On September 9, 2022, Biogen Inc. and Biogen MA Inc. (“Plaintiffs”) filed suit against Sandoz Inc., Sandoz International GMBH, Sandoz GMBH, and Polpharma Biologics S.A. (collectively, “Defendants”) in the District of Delaware concerning twenty-eight different patents. Although the complaint was filed under seal, the complaint appears to be related to Defendants’ natalizumab biosimilar (proprietary name of Tysabri®).  Sandoz announced on July 25, 2022 that the FDA had accepted its aBLA for natalizumab.  Biogen’s twenty-eight asserted patents have not yet been listed in the Purple Book.  This suggests that either (1) Sandoz already provided its 180-day notice of commercial marketing under 42 USC § 262(l)(8)(A), or (2) Sandoz may have opted out of the patent dance by refusing to produce its aBLA and associated documents (see § 262(l)(9)). On September 12, Judge Connolly granted Plaintiffs motion to file the complaint under seal. The order requires Biogen to file a redacted version of the complaint by September 19, which will then provide more details on the BPCIA litigation.  We will provide further updates as the case progresses.

Updated on September 20, 2022

The redacted, publicly available version of the complaint is now available. Based on the information in the complaint, Biogen claims that Defendants have provided some, but not all, of the information contemplated by 42 USC § 262(l) regarding the Defendants’ natalizumab aBLA product. Biogen asserts that Defendants have not provided all information requested under 42 USC § 262(l)(2)(A)-(B), and have not provided a complete response to Biogen’s list of asserted patents under 42 USC § 262(l)(3)(B)(ii). Because of these alleged failures to comply with the statute, Biogen has sought a declaratory judgment of patent infringement as permitted under 42 USC § 262(l)(9)(B).

On August 2, 2022, Coherus BioSciences announced that the U.S. Food and Drug Administration (FDA) has approved CIMERLI™ (ranibizumab-eqrn) as a biosimilar product interchangeable with Lucentis® (ranibizumab injection) for all five indications, meeting the FDA’s rigorous standards to the reference product, including safety, efficacy, and quality.  Coherus plans to launch CIMERLI™ in early October 2022.

In order for a biosimilar to acquire the “interchangeable” designation, in addition to meeting the requirements for a biosimilar (i.e., highly similar to, and no clinically meaningful differences from, an approved reference product), the manufacturer must show that the interchangeable biosimilar product is expected to produce the same clinical result as the reference product in any given patient. For biological products administered more than once to an individual patient, the manufacturer needs to further provide data ensuring that the risk in terms of alternating or switching between use of the interchangeable biological product and its reference product is not greater than the risk of using the reference product without switching.

The benefit of meeting these more extensive requirements is that, just like with a traditional generic drug, an “interchangeable” biosimilar can be substituted for the often pricier reference product by a pharmacist without the prescribing doctor’s intervention or approval (subject to state pharmacy laws). Importantly, CIMERLI™ will benefit from 12 months of first interchangeable biosimilar exclusivity.

CIMERLI™ belongs to the anti-VEGF therapy class of biologics that has been revolutionary in helping retinal patients maintain or gain vision. Retina indications for which CIMERLI™ is interchangeable include Neovascular (wet) Age-Related Macular Degeneration (AMD), Macular Edema following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME), Diabetic Retinopathy (DR), and Myopic Choroidal Neovascularization (mCNV).

“CIMERLI™, the only biosimilar product interchangeable with Lucentis® across all five indications, will provide both greater treatment access and choice for patients, payors and providers in the U.S. retinal disease community,” said Paul Reider, Chief Commercial Officer of Coherus. “Coherus is the only company in the $7 billion anti-VEGF ophthalmology market with a demonstrated track record of U.S. commercial biosimilar success. We intend to replicate our UDENYCA® achievements with a dedicated retina commercial team eager to leverage their experience and in-depth market understanding to drive CIMERLI™ share.”

Coherus CEO Denny Lanfear explained that the “approval of CIMERLI™ and its upcoming launch represent a strategic inflection point for Coherus as we transition to a multi-product revenue stream. UDENYCA®, our first product, established our track record of success competing in the U.S. biosimilars market. Our upcoming launch of CIMERLI™ and planned launch next year of our third approved product, our Humira® biosimilar, YUSIMRY™, will leverage this experience and knowledge. For Coherus, this portfolio is also our source of internally generated capital as we build a leading innovative oncology franchise that will drive our future growth.”

