skilled artisan could make the antibodies that Amgen claimed every time by following the patent’s specification. Amgen argues that this “full scope” decision is equivalent to imposing a numerosity or exhaustion requirement.  It argues that this “rewriting” of § 112 was unnecessary, as the Federal Circuit could have required, as it has before, that the challengers provide concrete evidence that a substantial number of embodiments cannot be made by following what the patent teaches. Amgen argues that the Supreme Court has never suggested that patents are invalid when skilled artisans can easily make embodiments within the claims, simply because ‘substantial time and effort’ is needed to make all embodiments. It argues the importance of the Supreme Court granting certiorari, as the Federal Circuit’s decision will raise the bar for enablement of genus claims far too high. Finally, Amgen argues that this case is an ideal vehicle for Supreme Court review: “Two different juries heard the evidence and found Amgen’s patents enabled—yet the Federal Circuit reaches a contrary result. Who decides enablement was clearly outcome-dispositive.”

[1] See In re Wands, 858 F.2d 731 (Fed. Cir. 1988).

[2] Wood v. Underhill, 46 U.S. (5 How.) 1, 4 (1846).

On March 16, 2022, the Federal Circuit denied Biogen’s petition for rehearing of its November 2021 decision in Biogen Int’l GmbH v. Mylan Pharms., Inc., 18 F.4th 1333, 1343 (Fed. Cir. 2021), which found that Biogen’s patent U.S. 8,399,514 (“the ’514 patent”) covering the treatment of multiple sclerosis (MS) with dimethyl fumarate (DMF, Brand name Tecfidera®) invalid for lack of written description.

The core issue in the panel’s 2-1 decision in November 2021 was whether the specification of the ’514 patent sufficiently supported the claimed therapeutically effective DMF dose 480 mg per day (DMF480) in MS treatment.  The panel majority found that the DMF480 dose was disclosed only once in the specification and only appeared at the end of a dose range among a series ranges, and held that the specification’s focus on basic research and the mere disclosure of broad dosage ranges showed that the inventors did not possess the therapeutically effective DMF480 dose at the time of filing the application.  The panel majority asserted that what matters in this case is whether “a skilled artisan could deduce simply from reading the specification that DMF480 would be a therapeutically effective treatment for MS.”   Biogen at 1344.

In dissent, Judge O’Malley cited Biogen’s explanation that while clinical efficacy would require a showing of superior clinical endpoints compared to the standard care of MS, therapeutic efficacy refers to the drug dose that can prevent, delay onset of, or ameliorate symptom of MS.  Judge O’Malley argued that the majority erred by conflating therapeutic efficacy and clinical efficacy, and by requiring the patent specification to show clinical efficacy to satisfy its heightened written description test.  In Judge O’Malley’s view, where only therapeutic efficacy should be sufficient.  Indeed, Judge O’Malley succinctly summarized the problem created by the district court and propagated by the majority, i.e., “after acknowledging that clinical data demonstrating effectiveness is not required to satisfy written description, the district court went on to find that the ’514 patent does not demonstrate possession because it lacks clinical efficacy data.”   Id at 1349.

In its rehearing petition, Biogen argued that the panel’s decision created a higher standard of written description by requiring (a) the proof of the efficacy rather than the disclosure of the claimed method and (b) the specification repeatedly describing and singling out the claimed drug dose.  Biogen’s petition was supported by amicus briefs filed by various pharmaceutical groups including The Pharmaceutical Research and Manufacturers of America, Biotechnology Innovation Organization, and the American Chemical Society.

Judge Lourie, joined by Judges Moore and Newman, dissented from the court’s denial of rehearing the case.  Judge Lourie reviewed various precedential cases where the Federal Circuit had found lack of written description, but asserted that “this case, in which every claim limitation is expressly described in the disclosure of the patent specification, is at the farthest end of the spectrum of cases where written description has not been found.  It is an outlier.”

Judge Lourie argued that there are four grounds of errors in the panel majority’s decision that the en banc court should have corrected.  For the first ground, he argued that one mention in the specification is enough to support a claim element, but the panel majority overly emphasized unclaimed disclosures in the specification and did “irrelevant comparisons between the amount of disclosure of the claimed subject matter versus the unclaimed subject matter.”  On the second ground, Judge Lourie pointed out that the specification expressly states the DMF480 dose and argued that the Federal Circuit precedent does not require the specification to prove the efficacy of the claimed pharmaceutical composition, which would be the province of the FDA.  The third ground in Judge Lourie’s dissent is that the panel majority’s decision had imported “extraneous legal considerations into the written description analysis,” including enablement and best mode requirements, and “create[d] confusion…regarding what is required to meet the written description requirement.  Regarding the last ground, Judge Lourie argued that the panel majority’s consideration of extrinsic evidence is improper because “extrinsic evidence should be used only as part of an objective inquiry into what is meant by the disclosure in the patent specification,” but “[m]eaning is not in question in this case.”

The majority’s opinion appears to set a higher standard for written description requirement at least for claims directed to therapeutic methods.  However, in a recent decision Novartis Pharms. Corp. v. Accord Healthcare, Inc., 21 F.4th 1362, 1370 (Fed. Cir. 2022), the Federal Circuit found that a claim element “absent an immediately preceding loading dose regimen,” which was nowhere disclosed in the specification, satisfied the written description requirement.  These decisions can be difficult to reconcile.  Also in view of the vigorous dissenting opinions discussed above, this case may be headed to the Supreme Court.  We will keep monitoring this case and report on future developments.

