{"id":38837,"date":"2026-06-22T10:52:00","date_gmt":"2026-06-22T14:52:00","guid":{"rendered":"https:\/\/www.drugpatentwatch.com\/blog\/?p=38837"},"modified":"2026-05-11T08:25:45","modified_gmt":"2026-05-11T12:25:45","slug":"formulation-forensics-how-to-reverse-engineer-blockbuster-drug-patents-for-a-competitive-design-around","status":"publish","type":"post","link":"https:\/\/www.drugpatentwatch.com\/blog\/formulation-forensics-how-to-reverse-engineer-blockbuster-drug-patents-for-a-competitive-design-around\/","title":{"rendered":"Formulation Forensics: How to Reverse-Engineer Blockbuster Drug Patents for a Competitive Design-Around"},"content":{"rendered":"\n
\"\"<\/figure>\n\n\n\n

A practitioner’s guide for IP teams, generic manufacturers, and pharmaceutical investors who need to decode what a competitor’s formulation patent actually protects \u2014 and find the legal white space around it.<\/p>\n\n\n\n

The Patent Is a Map, Not a Wall<\/strong><\/h2>\n\n\n\n

Every pharmaceutical patent application begins with the same legal obligation: the inventor must teach the public how to practice the invention. That obligation, encoded in 35 U.S.C. \u00a7 112, is where the competitive opportunity hides. Pharmaceutical companies spend years constructing what patent practitioners call a ‘claims perimeter.’ A smaller number of companies spend equal time reading those claims to find the gaps.<\/p>\n\n\n\n

This guide is for the second group.<\/p>\n\n\n\n

When most pharma professionals see a formulation patent on a blockbuster drug, they treat it as a countdown timer: they wait for it to expire, file an Abbreviated New Drug Application (ANDA) with a Paragraph III certification, and avoid litigation. That is a rational response to an expensive legal system. It is not the only response. A well-executed design-around \u2014 a formulation that achieves the same therapeutic objective without infringing the claims in force \u2014 can put a product on the market years ahead of expiry. In some cases, it produces a better drug.<\/p>\n\n\n\n

The stakes are not abstract. DrugPatentWatch<\/a> tracks over 190 drugs facing loss of exclusivity between 2024 and 2030, representing roughly $300 billion in cumulative annual revenues. The top of that list reads like a pharmacy bestseller shelf: Keytruda at $29.5 billion, Eliquis at $13 billion, Stelara, Opdivo, Ibrance, Jardiance. Every one of these drugs carries multiple formulation patents layered on top of its core composition-of-matter patent. Each of those formulation patents is, structurally, a detailed technical disclosure that describes what the innovator believes makes the product work \u2014 and that description is your starting point.<\/p>\n\n\n\n

This article covers how formulation patents are built, what they really protect versus what their language suggests, and a step-by-step analytical process for identifying design-around opportunities. It works through real cases \u2014 Novartis’s Entresto, Collegium’s Xtampza ER, Amarin’s Vascepa, and AbbVie’s Humira \u2014 where generic and biosimilar manufacturers navigated, circumvented, or demolished formulation barriers. It also covers the legal doctrine that governs when a design-around works and when it creates a new infringement exposure.<\/p>\n\n\n\n

Nothing in this article constitutes legal advice. Design-around analysis requires qualified patent counsel with pharmaceutical science expertise. What this article provides is a technical and strategic framework for understanding the terrain before that counsel engagement begins.<\/p>\n\n\n\n

What a Formulation Patent Actually Protects<\/strong><\/h2>\n\n\n\n

The Three Layers of Pharmaceutical Patent Protection<\/strong><\/h3>\n\n\n\n

A mature blockbuster drug sits under three overlapping layers of patent protection. Understanding each layer is necessary before deciding which to challenge, design around, or wait out.<\/p>\n\n\n\n

The first layer is the composition-of-matter patent. This covers the active pharmaceutical ingredient itself \u2014 its molecular structure, its stereochemistry, often its salt forms. Composition-of-matter patents are the strongest in the pharmaceutical portfolio because they cover the molecule regardless of how it is formulated or used. When the composition patent expires, it expires completely. There is no carve-out for a particular delivery form. These patents typically last 20 years from filing, adjusted for patent term extension under 35 U.S.C. \u00a7 156, which can add up to five years for regulatory delay. This is the patent that defines the primary exclusivity window.<\/p>\n\n\n\n

