On November 20, 2020, the U.S. Food & Drug Administration (“FDA”) released a Q&A-format draft guidance to address four questions regarding the submission of biologics license applications (BLAs) and labeling for interchangeable biosimilar products. 85 FR 74345 (“Draft Guidance”). The Q&As in the Draft Guidance will be finalized by adding them as a revision to the final guidance document, Questions and Answers on Biosimilar Development and the BPCI Act. A biosimilar product is one that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. Section 351(i)(2) of the Public Health Service Action (“PHS Act”). An interchangeable product is one that is shown to meet the standards described in section 351(k)(4), means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. Section 351(i)(3). To date, the only known BLA under review for a proposed interchangeable biosimilar product is Boehringer Ingelheim’s BLA for an Adalimumab to be interchangeable with Abbvie’s Humira®. As more applicants file interchangeability BLAs and the FDA gains more experience with interchangeable biosimilars, the FDA intends to provide additional recommendations in future guidance documents.

The four Q&As addressed in the Draft Guidance are summarized as follows:

  1. How may the applicant seek FDA review for licensure for an interchangeable biosimilar, and how does FDA intend to review the application?

To seek FDA review for licensure for an interchangeable biosimilar, the applicant must submit a BLA under section 351(k) of the PHS Act with an affirmative statement in the cover letter indicating that the product meets the standards described in section 351(k)(4) for licensure as an interchangeable biosimilar or clearly requesting “INTERCHANGEABLE-ONLY REVIEW.”

If an applicant includes a statement for 351(k)(4) licensure, the FDA will evaluate the BLA as both an application for licensure of a biosimilar product and an application for licensure of an interchangeable biosimilar. If the application then only supports licensure of the product as a biosimilar product but not an interchangeable biosimilar, the FDA will split the action for administrative purposes. By splitting the action, the FDA could license the product as a biosimilar product and then convey any deficiencies in the application for licensure as an interchangeable biosimilar. The FDA could then make a later determination of interchangeability for the product upon submission of a supplement of additional data.

If the applicant requests interchangeable-only review, the FDA’s complete response letter will address any deficiencies of both interchangeability and biosimilarity because biosimilarity is a condition necessary for approval of a 351(k) BLA as an interchangeable product. However, the response letter will not address whether the application is sufficient to support a demonstration of licensure as a biosimilar product alone, as per the applicant’s request. If the application can support biosimilarity, but not interchangeability, the applicant may choose to amend and resubmit the application to address the deficiencies to support a demonstration of interchangeability or to amend and resubmit the BLA seeking licensure as a biosimilar product.

  1. How should a 351(a) BLA holder proceed if it seeks licensure of its biological product under section 351(k) as biosimilar to or interchangeable with another biological product licensed under section 351(a) (a “reference product”)?

For licensure of a proposed biological product as a biosimilar product, the applicant should submit an original application under section 351(k) of the PHS Act. For licensure of a proposed biological product as an interchangeable biosimilar product, the applicant should submit either an original application under section 351(k) of the PHS Act or a supplement to an approved application submitted under section 351(k) of the PHS Act. An applicant may, however, support a demonstration of biosimilarity or interchangeability under section 351(k) using relevant data and information from the applicant’s own 351(a) BLA for the reference product.

The Draft Guidance clarifies that it is not necessary for the holder of a 351(a) BLA for a biological product licensed or deemed licensed under section 351(a) to seek revocation of its 351(a) license in order to submit a 351(k) application. The 351(a) BLA holder may continue to market the reference product licensed or deemed licensed under section 351(a) while the 351(k) BLA is pending and after licensure of the biological product under section 351(k).

  1. Does FDA have recommendations for labeling of interchangeable biosimilars at this time?

Yes – the Draft Guidance explains that certain principles outlined in the FDA’s July 2018 Guidance for Industry: Labeling for Biosimilar Products (“Biosimilar Labeling Guidance”) also pertain to interchangeable biosimilar products.

Specifically, interchangeable biosimilar product labeling, like biosimilar product labeling, should incorporate relevant data and information from the reference product labeling, including clinical data that supported the FDA’s finding of safety and effectiveness of the reference product. As explained in the Biosimilar Labeling Guidance, labeling should not include a description of or data from clinical studies conducted to support a demonstration of biosimilarity or interchangeability because such studies would typically not be expected to facilitate an understanding of product safety and effectiveness.