On March 14, 2022, Regeneron Pharmaceuticals Inc. (“Regeneron”) filed a statutory disclaimer under 37 CFR § 1.321 disclaiming all claims of U.S. Patent No. 10,857,231 B2 (the “’231 patent”) in response to a petition for a post-grant review submitted by Celltrion Inc. (“Celltrion”). On September 7, 2021, Celltrion submitted a petition for post-grant review of the ’231 patent, requesting a review of claims 1-11, 17-21, 27-32, 41-53, and 58-67 (the “Challenged Claims”) of the ’231 patent.[1] In response, Regeneron submitted a Preliminary response, and later, a Sur-reply to Celltrion’s reply to Regeneron’s Preliminary response.[2]

Prior to issuance of an institution decision by the Patent Trial and Appeal Board (the “Board”), however, Regeneron submitted an unopposed Motion to Withdraw its preliminary response and sur-reply.[3] In an email to the Board accompanying the motion, Regeneron stated that it has reason to question whether the data presented in Table 7 of the ’231 patent corresponds to the formulation described in Example 4 at column 10, lines 27–38.[4] Further, one day before the statutory date for the Board’s Decision on Institution, Regeneron notified the Board, via an email, that it intended that day to file a Notice of Disclaimer with the U.S. Patent and Trademark Office, disclaiming all claims of the ‘231 patent.[5] Upon disclaimer of all claims, the Board denied institution of the requested post-grant review. See 37 C.F.R. § 42.207(e) (“No post-grant review will be instituted based on disclaimed claims”).[6]

The Challenged Claims were broadly directed to formulations comprising 10-50 mg/ml aflibercept (or VEGF antagonist fusion proteins more generally); a stabilizing agent comprising a sugar, an amino acid, or both; an organic co-solvent comprising polysorbate; and a histidine buffer. In its petition, Celltrion asserted that the challenged claims were unpatentable on a number of grounds, including lack of written description, lack of enablement, indefiniteness, and obviousness.

At this time, it is unclear what the broader impact of Regeneron’s disclaimer will be on other patents in the family of the ‘231 patent and its priority application, PCT/US2006/010600 (WO2006104852; the “Dix family”).  The Dix family includes nine issued U.S. patents and four pending U.S. applications, most of them directed to formulations of VEGF antagonist fusion proteins.  The patents and applications in the Dix family claim priority to March 25, 2005, and are expected to expire on March 25, 2025, absent patent term adjustments or further disclaimers or invalidity determinations.

[1] Celltrion, Inc. v. Regeneron Pharmaceuticals, Inc., PGR2021-00117, Paper 1 at 1 (PTAB Sept. 7, 2021)

[2] Celltrion, Inc. v. Regeneron Pharmaceuticals, Inc., PGR2021-00117, Paper 6 (PTAB Dec. 15, 2021); Celltrion, Inc. v. Regeneron Pharmaceuticals, Inc., PGR2021-00117, Paper 11 (PTAB Jan. 25, 2022)

[3] Celltrion, Inc. v. Regeneron Pharmaceuticals, Inc., PGR2021-00117, Paper 13 (PTAB Mar. 3, 2022)

[4] Id. at 1

[5] Celltrion, Inc. v. Regeneron Pharmaceuticals, Inc., PGR2021-00117, Paper 16 at 2 (PTAB Mar. 15, 2022)

[6] Id.

On March 8, 2022, Alvotech announced that it has executed a U.S. settlement agreement with Abbvie that grants Alvotech non-exclusive rights to market AVT02 (adalimumab) in the U.S starting July 1, 2023. AbbVie confirmed the resolution of disputes and stated that Alvotech will take a non-exclusive license to the patents, and in return, pay royalties and acknowledge the licensed patents’ validity. AVT02 is a biosimilar to the high-concentration 100 mg/ml formulation of Humira® (adalimumab). We previously reported on AbbVie’s expansive Humira® patent portfolio asserted against Alvotech’s AVT02 (here). Further, Abbvie filed a Section 337 Complaint before the International Trade Commission (“ITC”), seeking to block imports of Alvotech’s AVT02. With the settlement, all ongoing U.S. disputes, including the ITC action brought in December 2021, between Abbvie and Alvotech related to AVT02 have been fully resolved.

In February 2022, the FDA accepted Alvotech’s Biologics Licensing Application (BLA) for review for AVT02 that includes new data supporting interchangeability between ATV02 and Humira® and stated that it will reach a decision by December 2022. With the final barrier, the ITC action brought by Abbvie, removed, Alvotech can launch its biosimilar product as early as July 1, 2023 (assuming timely FDA approval). Alvotech’s AVT02 is certainly not the only adalimumab biosimilar set to hit the market in 2023. As previously reported in our earlier post, there are at least eight adalimumab biosimilars that are due to launch by the end of 2023 in the U.S., where Abbvie secured over $20 billion of its Humira® sales revenues in 2021. With the launch of adalimumab biosimilar products in Europe in 2018, the sales of Humira® dropped by 30 percent in the following year. Thus, evidence from Europe suggests that biosimilar companies are likely to take a significant portion of Humira®’s U.S. market share with aggressive discounting.

