A number of legal trends have emerged in biologics litigation over the summer. Below we discuss 5 of the most significant.

One Notice Is Sufficient if the Underlying Biologic Remains the Same

Under the Biologics Price Competition and Innovation Act of 2009 (BPCIA), one step of the infamous “patent dance” requires a pharmaceutical company seeking to market a biosimilar product to notify the biologics product reference application holder “not later than 180 days before the date of the first commercial marketing” of the biosimilar. But does an applicant have to renotify the reference product sponsor when it supplements its initial abbreviated biologics license application (aBLA)? That was the issue posed to the United States Court of Appeals for the Federal Circuit in 

Genentech Inc v Immunex Rhode Island Corp.

The court ultimately concluded no additional notice is required.

Immunex (a company acquired by Amgen) filed an aBLA with the FDA and subsequently notified Genentech, the reference drug sponsor for Avastin®, that it intended to market a biosimilar version, Mvasi™. After providing its initial notice, Amgen submitted 4 supplemental applications, which included changes to the manufacturing facility and label. Genentech filed an emergency motion seeking to preclude Amgen from commercially marketing Mvasi™, arguing that Amgen did not provide proper commercial notice because the supplemental applications amending the manufacturing facility and label effectively reset the 180-day period. The district court disagreed, and on appeal, the Federal Circuit affirmed the decision. According to the Federal Circuit, supplemental applications do not require a new notice so long as the biological product that is the subject of the application does not change.

Practically speaking, the Genentech decision is a relief to biosimilars companies that may previously have been fearful that an aBLA cannot be amended during the normal FDA regulatory review process. That said, the court did not provide clear guidance about when the biological product has undergone a change sufficient to require a second notice of commercial marketing. Thus, beyond the facts of 

, the precise contours of when an aBLA supplement may require renewed commercial notice still remain to be seen.

Don’t Invalidate Your Biologics Patents by Licensing Them

It’s well known that biologics patent portfolios are extensive, and that licensing them can be quite lucrative for the patent owner and the licensee manufacturer. But a recent case serves as a stark reminder that companies must nevertheless be cautious when licensing patents, lest they accidentally invalidate their own portfolio through common ownership.

Under the doctrine of statutory double patenting, a patent is invalid if it covers subject matter identical to another patent owned by the same entity. This concept was implicated in 

, where the primary issue was whether, by a transfer of rights from Hoffman-La Roche in the 1990s, Immunex alone owned patents-in-suit covering Enbrel® (etanercept).

 Because Immunex owned other patents that covered the same technology, if Immunex had owned the asserted patents outright, Sandoz may have been able to invalidate the asserted Enbrel® patents on grounds of statutory double patenting.

Considering this among other issues, the Federal Circuit determined that the Roche-Immunex license did not transfer “all substantial rights” to Immunex, thus eliminating a statutory double-patenting defense. The license at issue granted Immunex an irrevocable, exclusive license and control over the prosecution of the pending Enbrel® patent applications. The agreement also granted Immunex the right to sublicense the patents and the first right to sue any potential infringers. Notably, Roche was obligated to cooperate with any prosecution and enforcement of the patents and retained a secondary right to sue if Immunex did not file suit. Roche also retained the ability to object to any sublicenses for the patents.

In its analysis, the majority gave significant weight to Roche’s retention of a secondary right to sue and the ability to prevent Immunex from further licensing the patents. Because these rights are inconsistent with the transfer of all substantial rights for a patent, the court reasoned, Immunex was not an owner. In dissent, Judge Jimmie V. Reyna argued that the license transferred all substantial rights to Immunex, rendering it the sole owner of the asserted patents.

This case shows that companies must be diligent when entering license agreements and appropriately structure such agreements to avoid being considered an owner if the covered matter substantially overlaps with existing portfolio assets. Indeed, in the case of large biologics portfolios, such caution is all the more necessary.

By their nature, biologics portfolios are large; AbbVie’s Humira® (adalimumab) is covered by approximately 247 patent applications that resulted in 132 patents, over 100 of which trace back to just 20 original applications. So, it was no surprise that after AbbVie settled several large-scale litigations relating to Humira® with a variety of biosimilars companies, a group of indirect purchasers sued in federal court alleging that the settlements were antitrust violations.