The second layer is the formulation patent. These patents cover the delivery architecture: how the API is combined with excipients, what physical form it takes (tablet, capsule, suspension, transdermal patch, injectable solution), what release kinetics it exhibits, and what manufacturing processes are required to produce it consistently. Formulation patents are filed after the composition patent, typically during Phase 2 or Phase 3 clinical development when the commercial presentation is being finalized. Because they are filed later, they expire later \u2014 often by five to eight years. That differential is precisely why they matter commercially.<\/p>\n\n\n\n

The third layer is the method-of-use patent. These cover specific therapeutic indications, patient populations, dosing regimens, and treatment protocols. They do not cover the drug itself or how it is made; they cover how it is used clinically. Method-of-use patents are the basis for ‘skinny label’ strategies, where a generic manufacturer accepts FDA approval for a non-patented indication and carves out the patented indications from its label. The Vascepa litigation, discussed in detail later, is the most instructive recent example of where skinny labels succeed and where they create new infringement risk.<\/p>\n\n\n\n

Why Formulation Patents Outlast the Chemistry<\/strong><\/h3>\n\n\n\n

The standard narrative is that formulation patents are secondary \u2014 weaker, later-filed, more vulnerable to obviousness challenges. That narrative is sometimes true and often wrong. A well-constructed formulation patent can be harder to design around than a composition patent, for two reasons.<\/p>\n\n\n\n

First, the person having ordinary skill in the art (PHOSITA) standard for formulation patents is calibrated to a trained pharmaceutical scientist who knows the full toolkit of available excipients, delivery platforms, and processing techniques. If the patented formulation achieves a technically non-obvious result \u2014 a 40% improvement in oral bioavailability, an extended-release profile that prevents dose dumping under fed conditions, an amorphous solid dispersion that stabilizes a highly insoluble BCS Class II compound \u2014 that result provides strong evidence of non-obviousness. Generic challengers who argue ‘obvious to try’ must explain why, from the hundreds of available excipient combinations and processing approaches, a skilled formulator would have arrived at the specific combination claimed.<\/p>\n\n\n\n

Second, some formulation patents create what practitioners call ‘unavoidable infringement.’ If the patented physical form of a drug \u2014 a specific co-crystal, a specific amorphous solid dispersion, a specific polymorphic form \u2014 is the only commercially viable way to manufacture a stable, bioavailable product, a generic manufacturer who wants to produce a bioequivalent product may have no practical path that avoids the claims. The Entresto litigation, centered on the sacubitril-valsartan complex that spontaneously forms during manufacture, is the clearest recent example: Novartis argued, and the Federal Circuit agreed in January 2025, that the complex was necessarily present in any ANDA product based on the approved mechanism of action, even though it had not been described in the original patent filing [1].<\/p>\n\n\n\n

Reading Claim Scope: The Gap Between Language and Protection<\/strong><\/h3>\n\n\n\n

Patent claims use defined legal terms. Every word in an independent claim has been negotiated with a patent examiner, sometimes across years of prosecution history, and that prosecution history defines the outer boundary of the claim’s reach through the doctrine of prosecution history estoppel. A design-around works when your formulation falls outside those boundaries.<\/p>\n\n\n\n

Claim language operates on a spectrum from broad to narrow. Consider a hypothetical independent claim: ‘A pharmaceutical composition comprising [drug X] in an extended-release matrix comprising hydroxypropyl methylcellulose (HPMC) in an amount of 15-35% by weight.’ This claim is limited to HPMC as the release-controlling polymer, in a specific concentration range, in a matrix configuration. A formulator who uses ethyl cellulose instead of HPMC, or who uses HPMC at 12% or 38% by weight, or who uses a membrane-coated pellet system rather than a matrix, has moved outside the literal scope of that claim. Whether that movement also avoids infringement under the doctrine of equivalents \u2014 which extends protection to insubstantial variations \u2014 depends on what the prosecution history shows about why the patentee chose those specific limitations.<\/p>\n\n\n\n

This is where formulation forensics begins: systematic analysis of what the claims actually say, what the prosecution history explains about why they say it, and what formulation alternatives exist outside those boundaries that would still produce a bioequivalent product. Databases like DrugPatentWatch<\/a> aggregate the Orange Book patent listings, prosecution histories, and litigation outcomes for every NDA-listed drug in the United States. A competent design-around analysis starts with that data and works backward through the technical literature.<\/p>\n\n\n\n