As discussed in our earlier post, AbbVie’s assertion of its “thicket” of adalimumab-related patents against biosimilar manufacturers prompted an unprecedented antitrust suit against AbbVie in which the district court judge ultimately sided with AbbVie, but which was later appealed to the 7th Circuit.  The 7th Circuit heard arguments in that case in February 2021, but has not yet issued a decision.

We continue to provide a comparison of the U.S. and Europe on Biosimilar product authorizations and pipeline products. For our most updated version, please visit here.

  • FDA and EMA both approve additional biosimilar versions of Humira® (adalimumab).
  • FDA also approves its third biosimilar version of Neupogen® (filgrastim).
  • EMA has not approved any new biosimilars in 2022, but has recommended approval of teriparatide biosimilar Sondelbay and the pegfilgrastim biosimilar Stimufend.

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 $85 billion in 2020[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 a January 2022 report, IQVIA updated global estimates showing estimated biosimilar sales of about $40 billion in 2025 and $75 billion in 2030.

In the FDA’s Center for Drug Evaluation and Research’s (CDER) annual report, the FDA highlighted the three biosimilar approvals in 2020 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 83 applications have been approved in Europe.  Fourteen 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, 33 other biosimilar drugs have gained U.S. approval to date including two interchangeable products (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 2021 and thus far in 2022, relatively fewer biosimilars have been approved by both FDA and EMA than in prior years.  Given the increasing competition between biosimilar manufacturers in Europe, four EMA-authorized biosimilar products were withdrawn in 2021.

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.  Further, given the difficult patent litigation and competitive landscapes, there appear to be fewer biosimilar BLAs than in 2017-2019, and launches of FDA-approved adalimumab and rituximab biosimilars are delayed due to settlements of patent litigations.  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, fourteen 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 December 20, 2021, the FDA approved Coherus’ adalimumab YusimryTM biosimilar. “YUSIMRY represents an enormous commercial opportunity for Coherus as we continue our mission of increasing patient access to important biologic medicines while at the same time lowering the cost of care,” said Paul Reider, Chief Commercial Officer of Coherus. “Humira is the top-selling drug in the U.S. with 2020 net sales exceeding $16 billion, and demand is high across the healthcare ecosystem for a less expensive Humira biosimilar. We will deliver a compelling value proposition to all stakeholders and look forward to launching YUSIMRY in 2023.”  On February 28, 2022, the FDA approved Amneal and Kashiv’s filgrastim ReleukoTM biosimilar. “The U.S. approval of our first biosimilar is a very significant milestone for Amneal. Biosimilars represent the next wave of providing access to affordable medicines in the U.S. We are building a global biosimilars business by leveraging partner assets to start and then leveraging our own key capabilities over time. Our goal is to become a meaningful long-term player in biosimilars,” said Chirag and Chintu Patel, Co-Chief Executive Officers.

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated March 13, 2022).

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 March 8, 2022 and published on March 11, 2022).

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 ($20.39B), 2. Keytruda—Merck ($14.38B), 3. Eylea—Aflibercept ($8.36B), 4. Stelara—Johnson & Johnson ($7.94B), 5. Opdivo—Bristol-Myers-Squibb ($7.92B), 6. Enbrel—Pfizer/Amgen ($6.37B), 7. Avastin—Roche ($5.32B), 8. Trulicity—Eli Lilly ($5.07B), 9. Ocrevus—Roche ($4.61B), 10. Rituxan—Roche ($4.52B).

On January 3, 2021, The Federal Circuit held in a 2-1 decision in Novartis Pharmaceuticals Corp. v. Accord Healthcare, Inc. (Fed. Cir. 2022) that the claims of Novartis’ U.S. Pat. No. 9,187,405 (“the ’405 patent”) met the written description requirement under 35 U.S.C. § 112(a). Defendant HEC Pharm Co. Ltd. was the only remaining defendant at trial.

The ’405 patent covers a method for treating recurring remitting multiple sclerosis with the drug fingolimod marketed by Novartis as Gilenya®.  Representative claim 1 recites:

  1. A method for reducing or preventing or alleviating relapses in Relapsing-Remitting multiple sclerosis in a subject in need thereof, comprising orally administering to said subject 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form, at a daily dosage of 0.5 mg, absent an immediately preceding loading dose regimen.

This case was appealed from an ANDA litigation in which the generics alleged invalidity because of lack of written description for two elements in claim 1: (1) the daily dosage of 0.5 mg; and (2) the negative limitation of no immediately preceding loading dose.

Regarding the first element, the court affirmed that the daily dosage of 0.5 mg met the written description requirement because it was explicitly disclosed in a prophetic clinical trial example.  Also, the specification disclosed an animal study that used a 0.3 mg/kg/week dose for treating the rats.  The court found this dose equivalent to the 0.5 mg dose recited in claim 1.