What was surprising, however, were the plaintiffs’ theories about the case. To be sure, the plaintiffs asserted the typical claim that the settlements were illegal restraints of trade, an argument that failed because the district court concluded that AbbVie’s settlements (which permitted competitors to immediately enter the European market but refrain from entering the US market until 2023) were not unlawfully anticompetitive. However, the plaintiffs also advanced a second, more creative theory: that AbbVie impermissibly monopolized the domestic market for Humira® by obtaining and asserting invalid, unenforceable, or noninfringed patents without regard to the merits of such assertions. This argument likewise failed. The district court found that AbbVie’s conduct was not objectively baseless for multiple reasons, including because the United States Patent and Trademark Office had granted more than half of AbbVie’s patent applications and a substantial majority of the patents challenged in inter partes review proceedings had survived. These successes convinced the district court that AbbVie’s conduct was not unreasonable and shielded AbbVie from antitrust scrutiny.

The plaintiffs filed a notice of appeal this past July, and a decision from the United States Court of Appeals for the Seventh Circuit is expected sometime next year. If this decision stands on appeal, it could potentially encourage biologics companies to create judicially sanctioned dense patent portfolios. In any event, biologics companies should have a focused and well-defined strategy when developing new products to ensure that they can reap the full benefits of patent protection while simultaneously avoiding antitrust exposure.

Federal Circuit Reaffirms That Common, Broad Claim Terms Are Broadly Construed

The Federal Circuit delivered a recent victory to patent owners seeking to give broad scope to the meaning of common terms in patent claims. At issue on appeal were the district court’s constructions of the terms 

 in a patent asserted by Baxalta purportedly covering Genentech’s Hemlibra® (emicizumab).

 Notably, the district court opinion was issued by Federal Circuit Judge Timothy B. Dyk, who was sitting by designation in the District of Delaware.

The district court had concluded that without structural context, the term 

 had multiple, commonly accepted meanings. Choosing between Baxalta’s broad proposal—“molecule having a specific amino acid sequence comprising two heavy chains (H chains) and two light chains (L chains)”—and Genentech’s narrower one—“immunoglobulin molecule, having a specific amino acid sequence that only binds to the antigen that induced its synthesis or very similar antigens, consisting of two identical heavy chains (H chains) and two identical light chains (L chains)”—the district court sided with Genentech. In doing so, it relied primarily on 2 pieces of evidence: (1) the specification’s description of 

 and (2) a claim amendment made during prosecution.

On appeal, the Federal Circuit unanimously reversed the ruling. Placing nearly dispositive weight on the claim language of 

 (which does not itself require 2 identical heavy chains and 2 identical light chains or binding only the antigen that induced its synthesis or similar), the court found no reason to limit the plain meaning of the term. It drew additional support from language in a dependent claim identifying certain subsets of antibodies that fell outside the district court’s construction of the term 

. Although the district court would have reconciled the difference by invalidating the inconsistent claims, the Federal Circuit instead found that they provided significant evidence of the breadth of the term. And contrary to the district court, the Federal Circuit refused to adopt a definition excluding claimed embodiments and disagreed that the prosecution history clearly limited the scope of the claim.

Although claim construction is a patent-specific inquiry, the Federal Circuit’s opinion reaffirms that broad terms will be given broad meaning absent a reason demonstrating that the patentee intended otherwise.

New Regulations for Biologics Are (Possibly) Coming

Earlier this year, the FDA announced that it intended to issue substantive regulations governing biologics to clarify existing requirements and procedures related to BLAs.

 The proposed rules are expected to be released in December 2020. The update would further “promote the goals associated with the FDA’s implementation of the abbreviated licensure pathway created by the” BPCIA. But with the details still in the works, it is unclear what changes the FDA intends to make. Certainly, with a relatively low rate of market penetration and cost savings to would-be biosimilar consumers, there could be much worth considering. Although the FDA has yet to issue any proposed rules, industry stakeholders should continue to monitor the agency’s proposed regulations to determine how the regulations could affect the biologics industry.

In sum, this has certainly been an interesting summer for biologics. From basic statutory interpretation to antitrust issues, the legal and business landscape for biologics continues to evolve at a rapid pace. Companies must remain adaptable and continually take appropriate measures to position themselves for future success.