CIMERLI™ will follow Samsung Bioepis and Biogen’s Byooviz (ranibizumab-nuna) into the market although CIMERLI™ will be benefit from interchangeable exclusivity.  It will be interesting to see how the landscape for ranibizumab products and pricing changes with the launch of CIMERLI™.

Disclaimer: The information contained in this posting does not, and is not intended to, constitute legal advice or express any opinion to be relied up legally, for investment purposes or otherwise. If you would like to obtain legal advice relating to the subject matter addressed in this posting, please consult with us or your attorney. The information in this post is also based upon publicly available information, presents opinions, and does not represent in any way whatsoever the opinions or official positions of the entities or individuals referenced herein.

Patent thickets, particularly those involving pharmaceutical patents, appear to have caught the ire of many U.S. senators. Within the past few weeks, two separate letters have urged action to find ways to prevent issuance of overlapping patents covering a single pharmaceutical product. The letters provide insights into the tools they believe are available to address such alleged patent abuse.

On May 25, 2022, U.S. senators Bill Cassidy, M.D. (R-LA) and Maggie Hassan (D-NH) alleged that “lack of coordination” between the U.S. Food and Drug Administration (FDA) and Patent and Trademark Office (“PTO”) allowed patent thickets to grow in a letter to Kathi Vidal, Director of the PTO, and Dr. Robert M. Califf, Administrator of the FDA. The letter alleged that lack of inter-agency coordination allowed the pharmaceutical industry to obtain patents of questionable validity that block entry of generic drugs and extend monopoly prices. In the letter, the senators expressed concern regarding drug manufacturers’ increasing reliance on patent thickets to evade competition.

Between 2005 and 2015, 78% of drugs associated with new patents were not new drugs, but existing ones, and the number of drugs with three or more patents added to them in one year doubled. These thickets can preserve a drug company’s monopoly and block the launch of generic drugs for years or even decades after the expiration of the drug’s original patent. In the intervening period, patients are deprived of significant savings: drug prices drop by as much as 20% when the first generic enters the market and as much as 85% when multiple generics enter the market.

In the letter, the senators postulated that the lack of coordination between the PTO and FDA may lead to patent thickets, enabling manufacturers to obtain patents that do not satisfy the Patent Act’s requirement. As an example, the letter mentions the drug manufacturer’s disclosure of its manufacturing process of an already marketed product to the FDA more than a year prior to submitting the patent application to the PTO coupled with the drug manufacturer’s contradictory statements made to the FDA and to the PTO.  In this regard, the senators noted that existing sections of the Federal Food, Drug, and Cosmetic Act authorize the FDA to share information with the PTO. Thus, in order to improve the inter-agency coordination, the senators requested Director Vidal and Administrator Califf to address the following questions by June 24, 2022:

  1. How does the PTO determine whether an application is connected to pharmaceutical product(s) (small molecule drugs or biologics)?
  2. In the past five years, how many patent applications connected to pharmaceutical products did the PTO review?
  3. Did the PTO request information from the FDA during the patent application review of the cases in question 2? If so,
    a. Did the FDA provide the PTO with information?
    b. Was the FDA information adequate to guide the PTO’s analysis?
  4. Do the PTO and the FDA have a process to collaborate when the PTO reviews pharmaceutical-related patent applications?
    a. If not, when will the agencies establish a process?
    b. If so, what actions are the agencies taking to improve it, and what is the timeline for implementing these improvements?

Relatedly, on June 17, 2022, Senators Dick Durbin (D-IL), Thom Tillis (R-NC), and Chuck Grassley (R-IA) introduced the “Interagency Patent Coordination and Improvement Act,” or S. 4430, a bill to establish a joint task force between the PTO and FDA to “enhance information sharing on each agency’s processes, standards and methods; improve dialogue on new technologies and scientific trends; enable confidential reciprocal access to information, if requested and only as needed; ensure accurate representations by companies between the two agencies; and ensure accuracy of patent listings.”[1]  Notably, Senator Tillis commented that, “[h]aving access to accurate prior art is critical to ensure that the USPTO issues high-quality patents. By improving coordination between the USPTO and FDA, Congress can ensure that patent examiners have access to all of the relevant information that they need to help them make a sound determination regarding patentability. This bill is a simple good-government measure that will protect the strength of the patent system, improve patent quality, and cut down on unnecessary bureaucracy between these two agencies.”[2]