Interchangeable biosimilar labeling should meet the content and format requirements of the physician labeling rule (PLR) as described in 21 CFR 201.56(d) and 201.57, as well as the final pregnancy and lactation labeling rule (PLLR) as described in 21 CFR 201.57(c)(9)(i)-(iii). Interchangeable biosimilar labeling should also follow the Biosimilar Labeling Guidance for revising biosimilar product labeling and submitting initial and revised labeling.

The Draft Guidance highlights certain differences between interchangeable biosimilar and reference product labeling. For example, interchangeable biosimilar product labeling conforming to PLR and/or PLLR may deviate from reference product labeling because the reference product labeling may not be required to conform to those requirements at the time of licensure of the interchangeable biosimilar. The interchangeable biosimilar product labeling may also differ from the reference product labeling if an applicant choses to seek licensure of the interchangeable biosimilar for fewer than all of the reference product’s licensed conditions of use.

  1. Does FDA recommend that the BLA-holder of an approved interchangeable biosimilar include a labeling statement on interchangeability?

Yes – a statement should be placed on the line immediately beneath the Initial U.S. Approval in the Highlights of Prescribing Information stating that the product is interchangeable with the reference product.


By addressing these questions, the FDA hopes to “enhance transparency and facilitate the development and approval of biosimilar and interchangeable products.” Comments and suggestions regarding the Draft Guidance should be submitted to the FDA by January 19, 2021.

On November 18, 2020, companies Samsung Bioepis Co., Ltd. and Biogen Inc. announced that the United States Food and Drug Administration (“FDA”) accepted for review the Biologics License Application for SB11, a proposed biosimilar referencing Genentech, Inc. product Lucentis® (ranibizumab).  Ranibizumab is an anti-VEGF (vascular endothelial growth factor) therapy for retinal vascular disorders, which are a leading cause of blindness in the United States.  SB11 is one of two opthamology biosimilar candidates jointly developed by Samsung Bioepis and Biogen in the U.S., Canada, Europe, Japan, and Australia, the other being aflibercept (“SB15”).  SB11 was accepted for review last month by the European Medicines Agency.

“The FDA filing acceptance for SB11 brings us a step closer to our goal of being able to offer affordable treatment options for people with retinal vascular disorders,” said Hee Kyung Kim, Senior Vice President and Clinical Sciences Division and Regulatory Affairs Team Leader at Samsung Bioepis.  Ian Henshaw, the Senior Vice President and Global Head of Biosimilars at Biogen, stated that SB11 and other biosimilars, “aim[] to ensure sustainability of healthcare systems by offering broader patient access to effective and more affordable treatment options.”

If approved, SB11 will join a Samsung Bioepis and Biogen biosimilar portfolio that includes three widely prescribed anti-TNF biosimilars in Europe: Benepali® (etanercept), ImraldiTM (adalimumab), and Flixabi® (infliximab).

Mark your calendars – on December 9th, the Federal Circuit is slated to hear oral arguments as to whether two Amgen patents claiming a genus of antibodies meet the enablement requirement of 35 U.S.C. § 112. The court’s decision may have a considerable impact on antibody-based drug development and the scope of patent protection available for antibody innovations.

In one corner, there’s Amgen, backed by amici Bristol-Myers Squibb and Merck. In the other, we have Sanofi and Regeneron, supported by amici Eli Lilly and Pfizer. The tension has been building since 2014, when Amgen sued Sanofi and Regeneron for patent infringement of two patents (U.S. Patent Nos. 8,829,165 and 8,859,741) drawn to a class of drugs called PCSK9 inhibitors (and covering Amgen’s cholesterol-lowering drug Repatha). While the defendants conceded infringement, the validity of the patents was brought into question, and following a years-long legal rollercoaster, Amgen is now challenging U.S. District Judge Richard G. Andrews’s decision invalidating the patents for lack of enablement.

In his August 2019 ruling, Judge Andrews found that the Amgen patents claimed a “vast” class of antibodies, and that it would take “undue experimentation” to practice the full scope of the invention. Specifically, he explained that the claims were directed to a large genus of antibodies (Amgen says the genus comprises about 400 distinct antibodies; Sanofi argues the number is actually in the millions), but the written description only specified a small fraction of the species that fell within that genus. With a substantial gap between the number of potential and actual species, and a lack of significant guidance or direction in the patent to a person of ordinary skill in the art on how to predict whether an antibody will bind to specific PCSK9 residues, Judge Andrews concluded that the claims were not enabled under Section 112.