The Anatomy of a Formulation Patent: What to Read and Where to Find the Gaps<\/strong><\/h2>\n\n\n\n

Claims: The Legal Perimeter<\/strong><\/h3>\n\n\n\n

The claims section of a patent is the operative legal document. The specification \u2014 the detailed description, the examples, the figures \u2014 exists to support the claims, not to expand them. A sophisticated patent reader starts at the back of the patent (the claims) and reads forward into the specification only to understand what specific claim terms mean.<\/p>\n\n\n\n

Independent claims define the full scope of protection. Dependent claims narrow that scope. For design-around purposes, you want to understand the independent claims precisely. Map every limitation in each independent claim. A limitation is any technical element that must be present for infringement to occur. Remove one limitation \u2014 or substitute an equivalent that falls outside the prosecution-defined scope \u2014 and you have, at minimum, a strong argument for non-infringement.<\/p>\n\n\n\n

When reading claims, watch for four structural patterns that create design-around opportunities:<\/p>\n\n\n\n

Closed Markush groups.<\/strong> A claim that recites ‘wherein the release-controlling polymer is selected from the group consisting of HPMC, HPC, and methylcellulose’ is literally limited to those three polymers. Ethyl cellulose, Eudragit RS, polyvinyl acetate, and xanthan gum are all outside this claim, absent a successful doctrine-of-equivalents argument. Prosecution history often forecloses equivalents arguments for elements that were expressly enumerated.<\/p>\n\n\n\n

Numerical ranges.<\/strong> Claims specifying a parameter range \u2014 ‘wherein the drug:polymer ratio is between 1:2 and 1:4 by weight’ \u2014 define a cliff at each boundary. A ratio of 1:1.9 or 1:4.1 is outside the literal claim. Whether that difference is ‘insubstantial’ under the doctrine of equivalents depends on whether the patentee distinguished prior art formulations that used ratios outside the claimed range. If the patentee argued to the examiner that the claimed range was critical to achieving the inventive result, a court will likely hold that the prosecution history precludes equivalents at the boundaries.<\/p>\n\n\n\n

Process limitations.<\/strong> Some formulation claims recite manufacturing steps as limitations: ‘wherein the tablet is prepared by hot melt extrusion at a temperature of 140-160\u00b0C.’ A product prepared by spray drying, wet granulation, or co-precipitation may fall outside this claim even if it produces an identical physical product. This matters because the FDA evaluates products by their properties, not their process; a bioequivalent product made by a different process can be approved even if the patentee’s process is separately patented.<\/p>\n\n\n\n

Functional claim language.<\/strong> Claims drafted around a result rather than a structure (‘a pharmaceutical composition that releases at least 80% of the drug within 8 hours in simulated intestinal fluid at pH 6.8’) are both powerful and vulnerable. They are powerful because they capture any formulation that achieves the result, regardless of mechanism. They are vulnerable because a challenger who achieves the same result by a mechanism the specification did not contemplate can argue that the written description requirement has not been met \u2014 the patent has claimed more than it disclosed. This argument succeeded against Amgen’s broad functional antibody claims in Amgen v. Sanofi<\/em> in 2023 and is increasingly potent against formulation patents that define protection by outcome rather than structure [2].<\/p>\n\n\n\n

The Detailed Description: The Inventor’s Laboratory Notebook<\/strong><\/h3>\n\n\n\n

The detailed description is where the inventor discloses every formulation iteration that did not work alongside the one that did. For a design-around analyst, the failed experiments are as valuable as the successful ones. A specification that reports ‘attempts to use ethyl cellulose as the sole release-controlling agent produced unacceptable burst release under fed conditions’ is telling you two things simultaneously: ethyl cellulose was tried, and it failed under fed conditions. Whether that failure is inherent to the polymer or an artifact of the specific processing conditions used is a formulation science question worth pursuing.<\/p>\n\n\n\n

The examples section of a formulation patent is particularly dense with usable intelligence. Patent law requires that examples in the specification be ‘reduced to practice’ \u2014 either actually performed or constructively reduced to practice with enough detail that a skilled practitioner could replicate them. Working examples typically contain precise excipient identities, weight percentages, grade specifications (which matter enormously: HPMC K4M behaves differently from HPMC K100M), processing parameters, and dissolution data. A competitor reading this data can construct a design space map of what the patentee tried, what worked within the claimed range, and where the performance boundaries are.<\/p>\n\n\n\n