Genentech Inc v Immunex Rhode Island Corp

In re Humira (Adalimumab) Antitrust Litigation

, Appeal No. 2019-1527 (Fed Cir August 27, 2020).

Biologics Regulation Modernization. Reginfo.gov. Accessed September 2, 2020. https://www.reginfo.gov/public/do/eAgendaViewRule?pubId=202004&RIN=0910-AI14

Intellectual property law attorneys from the Washington, DC, offices of McDermott Will & Emery LLP, discuss 5 of the most significant trends in biologics litigation that have emerged in recent months.

What We Learned About Biologics on Summer Vacation

Christopher M. Bruno is an associate in the Intellectual Property group at McDermott, Will, & Emery LLP, and a former law clerk of the United States Court of Appeals for the Federal Circuit and of the United States District Court for the Central District of California. With a focus on pharmaceutical patent litigation, he has litigated Hatch-Waxman Act cases from pre-complaint investigation through appeal in district courts, the Federal Circuit, the Supreme Court, and the International Trade Commission. Chris was one of the first attorneys with experience litigating the meaning of provisions of the Biologics Price Competition and Innovation Act of 2009, and he continues to play a role in decoding the relatively nascent territory of biosimilar litigation.

Christopher M. Bruno, JD

In the United States, although the first biosimilar obtained approval from the FDA in 2015, these drugs have been slow to gain support and implementation in clinical practice. Biosimilars of several anti–tumor necrosis factor (TNF) agents have been approved. Currently, 3 infliximab biosimilars are available for the treatment of inflammatory bowel disease (IBD).

Although the infliximab biosimilars are approved for the same indications as the reference infliximab, research shows that many gastroenterologists are still reluctant to use infliximab biosimilars for Crohn disease (CD) or ulcerative colitis (UC).

 Perhaps the most common reason is that insurance coverage for biosimilars has not been widely available, making it difficult to prescribe or switch them. However, even when biosimilars are covered, providers may still hesitate to use these agents. They may not know about biosimilars or their safety and efficacy, or they may lack clinical experience in using them.

A biosimilar is a biological product that is highly similar to and has no clinically meaningful difference from an existing FDA-approved reference product.

 In order to understand biosimilars, one must understand the “totality of evidence” approach, which forms the foundation of biosimilar development programs. In the early stages of biosimilar development, extensive, rigorous studies are conducted to demonstrate structural and functional similarity between the reference biologic and biosimilar. Once this similarity is established, clinical studies are conducted in one or more sensitive populations to “confirm” equivalent efficacy and safety.

 Biosimilars undergo a thorough regulatory review process, and biosimilars approved by the FDA can be regarded as safe and effective for use based on robust scientific evidence.

Are Biosimilars Safe for Patients With IBD?

Biosimilars were introduced earlier in Europe than in the United States, and they have been used without major safety issues for more than 10 years. Several real-world studies conducted in Europe demonstrate the safety of switching from reference infliximab to biosimilars, or from one biosimilar to another biosimilar in the IBD population. One long-term observational, prospective cohort study conducted in Germany showed that switching 148 patients with IBD (96 with CD, 52 with UC) from reference infliximab to a biosimilar did not lead to any increase in disease activity.

 In another prospective, single-center observational study conducted with 221 patients (179 with CD, 42 with UC), there was no adverse effect on IBD control or drug levels after the first or second switch.

In the United States, real-world evidence on biosimilars for patients with IBD has been rather limited, but the data are growing with increasing use of biosimilars. Recently, at the American College of Gastroenterology (ACG) 2020 Virtual Annual Scientific Meeting, held from October 26 to 28, 2020, real-world data on US veteran patients with IBD revealed that a single switch from reference to biosimilar infliximab, or a double switch from the reference product to a biosimilar to another biosimilar, did not lead to any significant safety issues.

 Patients who were stable on the original infliximab medication for at least 3 months were eligible for the study, and they continued to remain stable after switching.

In another real-world study conducted by Cleveland Clinic, patients were randomized to switch to infliximab biosimilar or continue on reference infliximab. The study demonstrated that there was no significant difference in the use of corticosteroid taper, maintenance of remission rates, fecal calprotectin levels, infliximab concentrations, or antibody levels between these 2 groups.