The question of antibody genus patentability raises unique challenges considering the industry of big pharma and the research and development efforts that goes into antibody-based drugs. On one hand, antibody development has been described as extremely costly, complex, unpredictable, and time-consuming, such that it makes more sense for a company to seek patent protection for the genus as soon as they have a discernible universe of antibody species. But on the other hand, as Sanofi argues, allowing such broad claims to antibodies not actually discovered may be just a strategic means to stifle competition.

Could the outcome of this case ultimately threaten antibody innovation? Or will companies just have to get more creative with patent claims? Stay tuned for a summary of the Federal Circuit oral arguments and predictions about the case moving forward in a follow-on December post.

In Valeant Pharmaceuticals North America LLC v. Mylan Pharmaceuticals Inc., No. 2019-2402 (Fed. Cir. Nov. 5, 2020), the Federal Circuit clarified the venue analysis of 28 U.S.C. § 1400(b), which controls venue for patent infringement cases.  Section 1400(b) provides that an action for patent infringement may be brought in the judicial district where the defendant resides (i.e., its state of incorporation), or where the defendant has committed acts of infringement and has a regular and established place of business.[1]

The Valeant case analyzes where “acts of infringement” occur in Hatch-Waxman litigation initiated based on the filing of an Abbreviated New Drug Application (“ANDA”) and before launch of the generic drug product.  The case involves issues similar to those that will arise in cases brought under the Biologics Price Competition and Innovation Act (“BPCIA”), where litigation is initiated based on the filing of an abbreviated biologics license application (“aBLA”) and before the launch of a biosimilar product.

The Valeant litigation arose from an ANDA filed by Mylan seeking approval to market a generic version of Jublia®, a medication to treat fungal infections of toenails.  Valeant filed suit against Mylan in the District of New Jersey, alleging infringement of Orange Book listed patents pursuant to the Hatch-Waxman Act.  Mylan sought dismissal for improper venue because the defendants do not have a regular and established place of business in New Jersey and the only alleged act of infringement—submission of the ANDA—did not occur in New Jersey.  The district court granted the motion and dismissed the complaint.  Valeant appealed.

The Federal Circuit characterized its issues as determining: (1) proper venue in Hatch-Waxman cases after TC Heartland, and (2) proper venue for patent cases brought against foreign entities.  Because the defendants were not incorporated in New Jersey, the court proceeded to determine “where the defendant has committed acts of infringement,” as § 1400(b) requires.

Under the Hatch-Waxman Act, submitting an ANDA for a drug claimed in a patent is an act of infringement.  The court recognized that there has been inconsistent interpretation by the district courts over whether future distribution of the generic drug is contemplated in the act of infringement.  In rejecting venue as proper in all judicial districts where a generic is likely to be distributed, the court noted the past tense requirement of the venue statute, “the defendant has committed acts of infringement,” as well as the speculative nature of future distribution allegations.  Despite the strong policy considerations argued by Valeant to take a broader approach, the statute was not ambiguous.  Venue is proper only in those districts that are sufficiently related to the ANDA submission.

The court did not elaborate on what acts would be required to be sufficiently related to the ANDA submission, but nothing suggested any acts occurred in New Jersey, so venue was not appropriate there.  Mylan sent the ANDA from its West Virginia corporate office to the FDA in Maryland.  Regardless of sending the ANDA, venue in West Virginia would have been appropriate because Mylan is incorporated there.  The court declined to determine whether the ANDA submission to the FDA in Maryland would make venue there appropriate.

On the issue of venue in cases against foreign defendants, the Federal Circuit remanded the district court’s dismissal of one defendant, Mylan Laboratories Ltd. (“MLL”).  MLL is an Indian corporation, and therefore, subject to venue in any judicial district.  Dismissal of MLL in the lower court for improper venue was incorrect, but the Federal Circuit remanded for the district court to determine whether MLL was sufficiently involved with the submission of the ANDA to overcome its 12(b)(6) motion to dismiss.