Pay particular attention to the comparative examples. When a patentee argues non-obviousness by showing unexpected results, those results appear in the specification as comparisons between the claimed formulation and formulations outside the claimed range. These comparisons define the edges of the inventive result and, consequently, the edges of the claims. A formulation that falls outside the comparative range while still meeting the therapeutic performance criteria \u2014 dissolution, bioavailability, stability \u2014 is a design-around candidate.<\/p>\n\n\n\n

Prosecution History: The Negotiated Boundary<\/strong><\/h3>\n\n\n\n

The prosecution history \u2014 the complete record of communications between the applicant and the USPTO examiner during the patent application process \u2014 is a public document. It is available through the USPTO’s Patent Center, and it defines the outer boundary of the claims through prosecution history estoppel.<\/p>\n\n\n\n

When a patent applicant narrows a claim to overcome a prior art rejection, the narrowed element is estopped from later being asserted to cover the surrendered subject matter under the doctrine of equivalents. This is the most important legal concept in formulation design-around work. An applicant who argued during prosecution that ‘our formulation is distinguishable from the HPMC-based matrix disclosed in Smith et al. because we use ethyl cellulose at a specific concentration’ cannot later assert that patent against an ethyl cellulose-based matrix.<\/p>\n\n\n\n

Read every office action and every applicant response in the prosecution history. Examiners frequently cite prior art that defines the technical landscape the applicant had to distinguish from. Applicant responses to those rejections reveal both the legal strategy and the scientific reasoning behind each claim limitation. Those revealed limitations are your design-around map.<\/p>\n\n\n\n

The Orange Book and Patent Term: Mapping the Competitive Window<\/strong><\/h3>\n\n\n\n

Every NDA holder must list in the FDA’s Orange Book all patents that ‘claim the drug or a method of using the drug.’ The Orange Book is the ANDA filer’s first roadmap and, after the FTC’s aggressive delisting campaign between 2023 and 2025, it is less cluttered with device patents than it was two years ago. The FTC challenged over 400 improperly listed Orange Book patents between November 2023 and April 2024 [3], and the December 2024 Federal Circuit ruling ordering Teva to delist five inhaler patents \u2014 followed by Teva’s removal of over 200 listings and a $35 million settlement \u2014 removed a substantial anticompetitive obstruction from the Hatch-Waxman system [4].<\/p>\n\n\n\n

For each Orange Book-listed patent, DrugPatentWatch provides the expiry date, the claim type (composition, formulation, method of use), and the litigation history. The analytical framework recommended by DrugPatentWatch for portfolio evaluation identifies three critical dates: the composition-of-matter expiry, the formulation and method-of-use patent cluster expiry, and the expected date of first ANDA or biosimilar filing. The gap between those three dates, adjusted for litigation probability, defines the commercial window [5]. A drug with a 2027 primary expiry but a formulation cluster extending to 2032 has a five-year design-around opportunity \u2014 or a five-year litigation risk, depending on which side of the negotiating table you sit on.<\/p>\n\n\n\n

\n

‘The pharmaceutical industry spent roughly $260 billion on R&D globally in 2023. A substantial fraction of that capital goes toward one of the most legally peculiar obligations in commerce: mandatory public disclosure. Every patent filed is a sworn, detailed account of how an invention works, published for the world to read. Pharma IP teams spend years constructing barriers from these disclosures. A smaller number of teams spend equal energy reading through them. That asymmetry is where the opportunity lies.’\u2014 DrugPatentWatch, ‘Drug Patent Formulation Intelligence: The Definitive Guide to Decoding Competitor Strategy,’ 2026 [6]<\/p>\n<\/blockquote>\n\n\n\n

The Six Design-Around Vectors in Formulation Science<\/strong><\/h2>\n\n\n\n

Formulation design-arounds are not guesswork. They follow a defined set of technical vectors, each corresponding to a category of formulation patent claim that has proven historically vulnerable. Here is a systematic overview of the six main vectors, with practical guidance on when each applies.<\/p>\n\n\n\n

Vector 1: Alternative Excipients<\/strong><\/h3>\n\n\n\n

The most direct formulation design-around replaces the patented excipient system with functionally equivalent materials outside the claim scope. This works when the claims use a Markush group, a specific named excipient, or a narrow concentration range. Its viability depends on two factors: whether equivalent excipients are available from a formulation science standpoint, and whether the prosecution history forecloses equivalents arguments for the substitution.<\/p>\n\n\n\n