The court’s discussion about the second element has attracted more interest and was discussed in Judge Moore’s dissent.  The negative claim limitation of “absent an immediately preceding loading dose” is not explicitly disclosed in the specification.  Novartis asserted that this limitation is implicitly disclosed in the animal study and the prophetic clinical trial example.  Accord argued that silence in the specification cannot support this negative claim element.

The court agreed with Novartis and held that a negative element may be supported by a specification that is silent on the element.  The majority opinion acknowledged that the Manual of Patent Examining Procedure (MPEP) states that “the ‘mere absence of a positive recitation’ is not enough and ‘silence alone is insufficient.’”  However, the majority argued that what matters in this case is “how a skilled artisan reads a disclosure”, and “[w]ritten description may take any form, so long as a skilled artisan would read the disclosure as describing the claimed invention.”

The majority rejected what it characterized as HEC’s “attempts to create a new heightened written description standard for negative limitations” contrary to the “central tenet of [the Court’s] written description jurisprudence—that the disclosure must be read from the perspective of a person of skill in the art.” Citing precedential cases, the majority argued that a negative limitation is sufficiently supported if the specification “describes a reason to exclude the relevant limitation.”  The majority asserted that the reasons to exclude need to be apparent to the person of ordinary skill in the art, but does not need to be expressly articulated in the specification.  Based on this proposition, the majority relied on expert testimony supporting that a person of ordinary skill in the art would have recognized that the silence about the loading dose in the prophetic clinical trial example and the animal study example would convey that no loading dose should be used in the treatment regimen.  Further, the majority found that the prophetic clinical trial example only describes a daily dose of 0.5 mg and stated that initially patients receive treatment for 2 to 6 months.  The court then asserted that these descriptions teach that no loading dose was used because, if a loading dose was needed, the specification would have stated so.

In dissent, Chief Judge Moore warned that, “[i]f silence were sufficient then every later-added negative limitation would be supported as long as the patent makes no mention of it.  This is a fundamental error of law.”

The Chief Judge argued that sufficient support for a negative limitation requires the specification to provide some reason to exclude the element, e.g., by listing the disadvantages or reciting alternative features.  Focusing on the specification itself, the Chief Judge found that “nowhere in the patent does it say a loading dose should not be administered.  Nowhere does it discuss alternatives…  Nowhere does it give advantages or disadvantages… Indeed, it provides no reason to exclude a loading dose.”

The Chief Judge argued that although the knowledge of a person of ordinary skill in the art may be used to inform what is disclosed in the specification, it cannot be used to teach a limitation that is not in the specification, even if it would have been obvious to a person skilled in the art to exclude an element in view of the disclosure.  The Chief Judge asserted that the majority’s reading of the specification is rewriting the specification with expert testimony to arrive at their conclusion regarding the adequacy of the written description.

The majority’s decision and Judge Moore’s dissent highlight how the Federal Circuit’s decisions can be difficult to reconcile, e.g., the recently decided Biogen v. Mylan case in a 2-1 decision held the claims invalid for lack of written description for a dosage of “about 480 mg per day” where the specification disclosed “480 mg per day” whereas the Novartis decision found that the phrase “absent an immediately preceding loading dose regimen,” which was nowhere disclosed in the specification, satisfied the written description requirement.  Thus, where silence can be construed as disclosure and actual disclosure can be disregarded as insufficient disclosure to uphold or invalidate patents, patent drafters would be well-advised to include as many different positive and negative limitations as possible, and the importance of the strength of expert testimony during district court litigation cannot be understated.

Last week, a federal court in Delaware unsealed an opinion supporting its grant of summary judgment that U.S. Patent No. 7,033,590 (“the ’590 Patent”) is invalid for lack of enablement.[1] The ’590 Patent is owned by Baxalta Inc. (“Baxalta”), a subsidiary of Takeda Pharmaceutical Co. Ltd (“Takeda”).

As we previously discussed, Baxalta sued Roche’s subsidiary Genentech Inc. (“Genentech”), alleging that that the blockbuster drug Hemlibra, made by Genentech, infringes Baxalta’s ’590 patent. Genentech denied Baxalta’s allegations and alleged, inter alia, that claims 1–4, 19, and 20 of the ’590 patent were invalid for lack of enablement.[2]

The ’590 patent is entitled “Factor IX/Factor IXa Activating Antibodies and Antibody Derivatives” and was issued on April 25, 2006. Its patent application, filed on September 14, 2000, claimed priority to a foreign application filed on September 14, 1999. At issue are claims 1–4, 19, and 20 of the ’590 patent, which cover a genus of antibodies that bind to factor IX/factor IXa, thereby increasing the procoagulant activity of FIXa and restores blood clotting process in hemophilia A patients.

Claim 1 of the’590 patent recites:

  1. An isolated antibody or antibody fragment thereof that binds Factor IX or Factor IXa and increases the procoagulant activity of Factor IXa.