[1] See TC Heartland LLC v. Kraft Foods Grp. Brands LLC, 137 S. Ct. 1514 (2017).

The world-wide market share of biologic drugs is advancing at a staggering pace, with some estimates ranging from $ 300 billion to $452 billion in revenue within the next five years.[1],[2],[3]  The treatment costs for patients administered biologic drugs are very high relative to historic drug prices.  The one year average treatment costs for patients ranges from $20,000 – $30,000[4], but can be as much as $100,000 per year[5].

The high cost of biologic drugs has motivated governments and regulatory agencies to facilitate entry of biosimilars – generic versions of biologic drugs – into the respective markets in order to increase competition and reduce costs.  However, as reported here in our post tracking ongoing biosimilar approvals in the U.S. and Europe, as of October 12, 2020, the U.S. had approved only 28 biosimilar drugs compared to 70 approved biosimilars in Europe.  While European biosimilar approvals outpace those in the U.S., biologic drug prices remain high throughout the world[6].

To understand the key challenges limiting biosimilar entry, a recent study published in Nature Biotechnology[7] provides a qualitative study of biosimilar manufacturer and regulator perceptions on intellectual property and abbreviated approval pathways through a series of interviews with various stake-holders and regulatory officials in the U.S. and Europe.  Participants in the study identified regulatory hurdles and patent thickets as the two most significant factors impacting biosimilar development and market entry[8].

Although the branded biologic product provides biosimilar manufacturers with a starting point for development of a biosimilar version, biosimilar development remains a substantial challenge for drug manufacturers.  For example, in the U.S., biosimilar product sponsors must show that, to the extent the scope of the mechanism of action of the reference product are known, the biosimilar candidate drug utilizes the same mechanism of action for the approved conditions using the same route of administration, dosage form, and strength of the reference product.[9]  The regulatory requirements must be met amidst the backdrop of greater complexity in the manufacturing process.  In particular, different cell lines and variations in cell feed/growth conditions can result in a final product that varies both in structure and purity from the reference product.  Moreover, numerous downstream purification and stabilization requirements enhance the complexity of the process needed to produce an approved product.  As a result, a significant number of developmental and regulatory steps are needed for marketing approval of biosimilar versions of biologic drugs.

Biosimilar manufacturers report being encumbered by uncertainty about what studies are required to show biosimilarity and how regulators expect those studies to be conducted to satisfy the various regulatory agencies.[10]  Yet, such ambiguity may be intentionally baked into the regulatory process.  On the other hand, interviews with regulatory officials explain that ambiguity in the guidelines prevents manufacturers from repeating old methods that may be outdated and instead allow room for innovative new methods to meet approval guidelines.[11]

Biosimilar manufacturers often concurrently seek approval in both the U.S. and Europe and must navigate differing regulatory requirements and expectations.  The U.S. and Europe, in some cases, require different analyses, including distinct statistical treatments, which can affect study outcomes.[12]  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.  As a result, biosimilar manufacturers are forced to meet different study requirements and stringency between regulatory agencies and often heightened standards compared to standards required for originator manufacturers. Thus, even though biosimilar manufacturers avoid a significant portion of the basic research costs, challenges still reside in developing and refining chemistry, manufacturing, and control (CMC) processes, as well as in conducting studies to establish that the biosimilar drug has sufficiently similar efficacy, animal and clinical pharmacology, and stability profile as the reference product.

The other key challenge cited by biosimilar manufacturers is navigating the large patent portfolios that are often built around biologic drugs.[13]  So-called “patent thickets” arise when drug manufacturers take advantage of numerous aspects, including, to name just a few, aspects of processes for manufacturing, different treatment indications, delivery methods, delivery devices, excipients, and aspects relating to side effects, impurities, and pharmacology to create a web of patents that deter biosimilar manufacturers from developing competing versions.  Famously, AbbVie protected its adalimumab biologic (Humira®) with over 100 patents directed to the biologic itself along with numerous parts of the manufacturing process, formulation, and uses, and has enjoyed a monopoly in marketing adalimumab in the United States since 2002.[14],[15]