On June 8, 2022, U.S. senators Patrick Leahy (D-VT), John Cornyn (R-TX), Richard Blumenthal (D-CT), Susan M. Collins (R-ME), Amy Klobuchar (D-MN), and Mike Braun (R-IN) alleged that continuation and highly similar patents were being issued too frequently and too easily in a letter directed to Director Vidal.  The senators complained that drug manufacturers are able to obtain dozens or hundreds of patents on a single drug through minor tweaks to delivery mechanism, dosages, and formulations. The senators expressed concerns that the prevalence of continuation and other highly similar patents is contrary to the Patent Act, which envisions a single patent per invention and impedes generic drugs’ production, hurts competition, and extends exclusivity beyond the mandated patent term. Thus, the senators asked the director to change the PTO’s regulations and practices to address the problem during the examination phase and asked that the PTO issue a notice of proposed rule-making or a public request for comments by September 1, 2022 addressing the following questions:

  1.  Terminal disclaimers, allowed under 37 C.F.R. 1.321(d), allow applicants to receive patents that are obvious variations of each other as long as the expiration dates match. How would eliminating terminal disclaimers, thus prohibiting patents that are obvious variations of each other, affect patent prosecution strategies and patent quality overall?
  2.  Currently, patents tied together with a terminal disclaimer after an obviousness-type double patent rejection must be separately challenged on validity grounds. However, if these patents are obvious variations of each other, should the filing of a terminal disclaimer be an admission of obviousness? And if so, would these patents, when their validity is challenged after issuance, stand and fall together?
  3.  Should the USPTO require a second look, by a team of patent quality specialists, before issuing a continuation patent on a first office action, with special emphasis on whether the claims satisfy the written description, enablement, and definiteness requirements of 35 U.S.C. § 112, and whether the claims do not cover the same invention as a related application?
  4. Should there be heightened examination requirements for continuation patents, to ensure that minor modifications do not receive second or subsequent patents?
  5.  The Patent Act requires the USPTO Director to set a “time during the pendency of the [original] application” in which continuation status may be filed. Currently there is no time limit relative to the original application. Can the USPTO implement a rule change that requires any continuation application to be filed within a set time frame of the ultimate parent application? What is the appropriate timeframe after the applicant files an application before the applicant should know what types of inventions the patent will actually cover? Would a benchmark (e.g., within six months of the first office action on the earliest application in a family) be preferable to a specific deadline (e.g., one year after the earliest application in a family)?
  6.  The USPTO has fee-setting authority and has set fees for filing, search, and examination of applications below the actual costs of carrying out these activities while maintenance fees for issued patents are above the actual cost. If the up-front fees reflected the actual cost of obtaining a patent, would this increase patent quality by discouraging filing of patents unlikely to succeed? Similarly, if fees for continuation applications were increased above the initial filing fees, would examination be more thorough and would applicants be less likely to use continuations to cover, for example, inventions that are obvious variations of each other?

One of the more interesting proposals raised by the senators is the elimination of terminal disclaimers. Obviousness-type double patenting is a judicially-created doctrine that is commonly raised during examination of continuation applications and can typically be overcome by filing a terminal disclaimer. In theory, eliminating terminal disclaimer practice would force applicants to only patent inventions that are not obvious variants of each other.  However, there are at least two complications. First, obviousness is a highly subjective inquiry and obviousness-type double patenting analysis is often even more confounding given that an examiner must decide what would have been an obvious variant of a given patent’s claim. Second, the scope of obviousness-type double patenting rejections and challenges has expanded in recent years and is routinely applied to applications that are not continuations, are not related to each other, and often are not even owned by the same entity. Given that obviousness-type double patenting rejections are extremely common, and thus terminal disclaimers are widely used, it remains to be seen how the PTO will respond to the complex issues posed by the senators’ questions and whether further legislative action would be required given that obviousness-type double patenting is a judicially-created doctrine with an expanding and amorphous reach. Moreover, it will be interesting to see how the PTO will respond to the proposals that will have difficult to predict impacts on activities that account for a significant portion of the application filing fees, terminal disclaimer fees, and maintenance fees that the PTO collects.

We will continue to monitor for further developments including how Director Vidal and Administrator Califf address the senators’ questions.

[1] https://www.grassley.senate.gov/news/news-releases/grassley-durbin-tillis-introduce-legislation-to-improve-coordination-between-uspto-and-fda

[2] Id.

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.