The litigation related specifically to infringement of the ’590 patent’s claims by Genentech’s Hemlibra (emicizumab), which was approved by the FDA for treatment of hemophilia A on October 4, 2018.[3] Baxalta itself has never commercialized a treatment for hemophilia A based on any of the antibodies covered by this patent.[4]

In his memorandum opinion, visiting Circuit Judge Timothy Dyk, who normally sits on Federal Circuit, held that the relevant claims of Baxalta’s patent were invalid for lack of enablement after applying the test articulated in In re Wands,[5] because undue experimentation would be required for a person skilled in the art to make and use the claimed invention.[6] The court found that neither the accused claims themselves nor the specification of the ’590 patent provided sufficient “guidance as to how to identify which antibodies will satisfy the claim limitations, nor [does it] describe what structural or other features of the disclosed antibodies cause them to bind to Factor IX/IXa or to increase the procoagulant activity of Factor IXa.”[7]

More specifically, based on the Wands factors, the Court cited to the following as supporting its finding of lack of enablement: (1) large amount of experimentation was needed because the number of candidates identified in the ’590 patent “number in the millions;” (2) there was no guidance as to how to identify the antibodies other than by trial and error; (3) the patent provided a very limited amount and variety of working examples; (4) the field of art (antibodies) was unpredictable; and (5) the breadth of the claims were too broad.[8] The Court concluded that “where, as here, there are a large number of potential candidates, few working examples disclosed in the patent, and no guidance in the specification as to how to practice the full scope of the invention except to use trial and error to narrow down the potential candidates to those satisfying the claims’ functional limitations—the asserted claims are not enabled.”[9]

The Court identified several Federal Circuit cases to support its finding that the asserted claims were not enabled as to their functional limitations.[10] For example, the Court points to Amgen Inc. v. Sanofi, Aventisub LLC, which we previously discussed here, where the Federal Circuit noted that where the patent at issue contained claims with broad functional language, the hurdles for fulfilling the enablement requirement were high.[11] There, the Federal Circuit found a lack of enablement on grounds that the claims were “far broader in functional diversity than the disclosed examples, [and] the only ways for a person of ordinary skill to discover undisclosed claimed embodiments would be through either trial and error… or by discovering the antibodies de novo.”[12] Judge Dyk also compared this case to Idenix Pharms. LLC v. Gilead Scis. Inc.,[13] Wyeth & Cordis Corp. v. Abbott Labs.,[14] and Enzo Life Scis., Inc. v. Roche Molecular Sys., Inc.,[15] to analogize the situation “where the inventors had identified a small number of compounds within the scope of the claims and the court found the claims were not enabled given the breadth of the claims and the lack of sufficient guidance in the specifications.”[16]  We discussed several of these cases here.

The Court also found that the functional scope of the ’590 patent was not sufficiently represented by working examples.[17] Rather, the Court concluded that the ’590 patent merely “disclose[d] a starting point for further research.”[18] For example, the ’590 patent did not provide any working examples of two of the four Markush-group members cited in its asserted claims, nor provide any guidance in its specification for one skilled in the art to identify those isotopes.[19]

Finally, the Court also held that the ’590 patent “does not remotely enable” the accused product, emicizumab. “None of the 11 disclosed antibodies in the specification increase the procoagulant activity of factor IXa more than 3.75%,” while emicizumab increases procoagulant activity by approximately 10%.[20] Furthermore, emicizumab was a bispecific humanized antibody and the ’590 patent provided no working examples of either a bispecific or humanized antibody.[21] Baxalta’s expert conceded that the patent’s language about the covered antibodies and their therapeutic utility was merely “aspirational”[22] and the Court concluded that it could not “allow Baxalta to provide a starting point for further research and then claim someone else’s solution to the problem.”[23]

Potential Impact

This decision follows the Federal Circuit’s judgment as a matter of law for lack of enablement in Amgen Inc. v. Sanofi, Aventisub LLC, for which a petition for a writ of certiorari has been filed as discussed here.  That petition raises the question of whether enablement is “a question of fact to be determined by the jury . . . as [the Supreme] Court has held,” or whether it is “a question of law that the court reviews without deference . . . as the Federal Circuit holds.”  Here, Judge Dyk held that “no reasonable jury could find the full scope of the asserted claims of the ’590 patent are enabled.”[24]

In view of the trend toward higher standards for written description and enablement for antibody claims and claims reciting broad functional language, patent drafters will be well-advised to provide more working examples in general, working examples for every Markush group, and more guidance in the patent specification for how to identify candidates within the claimed group. We will continue to follow further developments including a potential appeal of this decision and the Supreme Court’s decision on Amgen’s petition.

[1] Memorandum Op. at 1, Baxalta Inc. v. Genentech, Inc., No. CV 17-509-TBD (D. Del. Jan. 13, 2022).

[2] Id.

[3] Memorandum Op., supra note 1, at 8, 19.

[4] Id. at 16.

[5] 858 F.2d 731, 737 (Fed. Cir. 1988).

[6] Memorandum Op., supra note 1, at 5.

[7] Id.

[8] Id.at 29 to 31.

[9] Id at 31.

[10] Id.

[11] 987 F.3d 1080, 1087 (Fed. Cir. 2021).

[12] Id. at 1088 (internal quotations omitted).

[13] 941 F.3d 1149, 1155–56, 1162 (Fed. Cir. 2019)

[14] 720 F.3d 1380, 1385–86 (Fed. Cir. 2013).

[15] F.3d 1340, 1346–47 (Fed. Cir. 2019).

[16] Memorandum Op., at 37.

[17] Memorandum Op., supra note 1, at 38-42.

[18] Id. at 42.

[19] Id.