The extended-release polymer space illustrates this well. A patent claiming an HPMC-based hydrophilic matrix must be distinguished from the large body of prior art teaching hydrophilic matrix systems using other polymers \u2014 xanthan gum, sodium alginate, hydroxypropyl cellulose, carbopol, and various cellulose derivatives. Any of these can produce extended-release profiles depending on concentration and molecular weight grade. The formulator’s task is to identify which alternatives: (a) fall outside the literal claim scope, (b) fall outside the prosecution-defined equivalents scope, and (c) produce a dissolution profile that supports an FDA bioequivalence finding.<\/p>\n\n\n\n

The distinction between ‘different excipient’ and ‘equivalent excipient’ is both a formulation science question and a legal question. From a formulation science standpoint, HPMC K100M at 30% by weight and HPC L at 30% by weight in an otherwise identical matrix will produce different release profiles because they hydrate at different rates and form gels of different viscosity. Whether those different profiles are ‘insubstantial’ under the doctrine of equivalents depends on what the patent claims \u2014 if it claims the profile itself (functionally), the substitution may infringe; if it claims only the composition (structurally), it almost certainly does not.<\/p>\n\n\n\n

Vector 2: Alternative Polymorphic Forms and Salt Forms<\/strong><\/h3>\n\n\n\n

Polymorph and salt form patents are among the most litigated formulation patents because they create what is called ‘unavoidable infringement’ risk: the claimed crystalline form may spontaneously appear during manufacture or storage of any product containing the API. They are also among the most vulnerable to challenge because pharmaceutical polymorph discovery is considered by courts to be routine solid-state chemistry. A 2024 analysis of FDA-approved small-molecule drugs found that between 60% and 80% of newly approved innovative drugs incorporate polymorph patent strategies, primarily to create IP barriers against generic competition [7].<\/p>\n\n\n\n

Crystal Pharmatech’s analysis of the 2024 FDA cohort found that 68% of solid formulations in the class used crystal form patents as a primary exclusivity mechanism. The standard argument for design-around is that the claimed form is either: (a) not present in the generic product under normal manufacturing conditions, (b) not the thermodynamically stable form such that a different stable form can be prepared and used, or (c) obvious over the prior art given the finite number of crystalline forms that a compound can adopt. That last argument \u2014 that polymorph screening is routine, and therefore any discovered form is obvious \u2014 has had mixed success in litigation but succeeded completely in the context of Amarin’s icosapent ethyl patents, where the district court and Federal Circuit found the method-of-use patents obvious based on prior art teaching purified fish-oil formulations for cardiovascular applications [8].<\/p>\n\n\n\n

The Entresto litigation produced the opposite result. Novartis’s ‘659 patent claimed a pharmaceutical composition comprising sacubitril and valsartan administered in combination \u2014 without specifically claiming the supramolecular complex that forms when those molecules are co-formulated. Generic manufacturers argued that because the complex was not described in the original filing, the patent’s written description was insufficient to support the broad claim. The Federal Circuit rejected this argument in January 2025, holding that a patent’s written description requirement is met if the specification adequately describes what is claimed \u2014 not every form the claimed matter might later be found to adopt [9]. For formulation design-around work, this ruling means that a patentee can enforce claims against a physical form that spontaneously arises during manufacture, even if the patentee did not originally contemplate that form. Any ANDA product using sacubitril and valsartan would necessarily form the complex, making design-around here impossible without changing the API itself.<\/p>\n\n\n\n

Vector 3: Alternative Release Architectures<\/strong><\/h3>\n\n\n\n

Extended-release patents often cover a specific delivery architecture: hydrophilic matrix, osmotic pump, reservoir-membrane system, multilayer tablet, pellet-in-capsule. An alternative architecture that achieves bioequivalent release kinetics without using the patented components or configuration is a strong design-around candidate because it is structurally distinct even if functionally similar.<\/p>\n\n\n\n

AstraZeneca’s quetiapine XR (Seroquel XR) is a textbook example. The original quetiapine composition patent expired in 2012. AstraZeneca held formulation patents on the extended-release tablet architecture based on an HPMC matrix system. Several generic manufacturers chose to develop extended-release formulations using pellet-in-capsule architectures rather than matrix tablets, arguing that the membrane-coated pellet system was architecturally distinct from the matrix claims. By 2011, the XR formulation was generating over $1 billion in annual worldwide revenue in its own right [10], making the design-around question commercially material.<\/p>\n\n\n\n

