Biosimilar Patents

The Biologics Price Competition and Innovation Act (BPCIA) of 2010 created a framework for biosimilar approval: WHAT IS A BIOSIMILAR: a biological product that is highly similar to an already-approved reference biological product (the 'reference product sponsor's' product); biologics are large, complex molecules (proteins, antibodies, vaccines) made from living cells; unlike small-molecule generics, biosimilars cannot be exactly identical to the reference product; BPCIA SECTION 351(k): added to the Public Health Service Act; allows an applicant to file a 351(k) application that relies on FDA's prior approval of a reference product; the applicant must demonstrate: biosimilarity (highly similar notwithstanding minor differences in inactive components; no clinically meaningful differences in safety, purity, potency); OR interchangeability (can be substituted for the reference product without physician involvement at the pharmacy level — higher standard); REFERENCE PRODUCT EXCLUSIVITY: 12-YEAR DATA EXCLUSIVITY: reference biological products receive 12 years of data exclusivity from first licensure; no 351(k) biosimilar application can be approved until 12 years after the reference product's first licensure; 4-YEAR FILING EXCLUSIVITY: no 351(k) application may be filed until 4 years after first licensure of the reference product; INTERCHANGEABILITY EXCLUSIVITY: the first biosimilar applicant to receive interchangeability designation gets exclusivity: one year after first commercial marketing; or 18 months after a final court decision or dismissal of all infringement suits; whichever comes first; COMPARISON TO HATCH-WAXMAN: Hatch-Waxman = 5-year small-molecule data exclusivity; 180-day first ANDA filer exclusivity; BPCIA = 12-year data exclusivity; 1-year interchangeability exclusivity; generally longer exclusivity periods.

The patent dance is BPCIA's structured patent dispute resolution process — a multi-step information exchange before any infringement litigation: STEP 1 — NOTICE OF APPLICATION: within 20 days of FDA accepting the 351(k) application, the biosimilar applicant must notify the reference product sponsor (RPS) that a 351(k) application has been filed; STEP 2 — EXCHANGE OF APPLICATION INFORMATION (§ 262(l)(2)): the biosimilar applicant provides the RPS a copy of the 351(k) application and information about the manufacturing process; this is highly confidential; the RPS uses it to identify relevant patents; STEP 3 — RPS'S LIST OF PATENTS (§ 262(l)(3)(A)): within 60 days of receiving the application, the RPS provides a list of patents they believe could reasonably be asserted against the biosimilar; STEP 4 — BIOSIMILAR APPLICANT'S RESPONSE (§ 262(l)(3)(B)): within 60 days after receiving the RPS list, the biosimilar applicant provides: a detailed statement describing on a claim-by-claim basis why each RPS patent is invalid, unenforceable, or will not be infringed; OR a statement that the applicant does not intend to market the biosimilar before the patent expires; STEP 5 — RPS'S RESPONSE: within 60 days, the RPS provides its own detailed statement for each patent on which it disagrees with the applicant's positions; STEP 6 — NEGOTIATION OF PATENTS FOR LITIGATION (§ 262(l)(4)): the parties must negotiate in good faith to agree on which patents will be the subject of the first infringement suit; if no agreement, each side provides a list; STEP 7 — FIRST SUIT: the RPS brings an immediate patent infringement action within 30 days on the agreed-upon (or listed) patents; AMGEN v. SANDOZ (S.Ct. 2017): participation in the patent dance is optional (not mandatory) for biosimilar applicants; but if the applicant opts out, the RPS can immediately seek a preliminary injunction.