A recent study comparing the three best-selling biologic drugs in 2018, i.e., Humira®, Enbrel®, and Rituxan®, versus the three best-selling small molecule drugs in 2018, i.e., Revlimid®, Eliquis®, and Lyrica®, found that the biologics were each covered by an average of 93 patents, while, in contrast, the small molecule drugs were each covered by an average of 41 patents.[16]  In fact, the study found that in comparing core patents, i.e., patents that are most likely to block entry of a generic drug maker, for example, an FDA approved use of the drug, the biologic drugs were each covered by an average of 47 core patents whereas the small molecule drugs were each covered by an average of only 13 core patents.[17]

Creating patent thickets surrounding biologic drugs is viewed as a deliberate attempt to block generic/biosimilar competition for as long as possible.  As an example, the price of Humira® in the U.S. doubled from about $19,000 in 2014 to about $38,000 in 2018 after applying available drug rebates.[18]  Moreover, AbbVie successfully thwarted biosimilar entry for years and eventually settled litigations with numerous biosimilar manufacturers to delay biosimilar competition until 2023.  As a result, AbbVie became the first company to face a “patent thicket” antitrust lawsuit over its patenting practices and assertions of its patents.[19]  While the complaint alleged that AbbVie improperly extended its exclusivity out to 2023, which is the earliest expected entry date of generic versions of Humira® to enter the U.S. market, the district court judge sided with AbbVie and held that “even when considered broadly and together for their potential to restrain trade – [the Plaintiffs’ allegations] fall short of alleging the kind of competitive harm remedied by antitrust law.”[20]

Biosimilar manufacturers note that some of the cost and uncertainty involved in navigating patent thickets could be addressed by requiring reference product sponsors to list all patents protecting their biologic products in the FDA’s purple book, an analog of the Orange Book, which would also make it easier to identify the patents that would need to be overcome or avoided in order to launch a biosimilar product[21].  By providing a searchable patent list, biosimilar manufacturers would be better situated to develop manufacturing and control (CMC) processes that can avoid process claims that protect manufacturing of the reference product.  Such lists would also clarify exclusivity timelines, making it easier and cheaper for biosimilar manufacturers to decide when and how to enter the regulatory process.

A bill introduced in the U.S. House of Representatives and Senate aims to require licensed biologic drug manufacturers to disclose all patents believed to be covering the drug.[22]  Both versions of the bill would require the list to provide (1) the official and proprietary name of the biological product; (2) the patents the license holder holds that would be infringed by making, using, offering to sell, selling, or importing into the United States of the biological product; (3) whether various market exclusivity periods apply to the product; and (4) information about whether the product is interchangeable with another biologic product.  Each bill would also require the Department of Health and Human Services (HHS) to make the information available to the public.  Notably, the current versions stipulate that if a patent that should have been listed was not timely disclosed to HHS, the patent holder would be estopped from asserting that patent in litigation.

Increasing market participation by biosimilar manufacturers is a critical component of the overall price reduction strategy for biologic drugs.  Comments from regulatory officials and stakeholders suggest that steps to achieve greater clarity and guidance for the biosimilar marketing approval process and requiring lists of patents protecting biologic products will help to achieve this goal.  Regulatory officials need to take steps to streamline and expedite the approval process and provide much needed guidance to biosimilar manufacturers without diminishing the flexibility needed to adequately assess each biosimilar seeking approval.  Likewise, policy makers can enhance efficiency and transparency by mandating patent lists as in the proposed Biologic Patent Transparency Act to facilitate entry of biosimilar versions of approved biologic drugs.  These foundational improvements will make the biosimilar approval and commercialization pathway more efficient and predictable.

[1] https://www.grandviewresearch.com/press-release/global-biologics-market

[2] https://www.verifiedmarketresearch.com/product/biologics-market/#:~:text=Biologics%20Market%20Size%20And%20Forecast,3.0%20%25%20from%202019%20to%202026.

[3] https://www.iqvia.com/insights/the-iqvia-institute/reports/advancing-biosimilar-sustainability-in-europe

[4] Gu, T., Shah, N., Deshpande, G., Tang, D. H., & Eisenberg, D. F. (2016). Comparing Biologic Cost Per Treated Patient Across Indications Among Adult US Managed Care Patients: A Retrospective Cohort Study. Drugs – real world outcomes3(4), 369–381. https://doi.org/10.1007/s40801-016-0093-2

[5] Evens, R. P. (2016). Pharma success in product development—does biotechnology change the paradigm in product development and attrition.