Osmotic delivery systems (the OROS platform and its variants) have been particularly productive for design-arounds because their mechanism of action is fundamentally different from matrix and reservoir systems. OROS tablets use osmotic pressure to drive drug solution through a laser-drilled orifice at a zero-order rate controlled by the rate of water ingress rather than drug diffusion through a polymer matrix. A claim to a ‘hydrophilic matrix extended-release tablet comprising HPMC’ does not encompass an OROS system, regardless of whether the release profiles are bioequivalent. The FDA’s bioequivalence evaluation is blind to mechanism; it measures in vivo or in vitro pharmacokinetic equivalence. Patent infringement analysis is mechanism-sensitive; it reads the claims against the structure of the accused product.<\/p>\n\n\n\n

Vector 4: Alternative Salt Forms, Co-crystals, and Solid-State Modifications<\/strong><\/h3>\n\n\n\n

The physical form of an API in a formulation is often the subject of secondary patents filed after the initial composition patent. Salt form patents, co-crystal patents, and solvate patents can be designed around if the generic formulator can prepare an equivalent product using a different solid-state form that achieves the required bioavailability.<\/p>\n\n\n\n

The Entresto co-crystal case illustrates both the power and the limits of this vector. Novartis held a separate patent on an ‘amorphous solid form comprising sacubitril anions, valsartan anions, and sodium cations’ \u2014 the ‘918 patent, expiring in November 2026. In the post-trial proceedings following the Delaware district court’s December 2024 decision, the court found that Novartis had failed to prove that MSN’s ANDA product infringed the ‘918 patent because the comparison analysis by Novartis’s expert was insufficient [11]. This is a solid-state characterization failure by the patentee, not a design-around by the generic. But it illustrates the practical point: proving that a generic product adopts a claimed solid-state form requires rigorous analytical evidence, and a generic manufacturer who can demonstrate through X-ray powder diffraction (XRPD), solid-state NMR, and differential scanning calorimetry (DSC) that its product uses a different solid-state form has a strong non-infringement argument.<\/p>\n\n\n\n

Co-crystal design-arounds are an active area of development. A co-crystal is a multi-component crystal in which the API and a co-former molecule occupy the same crystal lattice through non-covalent interactions. Co-crystal patents typically claim a specific API\/co-former combination with specific XRPD peak positions. A generic formulator who uses a different co-former \u2014 or who uses the amorphous form of the API rather than a co-crystal \u2014 is outside the literal scope of those claims. The formulation challenge is achieving equivalent bioavailability, which co-crystals are often designed to improve, using a form that does not adopt the patented crystal structure.<\/p>\n\n\n\n

Vector 5: Particle Size, Particle Engineering, and Nanotechnology<\/strong><\/h3>\n\n\n\n

Patents on nanoparticulate drug formulations, specifically formulations where particle size below 2000 nm is claimed as the critical element enabling bioavailability, have been an important battleground in the past decade. Elan’s nanoparticulate technology platform, licensed broadly through ANDA settlements and eventually acquired by Alkermes, generated substantial litigation around whether formulations using different particle size distributions infringed claims on particles ‘having an effective average particle size of less than about 2000 nm.’<\/p>\n\n\n\n

The practical design-around for nanoparticulate patents is a different particle engineering approach that produces the required bioavailability improvement by a different mechanism. Amorphous solid dispersions (ASDs) \u2014 where the drug is dissolved in a polymer matrix rather than crystallized into sub-micron particles \u2014 produce bioavailability enhancement through solubility-by-dissolution-rate rather than surface-area-by-particle-size. A patent on nanoparticulate crystals does not reach an amorphous solid dispersion with no discrete particles. Conversely, a patent on amorphous solid dispersions does not reach a nanoparticulate crystalline product.<\/p>\n\n\n\n

The FDA evaluates both systems based on bioavailability and bioequivalence, not mechanism. A generic formulator who demonstrates that their ASD product is bioequivalent to a branded nanoparticulate formulation \u2014 same Cmax, same AUC, same Tmax within the 80-125% confidence interval bounds \u2014 has met the FDA standard regardless of whether the delivery mechanisms are identical. The intellectual property question is then clean: does the ASD product infringe the nanoparticulate claims? The answer is almost always no, subject to a thorough prosecution history review.<\/p>\n\n\n\n