[20] Id. at 45.

[21] Id. at 45.

[22] Id.

[23] Id. at 47 (internal citations omitted).

[24] Id. at 7.

On January 4, 2022, the District Court for the District of Delaware granted Hikma Pharmaceuticals USA Inc.’s (“Hikma”) motion to dismiss Amarin Pharma Inc.’s (“Amarin”) infringement claims, finding that Hikma’s “skinny label” for its generic heart drug, icosapent ethyl, did not induce infringement of Amarin’s three patents. This decision comes on the heels of the Federal Circuit’s recent decision in GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 7 F.4th 1320, 1338 (Fed. Cir. 2021) and is a victory for generic manufacturers who raised concerns about the future of the generic industry and the use of “skinny labels.”

State of Federal Circuit Law on “Skinny Labels”

As we have previously reported, the generics industry has been concerned with infringement liability for selling drugs with labels that carve out patented uses (aka “skinny labels”) after the Federal Circuit twice ruled in favor of GlaxoSmithKline (“GSK”) in their case against Teva Pharmaceuticals. USA (“Teva”). First, in October of 2020, the Federal Circuit found that substantial evidence, i.e. Teva’s marketing of its drug as equivalent to the brand drug and physicians’ knowledge that brand drug could be used to treat the indication, supported the jury’s finding that Teva was liable for induced infringement for the patented indication it carved out of its skinny label.  However, the Federal Circuit’s opinion left several questions unanswered and raised several concerns about whether listing a generic drug as AB-rated meaning that it is therapeutically equivalent (displaying bioequivalence and pharmaceutical equivalence) to a brand drug could establish inducement and whether ANDA filers that carve out patented uses under section viii of 21 U.S.C. § 355(j)(2)(A) could be liable for infringement. After Teva filed a petition for rehearing which was supported by seven amicus curiae briefs, the original panel vacated its October 2020 ruling and decided to rehear the case entirely.

In August of 2021, after another round of oral arguments, the panel again affirmed the jury’s findings that Teva’s “partial label” induced infringement of GSK’s patent. The Federal Circuit held that substantial evidence demonstrated that “Teva’s partial label did not successfully carve out the patented use, and thus, Teva was selling its generic with a label which infringed the method claim.”[1] Accordingly, Teva’s label was “not a skinny label.”[2] The Federal Circuit also held that Teva’s marketing materials encouraged physicians to prescribe carvedilol in a manner that would cause infringement.[3] In its decision, the panel stated that the laws regarding generic drugs remain intact and quoted the language of an amicus brief to explain the law as follows:

“Generics could be held liable for actively inducing infringement if they marketed a drug with a label describing a patented therapeutic use or if they took active steps to encourage doctors or patients to use the drug in an infringing manner. But generics could not be held liable for merely marketing and selling under a ‘skinny’ label omitting all patented indications, or for merely noting (without mentioning any infringing uses) that FDA had rated a product as therapeutically equivalent to a brand-name drug.”[4]

The Federal Circuit clarified that its holding was a “narrow, case-specific review” and “does not upset the careful balance struck by the Hatch-Waxman Act regarding section viii carve-outs.”[5] According to the Federal Circuit, Teva did not omit all patented indications or note (without mentioning any infringing uses) that the FDA found a product therapeutically equivalent to a brand product.[6]  On October 7, 2021, Teva filed a Petition for Rehearing en banc.  In its Petition, Teva argues that “[t]he panel’s decision contradicts settled precedent, eviscerates the carve-out statute, and throws inducement doctrine into disarray.” [7]  Quoting Judge Prost’s dissent, Teva argues that “[b]ecause ‘the background facts here will seemingly persist in most skinny-label cases,’ the effects of the decision will be seismic.” [8]

After this decision, many generic companies raised concerns about whether this opinion materially altered the “skinny label” regime or at the very least removed it as a viable option for FDA approval.[9]

Aside from raising generic’s concerns, the Federal Circuit panel’s opinion in GlaxoSmithKline LLC v. Teva Pharms. USA, Inc. also raises the appearance of a split in Federal Circuit law on inducement of “skinny labels.” For example, previously, in Grünenthal GMBH v. Alkem Labs Ltd., 919 F.3d 1333, 1339-40 (Fed. Cir. 2019), a different panel affirmed the district court’s finding that the defendants’ “skinny labels” did not induce infringement band because neither label was specifically indicated for the patented treatment, or made a reference to the patented indication. The panel found that even though the label was indicated for “[m]oderate to severe chronic pain,” which included both infringing and non-infringing uses, it did “not specifically encourage use” of the generic for the patented “treatment of polyneuropathic pain.” [10] Grünenthal differs from the GSK case in that it did not involve statements by the generic regarding the equivalency of its drug to the branded drug. However, the panels’ competing views on inducement demonstrate a clear split and one that will continue to create uncertainty and concerns for the lower courts until its resolution.

Amarin Pharma, Inc. v. Hikma Pharms. USA, Inc.