 Since data are limited on multiple switching of biosimilars to reference product or from one biosimilar to another, this information would be important for the FDA to authorize interchangeable status for a biosimilar, which would allow pharmacists to independently substitute biosimilars when dispensing. No biosimilars have that designation to date.

How Does COVID-19 Affect the Use of Biosimilars?

Use of biosimilars can help drive down overall health care costs. Especially now, as the United States continues to battle the coronavirus disease 2019 (COVID-19) pandemic, there will be an increasing burden on the health care system to finance budgets and find savings to ease some of that burden for patients, providers, payers, and employers. Development of new vaccines and treatments for COVID-19 requires billions of dollars of funding from both private and public sources. And trillions of dollars are needed to support hospitals and health care providers for costs and expenses associated with COVID-19. This is an enormous strain on the health care budget, but there is room to drive down the cost of existing medicines through wider adoption of biosimilars.

Also, as patents expire on some biologic molecules in the next few years, there will be more biosimilars available for a wider spectrum of therapies in the market. For adalimumab, 6 biosimilars have FDA approval to enter the US market in 2023 and more are anticipated.

 Will rheumatologists, gastroenterologists, and dermatologists in the United States be ready to use biosimilars by then?

It will be interesting to see how biosimilars change the daily practice of IBD treatment in the coming years. With approximately 3 million Americans living with IBD, and the burden and prevalence of IBD continuing to increase,

 it’s time to embrace the change and think with a holistic point of view. Biosimilars, as treatment options with lower cost than reference products but with the same efficacy and safety, can be the optimal solution to maintain quality care for patients while reducing the cost burden on the health care system in the United States.

1. Park SH, Park JC, Lukas M, Kolar M, Loftus EV. Biosimilars: concept, current status, and future perspectives in inflammatory bowel diseases. 

. 2020;18(1):34-44. doi:10.5217/ir.2019.09147

2. FDA. Biosimilar and interchangeable products. Updated October 23, 2017. Accessed October 2020. 

https://www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeable-products

3. FDA. Biosimilar development, review, and approval. Updated October 20, 2017. Accessed October 2020. 

https://www.fda.gov/drugs/biosimilars/biosimilar-development-review-and-approval

4. Fischer S, Mesfin S, Klenske E, et al. P548 Efficacy, safety, and pharmacokinetics after switching from infliximab originator to biosimilar SB2 in inflammatory bowel disease patients: A long-term observational, prospective cohort study. 

2020;14(Suppl 1):S466-S467. doi:10.1093/ecco-jcc/jjz203.676

5. Luber R, O’Neill R, Singh S, Arkir Z, Irving P. P485 Switching infliximab biosimilar: no adverse impact on inflammatory bowel disease control or drug levels with the first or second switch. 

6. Pernes T, Patel M, Khan N. The safety of switching from originator infliximab or CT-P13 to SB2 among a nationwide cohort of inflammatory bowel disease patients. Presented at: ACG 2020 Virtual; October 23-28, 2020. Poster 1597.

7. Padival R, Heis F, Lee JA, et al. Real world comparison of originator infliximab versus the biosimilar infliximab-abda in the treatment of inflammatory bowel disease. Presented at: ACG 2020 Virtual; October 23-28, 2020. Poster 1625.

8. Davio K. FDA approves Pfizer’s adalimumab biosimilar, Abrilada. The Center for Biosimilars

. Published November 16, 2019. Accessed October 2020. 

https://www.centerforbiosimilars.com/view/fda-approves-pfizers-adalimumab-biosimilar-abrilada

9. Centers for Disease Control and Prevention. Inflammatory Bowel Disease Data and Statistics. Updated August 11, 2020. Accessed October 2020. 

https://www.cdc.gov/ibd/data-statistics.htm

Bincy P. Abraham, MD, explains that even when payers allow coverage for biosimilars, providers may still be hesitant to use them. 

Opinion: Embrace the Era of Next-Generation Biologics

Bincy P. Abraham, MD, MS, AGAF, FACG, is a professor of Clinical Medicine at Houston Methodist Academic Institute. She is also the distinguished professor and director of the Fondren Inflammatory Bowel Disease Program at the Underwood Center for Digestive Disorders and director of Gastroenterology Fellowship Program at Houston Methodist Hospital.