[6] Roy  A. Biologic medicines: the biggest driver of rising drug prices. Forbes. Published 2019. Updated March 8, 2019. Accessed March 15, 2020

[7] Druedahl, L.C., Almarsdóttir, A.B., Kälvemark Sporrong, S. et al. A qualitative study of biosimilar manufacturer and regulator perceptions on intellectual property and abbreviated approval pathways. Nat Biotechnol 38, 1253–1256 (2020). https://doi.org/10.1038/s41587-020-0717-7

[8] Druedahl, L.C., et al. at p.1253.

[9] 42 U.S.C. § 262(k)(2)(A)(i)(II)-(IV).

[10] Druedahl, L.C., et al. at p.1254.

[11] Ibid.

[12] Ibid.

[13] Druedahl, L.C., et al. at p.1253.

[14] In re: Humira (Adalimumab) Antitrust Litig., No. 19-VC-1873 (N.D. Ill. consolidated Jun. 4, 2019)

[15] Joe Cahill, Taking Aim at Humira’s Patent Fortress, CRAIN’S CHI. BUS. (Mar. 01, 2019), https://www.chicagobusiness.com/.

[16] Wu, J., & Cheng, C. W. C. (2019). Into the Woods: A Biologic Patent Thicket Analysis. Chi.-Kent J. Intell. Prop., 19, 93.

[17] Ibid.

[18]LUTHI, S (March 19, 2019), AbbVie sued over Humira ‘patent thicket’. Retrieved from https://www.modernhealthcare.com/politics-policy/abbvie-sued-over-humira-patent-thicket.

[19] Overley J. (March 27, 2019), “’Groundbreaking’ AbbVie Suits Test Bold Anti-Generic Tactics.” Retrieved from https://www.law360.com/articles/1055075.

[20] In Re: Humira (Adalimumab) Antitrust Litigation, No. 19-cv-01873, Slip. Op. (N.D. Ill. Jun. 8, 2020).

[21] Druedahl, L.C., et al. at p.1255.

[22] S.659 and H.R.4850: Biologic Patent Transparency Act

In the context of Immunex’s patent on IL-4 antibodies, the Federal Circuit says yes.

On October 13, 2020, the Federal Circuit affirmed the Patent Trial and Appeal Board’s (the “Board”) final written decision in IPR2017-01884, holding invalid all claims of U.S. Patent No. 8,679,487 (“the ’487 patent”) assigned to Immunex. The ‘487 patent is drawn to an isolated “human antibody” that binds to the human interleukin-4 (IL-4) receptor in competition with a reference antibody defined by specific heavy- and light- chain variable regions.

The Board found the claims invalid as obvious in view of a reference (Hart) that disclosed a murine antibody that binds IL-4 as required by claim 1, and a reference (Schering-Plough) that teaches humanizing of such murine antibodies by grafting CDRs onto an otherwise fully human antibody. The Board determined that a “humanized” antibody met its construction of “human” antibody, and therefore determined that claims 1-17 of the ‘487 patent were unpatentable as obvious over the cited references.

The issue before the Federal Circuit was whether an isolated “human” antibody is limited to a fully human antibody or further encompass a partially human antibody, including a “humanized” antibody as construed by the Board.

The Federal Circuit first determined that the broadest reasonable interpretation (“BRI”) standard applied, despite the ’487 patent having expired on May 26, 2020, two months prior to the oral argument on appeal. The patent expired early because Immunex filed a terminal disclaimer while the case was on appeal. The court recognized that the Phillips standard has been applied in IPRs where a patent expired on an appeal (citing Apple Inc. v. Andrea Elecs. Corp., 949 F.3d 697, 707 (Fed Cir. 2020)); however, the court distinguished Andrea Electronics, because in that case the patent term expired in its natural course, whereas Immunex’s action abruptly cut short the patent’s term after the parties had fully briefed claim construction under the BRI standard. Therefore, the court found it appropriate to “review the decision from which an appeal is taken on the record before the Patent and Trademark Office.” 35 U.S.C. § 144.