The most recent decision addressing these concerns came on January 4, 2022. In Amarin Pharma, Inc. v. Hikma Pharms. USA, Inc., No. 20-1630 (D. Del.), Judge Richard G. Andrews of Delaware issued an opinion dismissing Amarin’s induced infringement claims against Hikma. The three patents-at-issue in the litigation relate to methods of using icosapent ethyl for the reduction of cardiovascular risk. Amarin sued Hikman, alleging that Hikma had induced doctors to infringe the patents by encouraging them to prescribe the generic for patent protected indications. Amarin also sued Health Net, LLC (“Health Net”), alleging that its formulary placement induces infringement by encouraging Hikma’s generic for the patented use.

Amarin’s brand product, Vascepa® (icosapent ethyl), is used in the treatment of hypertriglyceridemia and cardiovascular risk reduction. Amarin’s patents only cover using icosapent ethyl to treat cardiovascular risk reduction. Hikma had received FDA approval to sell its generic version of icosapent ethyl for use in the non-patented indication of hypertriglyceridemia under the “skinny label” regime. Amarin argued that the label used by Hikma to sell its generic was “not-skinny-enough” and that this label combined with Hikma’s public statements resulted in induced infringement of the patented indication[11]. Specifically, Amarin asserted that Hikma’s label teaches cardiovascular risk reduction because it contains a warning for patients with cardiovascular disease and it does not explicitly state that the product should not be used for the patented indication.

Judge Andrews disagreed with Amarin and found that neither Hikma’s label nor its statements teach using the generic in cardiovascular risk reduction. As to the label, Judge Andrews held that the notice regarding side effects is a warning and not an instruction to use icosapent ethyl to reduce cardiovascular risk. Relying on Takeda Pharms. U S.A., Inc. v. W-Ward Pharm. Corp., 785 F.3d 625, 632 n.4 (Fed. Cir. 2015), Judge Andrews also found that the label’s silence regarding cardiovascular risk reduction does not plausibly amount to inducement because generic labels do not need to contain a statement discouraging use of the patented indication.[12] Judge Andrews further found that Hikma’s press releases and website did not support accusations of actual induced infringement. The fact that Hikma’s press releases described icosapent ethyl as the “generic equivalent” of Vascepa® was not sufficient to establish inducement. With respect to the website, Judge Andrews relied on Grünenthal GMBH v. Alkem Labs Ltd., 919 F.3d 1333, 1339-40 (Fed. Cir. 2019), and held that without more, the mere fact that Hikma advertises its product as “AB rated” in a therapeutic category that includes both patented and non-patented uses does not amount to specifically encouraging use for the patented treatment.[13]  In light of these facts, Judge Andrew granted Hikma’s motion to dismiss.

By contrast, Judge Andrews denied Health Net’s motion to dismiss the induced infringement claims. Judge Andrews found that formulary selection and the prior authorization process could amount to affirmative acts of induced infringement. Judge Andrews found that “Health Net’s prior authorization form supports an inference of specific intent because it lists the patented indication on the generic icosapent ethyl capsules form” and that its “placement of generic icosapent ethyl on a preferred tier encourages the substitution of the generic for the branded drug, including for the patented indication.”[14] Ultimately, Judge Andrews agreed with the recommendations of the Magistrate Judge that Amarin had pled enough to survive the motion to dismiss stage.

Conclusions

The decision in favor of Hikma provides some reassurance to generic companies that the “skinny label” regime remains alive and well and that the Federal Circuit’s decision in GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., was narrowly tailored to a specific set of facts.

However, the conversation continues as to the future of skinny-labeled generics and whether the language of press releases, web pages and other marketing materials requires more scrutiny. Additionally, the liability of insurance companies is coming into the spotlight. Amarin was able to defeat the motion to dismiss filed by Health Net, which suggests that we may see more cases against insurance companies in the future. It will be interesting to see whether other brand companies target not only insurers, but other companies in the supply network.

We will continue to provide updates on the evolving skinny-label landscape including the Federal Circuit’s decision on Teva’s en banc petition as well as any appeals of the Amarin decision.

 

[1] GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 7 F.4th 1320, 1338 (Fed. Cir. 2021).

[2] Id. at 1328.

[3] Id. at 1336-38.

[4] Id. at 1326.

[5] Id.

[6] Id.

[7] GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., No. 18-1976, Dkt. 195 at 10 (Fed. Cir. Oct. 7, 2021).

[8] Id.

[9] See GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., No. 18-1976, Dkt. 213 (Fed. Cir. Oct. 25, 2021) (Amicus Brief of Apotex, Inc.); see also Dkt. 217 (Amicus Brief of Mylan Pharmaceuticals Inc.).

[10] Id.

[11] Amarin Pharma, Inc. et al v. Hikma Pharms. USA Inc., No. 20-1630, slip op. at 6-7 (D. Del. Jan. 4, 2022).

[12] Id. at 7.

[13] Id. at 9.

[14] Id. at 11.

At the end of last month, three amicus curiae briefs were filed following the petition for a writ of certiorari in the Amgen, Inc. v. Sanofi, Inc. case. We previously discussed the petition for a writ of certiorari in detail here.