Bincy P. Abraham, MD

Requiring patients to switch from originator etanercept (Enbrel) to etanercept biosimilars caused no permanent, unintended changes in patterns of health care use, suggesting the change did not harm patient health and may have even reduced disease severity, according to a Canadian study.

Health Canada approved the biosimilar products 

 (etanercept-szzs) in August 2016 and April 2017, respectively. This new study, by researchers at the University of British Columbia, tracked the effects of the first phase of the British Columbia Ministry of Health’s Biosimilar Initiative, which required patients to switch to biosimilars starting in May 2019.

Investigators used administrative data on prescriptions, diagnoses, hospital admissions and other events for 2655 individuals in the provincial health plan. They compared health services utilizations in the 3 years before the switch and during the policy implementation period. The most common diagnosis among patients in the study was rheumatoid arthritis (58.8%–63.1%), followed by psoriatic arthritis (12.6%–17.7%), juvenile rheumatoid arthritis, ankylosing spondylitis, and undetermined conditions.

During a 6-month transition period, the percentage of prescriptions for biosimilars among all etanercept refills covered by the provincial drug plan rose from 17.3% (349 of 2016 prescriptions) in May 2019 to 96.9% (1887 of 1948 prescriptions) in December 2019.

Among other results, the study authors found that the average quantity of etanercept dispensed and average number of days on other types of drugs were similar or lower in the policy cohort compared to the historical cohort.

“The direction of the change in utilization suggested a possible benefit,” they wrote. “Specifically, patients in the policy cohort had fewer days on [conventional synthetic disease-modifying antirheumatic drugs,] csDMARDS, oral steroids, and [nonsteroidal anti-inflammatory drugs], which may suggest better control of disease severity.”

The historical and policy groups also switched to different biologic DMARDs at similar rates, at 8.2%-9.7% for the historical cohorts and 9.6% for the policy cohort.

The authors observed anticipated changes during the transition, such as a transient increase of up to +0.9% in the cumulative incidence difference in first visits to physicians, and a transient increase of up to 1.7% in second visits. No difference was detected in third visits, while fourth visits had a transient increase of up to 2.6%.

For visits to rheumatologists specifically, the maximal cumulative incidence difference was an increase of 12.8% for first visits and an increase of 12.7% for second visits. No difference was observed in the cumulative incidence of emergency department visits or hospital admissions.

Other changes were minor or transient, including a transient increase (up to 3%) in first and second refills of etanercept during followup. There was no difference in third and fourth refills. By the end of the transition, 65.1% (1102) of the patients in the policy cohort had switched to a biosimilar, and 88.1% (1493) had done so by the end of a 1-year followup period.

The investigators noted different findings on health services use in similar studies of non-medical switches to biosimilars, many of which focused on treatment discontinuation. A Danish study found that the use and costs of outpatient services increased after switching to biosimilar etanercept, while costs of admissions and drugs decreased.

Studies of switches to biosimilar infliximab have found increased visits to physicians, including an 83% increase to rheumatologists and other specialists in an Italian study, and significantly higher health services costs in outpatient settings in a Turkish study.

“An increase in visits after switching…may have indicated unintended negative impacts of a policy. Further research with a design similar to the Danish studies could provide a better understanding of this change in British Columbia,” the authors wrote.

Fisher A, Kim JD, Carney G, Dormuth C. Rapid monitoring of health services use following a policy to switch patients from originator to biosimilar etanercept-a cohort study in British Columbia. 

2022;6(1):5. Published January 27, 2022. doi:10.1186/s41927-021-00235-x.

Health Canada approved biosimilars Brenzys and Erelzi in August 2016 and April 2017, respectively. The study tracked effects of the first phase of the British Columbia Ministry of Health’s Biosimilar Initiative, which required patients to switch to biosimilars starting in May 2019.

Making Patients in Canada Switch to Etanercept Biosimilars Caused No Harm or Changes in Health Care Use, Study Finds

Meir Rinde, MS, is a freelance print and radio journalist based in Philadelphia, Pennsylvania.