Next, the court determined that the Board did not err in construing the term “human” antibody to encompass not only fully human but also partially human antibodies, based on the intrinsic record. The specification and prosecution history supported the notion that the “human” antibody as claimed encompassed both fully “human” antibody and a partially human antibody. The specification did not include an express definition of “human antibody.” In several instances, however, the specification refers to some “human” antibodies as “fully human” but includes other antibodies in the “human” category. For example, the specification states: “[p]rocedures have been developed for generating human antibodies in non-human animals. The antibodies may be partially human, or preferably completely human.” ‘487 patent at col. 19 ll. 41-44. The court found no “clear and unmistakable” disavowal of partially human embodiments during prosecution. Additionally, the Examiner expressly wrote that the amended “human” antibodies encompassed “humanized” antibodies, yet Immunex made no effort to correct the examiner of this understanding. Accordingly, the court determined that the language of the specification confirms the broadest reasonable interpretation of “human antibodies” as including partially human, “humanized” antibodies, and the prosecution history also supports the Board’s construction. The court gave little weight to the extrinsic evidence because it found the intrinsic record unequivocal.

Lastly, the court addressed the Board’s departure from an earlier district court’s claim construction. Two months prior to oral hearing in the IPR, a district court construed “human” in the context of the ’487 patent to mean “fully human” only. See Immunex Corp. v. Sanofi, No. CV 17-02613 SJO, 2018 WL 6252460, at *12-14 (C.D. Cal. Aug. 24, 2018). Immunex argued that under Power Integration, Inc v. Lee, 797 F.3d 1318, 1326 (Fed. Cir. 2015), the Board had not sufficiently explained why under the BRI standard, it reached a broader construction than that of the district court. However, the Court determined that the “Board’s opinion was sufficiently detailed to permit meaningful appellate review”, under Power Integrations, and concluded that the Board’s construction of the “human” antibody was correct.

There are a number of takeaways from this case. First, a party cannot alter the claim construction standard in an IPR by filing a terminal disclaimer to abruptly shorten the patent term. Second, Power Integrations sets a relatively low bar for the Board to explain why its claim construction under the BRI differs from a district court’s construction. Lastly, it is worthwhile to expressly specify the type of antibody intended in the claims. Further, it is recommended that the specification specifically define terms like “antibody” and “human antibody,” as the court will favor intrinsic evidence over extrinsic evidence of the meaning such terms may have to a person of skill in the art.

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

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

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

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

Teva argued that since it had carved out CHF from its initial 2007 label, citing the carve-out authorization in 21 U.S.C. § 355(j)(2)(A)(viii), it could not be found to induce prescribing physicians to infringe the ’000 patent, at least not before Teva amended its label.  However, the jury found that Teva induced infringement of the ’000 patent both before and after amending its label to add CHF as an indication as required by the FDA.

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

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

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

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

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

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

Updated October 12, 2020

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

As pharmaceutical drug costs attract increasing media attention and political scrutiny, a growing number of biosimilar drugs are set to enter the U.S. and European markets in the coming years.  Global sales for the top ten branded biologic drugs totaled approximately $81 billion in 2019[1].  In a September 2020 report, the IQVIA Institute for Human Data Science estimated biosimilar sales totaling $80 billion over the next five years compared to $14 billion during the previous five years (2015-2019), and that the availability and use of biosimilar medicines would reduce U.S. drug costs by $100 billion through 2024.

In the FDA’s Center for Drug Evaluation and Research’s (CDER) annual report, the FDA highlighted the ten biosimilar approvals in 2019 under the Biologics Price Competition and Innovation Act (BPCIA) of 2009, which was “designed to create competition, increase patient access, and potentially reduce cost of important therapies.”  The FDA’s Biosimilars Action Plan, unveiled in 2018, has been designed to aid the development of a market for biosimilars in order to increase competition for biologic drugs, which make up 40% of U.S. pharmaceutical spending.  Competition in the heavily regulated marketplace for these blockbuster therapeutics is expected to substantially impact the pharmaceutical industry and national health systems.  To date, the U.S. has considerably lagged behind Europe’s expansion of biosimilar drug options.

Since 2005, the biosimilar regulatory framework in Europe has been implemented through the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA).  The CHMP provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by the EMA.  Since Sandoz’s somatotropin biosimilar, Omnitrope®, was first authorized on April 12, 2006, an additional 69 applications have been approved in Europe.  Seven of the authorizations have been withdrawn post-approval (Table 1).