The first amicus brief was submitted by the Association of University of Technology Managers (AUTM), Biogen, Bristol-Myers Squibb, Corning, Merck Sharp & Dohme, and St. Jude Children’s Research Hospital, collectively. Amici began the brief by noting that they “also are competitors, and have been directly adverse to one another in litigation over their innovations and patent rights. Yet despite their diverse interests and disagreements on many issues, amici have joined a common brief in support of the petition for certiorari in this case to urge that the Court review and reverse the Federal Circuit’s decision below.” Amici argue that the Federal Circuit’s decision “threatens to disrupt the patent bargain,” because it replaces the former statutory enablement standard – that the disclosure be sufficient to enable any person skilled in the art to make and use the invention – with a new “special, atextual” rule for genus claims.

According to amici, this new rule allows for invalidation of the patent if practicing the “full scope of the claimed embodiments” requires “substantial time and effort.” Amici argue that if this law is not reversed, innovators will be compelled to divert time and resources away from additional discoveries. Instead, the innovators will need to spend their resources on testing additional examples of their invention and “adding information already known to skilled artisans to their patent applications.” Finally, amici note they practice in “fast-paced fields of research,” where fast-paced patent filings are needed to protect innovator’s rights. If innovators with limited resources, such as universities and non-profits, must spend more time and money generating additional examples, those innovators might choose to forego their patent rights altogether in order to focus on new discoveries.

Finally, Amici argue that the Federal Circuit’s decision that enablement is a question of law is an error. They note that the same court has ruled that written description, which is in the same sentence in 35 U.S.C. § 112(a), is a question of fact to be decided by a jury.[1] They argue that the Federal Circuit’s habit of “routinely set[ting] aside jury verdicts confirming the validity of patents against enablement challenges – as it did twice in this case – lead[s] innovators to doubt whether they will have reliable patent protection for their inventions even after prevailing at trial.”

GlaxoSmithKline, PLC (“GSK”) submitted the second amicus brief. Although GSK does not consider the issue of whether enablement is a question of fact to be decided by a jury, it makes multiple arguments why the Federal Circuit’s decision should be reversed. First, it argues that the Federal Circuit has created a new rule for genus claims that could devastate the chemistry and biotechnology fields. If the law is not reversed, GSK argues, innovators will be forced to draft narrower claims to avoid invalidation of their patents, even though “known techniques could permit competitors to circumvent the literal scope of a narrow claim by making insubstantial changes to a chemical compound or a biological molecule.” GSK argues that a genus claim is generally commensurate with the innovator’s discovery, and that “[a]llowing for a wide breadth of protection based on a genus is, as a practical matter, the only means to ensure that an inventor in these arts actually receives a commercially meaningful period of exclusivity contemplated by our patent system.” If these innovators cannot receive the full patent protection that they deserve, GSK argues, then the innovators may choose trade secret protection over patent protection and disclosure.

Additionally, GSK argues the Federal Circuit’s standard for genus claims is undesirable for innovators because “it would ‘force an inventor seeking adequate patent protection to carry out a prohibitive number of actual experiments’ and ‘discourage inventors from filing patent applications in an unpredictable area.’”[2] GSK notes that the Patent Act does not limit the number of species that a claim can have, “nor does the Patent Act require different, elevated tests for enablement for certain types of claims.”

Finally, GSK lists reasons why the “full scope” enablement test “erects a formulaic, inflexible requirement that tends toward a predetermined outcome: invalidating genus claims.” It argues the rule gives additional power to judges to set aside expert testimony and “real-world facts showing that artisans were able to exploit the invention following its teachings.” GSK notes that this test is similar to other rigid, atextual tests that the Supreme Court has previously rejected.[3]

The final amicus brief was submitted from intellectual property professors throughout the United States. Like GSK, these amici did not address whether enablement is a question of fact to be decided by a jury. Amici state, “The Federal Circuit has changed the law dramatically in recent years, to the point where it is no longer possible to have a valid genus claim in the chemical and biotechnology industries.” They note that the previous standard of providing enough information to allow one of ordinary skill in the art to make and use the invention is no longer enough for genus claims, and that the Federal Circuit is now rejecting the genus claims as invalid if “the genus contains thousands or millions of possible chemicals, unless the patent itself identifies exactly which of those myriad species will work.” This leaves one of two options for innovators: (1) spend extra time and resources identifying all the possible species, or (2) draw narrow claims that will be avoided by “minor modification.”

Amici emphasize that what constitutes “undue experimentation” should be decided on a case-by-case basis by examining the facts in the case. Additional experimentation is not automatically “undue experimentation,” but “is a common part of the PHOSITA’s work.” They state, “as long as the specification provides some working examples, that disclosure can give PHOSITAs sufficient guidance to enable the full scope of the genus claims.”

The petition for a writ of certiorari and the three amicus curiae briefs were distributed last week for Conference taking place on January 21. The Court asked Sanofi for a response by February 10, 2022, but Respondents have asked for a 30-day extension of time to file this response. We will continue to watch this case and post updates on any advancements.

[1] PIN/NIP, Inc. v. Platte Chem. Co., 304 F.3d 1235, 1243 (Fed. Cir. 2002).

[2] In re Angstadt, 537 F.2d 498, 502-03 (C.C.P.A. 1976).

[3] KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007); see also Octane Fitness, LLC v. ICON Health & Fitness, Inc., 572 U.S. 545, 553 (2014); Halo Elecs., Inc. v. Pulse Elecs., Inc., 579 U.S. 93, 104 (2016).