Meir Rinde, MS

Corey Greenblatt, MPH, is the manager of policy and advocacy of CreakyJoints and The Global Healthy Living Foundation. The Global Healthy Living Foundation is a 501(c)(3) non-profit organization whose mission is to improve the quality of life for people living with chronic illnesses (such as arthritis, osteoporosis, migraine, diabetes, psoriasis, and cardiovascular disease) by advocating for improved access to health care at the community, state, and federal levels, and amplifying education and awareness efforts within its social media framework. The Global Healthy Living Foundation is the parent organization of CreakyJoints, the digital community and advocacy organization for millions of arthritis patients and caregivers worldwide who seek education, support, advocacy, and patient-centered research through ArthritisPower, the first-ever patient-centered research registry for joint, bone, and inflammatory skin conditions. Visit 

Corey Greenblatt, MPH

Last week the US Food and Drug Administration (FDA) issued a revised draft guidance detailing its policies on mixing, diluting, and repackaging certain types of biological products outside of the scope of an approved biologics license application (BLA).

Diluting or mixing a biological product with other components, or repackaging a biological product by removing it from its approved container-closure system and transferring it to another container-closure system, in the absence of manufacturing controls, is highly likely to affect the safety and/or effectiveness of the biological product. The FDA says even minor manipulations of biologics can result in quality or safety issues due to their unique properties.

There are instances where appropriate to mix or dilute a biological product to meet the needs of specific patients. "For example, for some biological products there is no licensed pediatric strength and/or dosage form, so the product is diluted for use in pediatric patients." While there are exemptions from certain federal regulations for compounded drugs under sections 503A and 503B of the 

, these exemptions do not apply to biological products licensed under sections 351(a) or (k) of the 

In accordance, the FDA says that any biological product that is mixed, diluted, or repackaged outside the scope of an approved BLA is an "unlicensed biological product." It also does not intend to take actions for violations of section 351 of the PHS Act or sections 502(f)(1) or 582 of the FD&C Act if a state-licensed pharmacy, a federal facility, or an outsourcing facility mixes, dilutes, or repackages a biological product" in accordance with the guidance.

The guidance does not apply to investigational new drugs being studied under a new drug application or radioactive biological products.

Biologics Mixing, Diluting, and Repackaging: FDA Draft Guidance

Daniella (Dee) Latham

David T. Rubin, MD, AGAF, is a professor of medicine and section chief of gastroenterology, hepatology, and nutrition at University of Chicago Medicine. He is a fellow of the American Gastroenterological Association (AGA), which represents over 16,000 gastroenterologists worldwide and is dedicated to empowering clinicians and researchers to improve digestive health. He is also chair-elect of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, whose mission is to cure Crohn disease and ulcerative colitis, and to improve the quality of life of children and adults affected by these diseases. AGA is a member of the Biologics Prescribers Collaborative (BPC), an organization comprising medical societies whose members regularly prescribe biologic medicines. BPC strives to ensure that sound policies are in place to promote the safest possible development and use of all biologics, including biosimilars, for all patients.

David T. Rubin, MD, AGAF

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John Bujnoski is Managing Director of Pangea Advisory and Consulting, LLC, a strategic marketing consulting firm focused on the specialty biopharmaceutical and biosimilar market segments. John has extensive global biopharmaceutical industry expertise including extensive knowledge and understanding of the global market environment including pricing, market access, and reimbursement systems.

John Bujnoski

Safaraz Niazi, PhD, is an adjunct professor of biopharmaceutical Sciences at the College of Pharmacy at the University of Illinois at Chicago and a patent law practitioner. Additionally, he is the founder and executive chariman at Pharmaceutical Scientist, Inc, the executive chairman of Karyo Biologics, and the founder of Adello Biologics, which was acquired by Kashiv Biosciences in 2019. Niazi also serves on the advisory board for The Center for Biosimilars®.

Sarfarzaz K. Niazi

George C. Yu, JD, is a partner in the Intellectual Property group of Schiff Hardin LLP. He is an experienced patent attorney who focuses his practice focuses on patent infringement litigation and counseling and has worked in private practice and in-house positions. George has litigated patents relating to recombinant proteins, monoclonal antibodies, microarray technology, and small molecule therapeutics. George has advised companies developing novel biologics as well as biosimilars on patent strategy.

Authors