The U.S. did not implement a regulatory framework for biosimilar evaluation until after enactment of the Biologics Price Competition and Innovation Act (BPCIA) of 2009.  Given that the first U.S. biosimilar drug was approved almost a decade after the first in Europe, the number of authorized biosimilar drugs in Europe far exceeds the number of biosimilars approved in the United States.  Sandoz’s filgrastim biosimilar, Zarxio®, received the first U.S. approval in 2015, whereas nine filgrastim biosimilars have been approved in Europe dating back to multiple authorizations in 2008.  Zarxio® (in the U.S.) and Zarzio® (in Europe) are biosimilar to the reference product Neupogen® marketed by Amgen and originally licensed in 1991.  Subsequent to Zarxio®’s approval, 27 other biosimilar drugs have gained U.S. approval to date (Table 2).

As illustrated in the following graph, while the EU’s significant head start led to an imbalance in the number of biosimilar drugs available in the respective markets, the EU’s relatively higher rate of approvals in recent years has widened its lead over the United States, although the U.S. FDA reversed that trend in 2019 with ten approvals.  Through the first nine months of 2020, however, the FDA has only approved two biosimilar products, whereas the EMA has approved eight biosimilar products.  The COVID-19 pandemic has likely shifted regulatory and industry focus to vaccines and therapeutics, thereby causing delays in biosimilar approvals.

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

Currently, eleven biosimilar applications are under review by the EMA for marketing authorization (Table 3).  As an increasing number of patents expire on blockbuster biologic drugs, the number of abbreviated biologics license applications is also increasing.  Biosimilars for more than 26 different original biologics are currently navigating biosimilar pathways or are in late stage development in the U.S. (Table 4).

On February 20, 2020, the FDA redefined the term “biological product” to include all “proteins,” which the rule defines as “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.” Accordingly, the biosimilar and interchangeable pathways are now open to insulin products in the United States.  The EMA already considered insulin a biologic product.  This change by the FDA is expected to lead to additional biosimilar approvals because there are already many biosimilar insulin products approved in Europe, and those biosimilar insulin manufacturers will likely seek to expand into the U.S. market.  In its press release, the FDA explained that it intends “to balance innovation and competition and facilitate the development and approval of biosimilar and interchangeable products. Getting safe and effective biosimilar and interchangeable products approved will help ensure that the market is competitive, and patients may have more affordable access to the treatments they need.”  The FDA approved Mylan’s insulin glargine product SemgleeTM on June 11, 2020, as an equivalent to Sanofi’s Lantus® although it is not considered a biosimilar because approval was under 351(a) of the Public Health Service (PHS) Act (42 U.S.C.. 55. 262(k)).  “We are proud to be the first company, following the reference product, to receive FDA approval on and launch both the vial and pen presentations of an insulin glargine treatment with an identical amino acid sequence to Sanofi’s Lantus,” said Mylan CEO Heather Bresch. She estimated the potential market to be more than 30 million Americans.  In its press release, Mylan stated that it has submitted all necessary documentation to request FDA approval as a biosimilar to Lantus under the 351(k) pathway and “remains confident in seeking an interchangeability designation.”

Table 1. European Medicines Agency List of Approved Biosimilar Drugs (updated October 11, 2020).

Table 2. U.S. Food and Drug Administration List of Approved Biosimilar Drugs.

Table 3. European Medicines Agency List of Biosimilars Under Evaluation for Marketing Approval (Source: EMA list of applications for new human medicines compiled on September 4, 2020 and published on September 9, 2020).

Table 4. Biologics having already expired or nearing primary patent expiry in the U.S. and biologics that have biosimilars in the regulatory pipeline.

[1] Based on sales reported by respective manufacturers (1. Humira—Abbvie ($19.17B), 2. Keytruda—Merck ($11.08B), 3. Eylea—Aflibercept ($7.54B), 4. Opdivo—Bristol-Myers-Squibb ($7.20B), 5.  Avastin—Roche ($7.12B), 6. Rituxan—Roche ($6.52B), 7. Stelara—Johnson & Johnson ($6.36B), 8. Herceptin—Roche ($6.08B), 9. Enbrel—Pfizer/Amgen ($5.23B), 10. Remicade—Johnson & Johnson/Merck ($4.38B).

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

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

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

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

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

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

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

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

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

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