The BPCIA requires advance notice before biosimilar commercial launch, creating unique timing considerations: 180-DAY NOTICE REQUIREMENT (§ 262(l)(8)): the biosimilar applicant must provide the reference product sponsor with notice at least 180 days before the date of first commercial marketing; this notice triggers the window for the RPS to seek a preliminary injunction if patents remain unresolved; PURPOSE: gives the RPS time to seek emergency injunctive relief; allows patent disputes to be resolved before commercial launch creates market disruption; AT-RISK LAUNCH: a biosimilar applicant may launch commercially 'at risk' — before all patent disputes are resolved; this is called 'at-risk' because if the RPS wins the infringement litigation, the biosimilar company faces damages for sales during the at-risk period; PRACTICAL CONSIDERATIONS FOR AT-RISK LAUNCH: is there a final judgment against the biosimilar applicant? (if not, launch may be possible); does the relevant patent have strong validity? (is it likely to survive IPR challenge?); what is the financial exposure from royalties vs. the market opportunity of early launch?; how quickly would an injunction be sought and granted?; PRELIMINARY INJUNCTION STANDARD: the RPS must show: likelihood of success on the merits (likely to prove infringement and patent validity); irreparable harm; balance of hardships; public interest; at-risk launch by a biosimilar applicant can create irreparable harm arguments (market share loss; price depression); BUT courts have sometimes denied preliminary injunctions against biosimilar launches where the public interest (access to cheaper biologics) is significant; COVID-19 VACCINES: BPCIA framework applies to vaccines and monoclonal antibodies — categories growing in importance post-pandemic.

Biologics and small-molecule drugs have fundamentally different patent strategy environments: STRUCTURAL DIFFERENCES: small molecules: defined chemical structure; precisely replicable; generic ANDA applicant can make identical molecule; biologics: complex protein/antibody structures; made from living cells; impossible to make exact copy; biosimilar = highly similar but not identical; PATENT PORTFOLIO DIFFERENCES: small molecules: typically 3-5 patents (composition-of-matter; formulation; method-of-use); Hatch-Waxman ANDA triggers clear patent identification via Orange Book; biologics: can have dozens of patents across: composition-of-matter (protein sequence, structure); manufacturing process (cell line, fermentation, purification); formulation; dosing regimen; device (autoinjector, pen); different indications; patent thickets — overlapping patents extending exclusivity well beyond data exclusivity; EVERGREENING IN BIOLOGICS: biologics companies commonly extend protection through patent thickets; example: AbbVie's adalimumab (Humira) — over 130 patents filed; exclusivity extended well beyond the 12-year data exclusivity; BIOSIMILAR APPLICANT STRATEGY: IPR challenges on blocking patents; design-around manufacturing process; negotiate patent licenses; wait for data exclusivity to expire; challenge composition patents through IPR before filing 351(k); MANUFACTURING PROCESS PATENTS: a key difference from small molecules; the RPS's cell line and manufacturing process may be patented; the biosimilar must develop its own process — patents on specific process steps may be asserted; INTERNATIONAL DIFFERENCES: EU pathway: similar biosimilar framework via EMA guidelines; data exclusivity: 8 years; market exclusivity: 10+1 years; Japan: similar biosimilar pathway; India: robust biosimilar market with simpler approval process.

Interchangeability is the highest standard for biosimilar designation, with significant commercial and IP implications: INTERCHANGEABILITY STANDARD (§ 262(k)(4)): a biosimilar is interchangeable if it: meets the biosimilarity standard; AND can be expected to produce the same clinical result as the reference product in any given patient; AND the risk of switching or alternating between the biosimilar and the reference product does not pose a greater safety or efficacy risk than using the reference product without such switching; INTERCHANGEABILITY DESIGNATION PROCESS: requires additional clinical studies demonstrating safety with switching (switching study); higher burden than simple biosimilarity; FDA has approved multiple interchangeable biosimilars since 2021; COMMERCIAL SIGNIFICANCE OF INTERCHANGEABILITY: allows pharmacists to substitute the biosimilar for the reference product WITHOUT physician intervention (subject to state law); states have laws governing substitution — most allow interchangeable substitution; non-interchangeable biosimilars require physician prescribing or express authorization for substitution; automatic substitution = dramatic market uptake improvement; INTERCHANGEABILITY EXCLUSIVITY: the first interchangeable biosimilar gets an exclusivity period: 1 year after first commercial marketing; OR 18 months after resolution of all infringement litigation with the reference product sponsor; OR 42 months if patent litigation is ongoing; this exclusivity protects the first interchangeable from other interchangeable biosimilars (but NOT from other non-interchangeable biosimilars); STRATEGIC IMPLICATIONS: racing to interchangeability can be worthwhile — the commercial advantage of pharmacy substitution is large; but the additional clinical burden and the interchangeability exclusivity must be weighed against the cost of the switching studies; FORMULARY PLACEMENT: payers (insurance, PBMs) also influence biosimilar uptake through formulary placement; interchangeability is not the only driver of market share.