Vector 6: Route of Administration and Dosage Form<\/strong><\/h3>\n\n\n\n

The most architecturally complete design-around changes the dosage form entirely: from an oral tablet to a transdermal patch, from an intravenous solution to a subcutaneous formulation, from an immediate-release capsule to an extended-release suspension. This vector requires the most development investment but offers the cleanest IP position \u2014 a claim to ‘a tablet formulation comprising…’ literally does not reach a transdermal gel formulation regardless of the excipient overlap.<\/p>\n\n\n\n

Merck’s Keytruda presents an active example. The core IV formulation patents face expiry around 2028, with biosimilar developers at Amgen, Samsung Bioepis, and Bio-Thera Solutions preparing submissions. But Merck has been developing subcutaneous formulations of pembrolizumab using co-formulation with Halozyme’s ENHANZE technology (recombinant human hyaluronidase PH20). A subcutaneous Keytruda would need its own formulation patents \u2014 which Merck is actively prosecuting \u2014 and would produce a delivery route change that biosimilar developers would have to independently develop. That route-of-administration change creates both a new commercial product and a new IP barrier that the existing biosimilar development programs may not be positioned to replicate quickly [12].<\/p>\n\n\n\n

Case Study 1: Novartis Entresto and the Compound Patent That Wasn’t<\/strong><\/h2>\n\n\n\n

The Product and the Portfolio<\/strong><\/h3>\n\n\n\n

Entresto (sacubitril\/valsartan) is a fixed-dose combination for heart failure. Novartis launched it in 2015, and by 2024 it was generating over $7 billion in annual revenue. The patent portfolio that protected it was, until 2023, considered robust: multiple Orange Book-listed patents with expiries stretching between 2023 and 2036 including any pediatric exclusivity.<\/p>\n\n\n\n

The centerpiece was the ‘659 patent: ‘a pharmaceutical composition comprising sacubitril and valsartan administered in combination.’ This is a combination patent, not strictly a formulation patent, but it functioned as the primary exclusivity barrier because it covered any co-administration of the two APIs. Novartis filed it before discovering that co-formulating sacubitril and valsartan in the presence of sodium hydroxide produces a supramolecular complex: sacubitril hemicalcium salt valsartan hemicalcium salt. That complex is the actual commercial product, Entresto’s LCZ696.<\/p>\n\n\n\n

The Generic Strategy: Attack the Primary Patent<\/strong><\/h3>\n\n\n\n

MSN Pharmaceuticals and other ANDA filers challenged the ‘659 patent on two grounds. First, they argued invalidity based on obviousness: the combination of an angiotensin receptor blocker (valsartan) with a neprilysin inhibitor (sacubitril) was an obvious approach given the prior art teaching that dual ACE\/NEP inhibition provided cardiovascular benefit. Second, they argued written description insufficiency: the patent claimed a composition comprising sacubitril and valsartan, but the actual commercial product contained a complex that did not exist when the patent was filed. How could a patent’s written description cover a product that the inventor had not yet made?<\/p>\n\n\n\n

The Delaware district court agreed on invalidity in July 2023, finding the ‘659 patent invalid for obviousness. Novartis appealed. Meanwhile, the Federal Circuit affirmed in January 2025 that the written description challenge failed: a patent adequately describes what it claims as long as the specification teaches the claimed elements, not every form that those elements might subsequently adopt through chemical interaction [13]. The combination of sacubitril and valsartan was disclosed; the spontaneous formation of a complex during co-formulation did not require separate disclosure because it was an inherent consequence of the disclosed combination.<\/p>\n\n\n\n

The Practical Outcome and Lessons<\/strong><\/h3>\n\n\n\n

With the ‘659 patent invalidated and pediatric exclusivity expiring in July 2025, multiple generic manufacturers launched generic Entresto at the end of July 2025 after the Federal Circuit lifted Novartis’s preliminary injunction [14]. The ‘918 formulation patent (the amorphous complex) remained nominally in force through November 2026, but the Delaware court’s finding that Novartis had failed to prove infringement of that patent by MSN’s ANDA product \u2014 due to inadequate expert evidence on solid-state characterization \u2014 removed it as a practical barrier.<\/p>\n\n\n\n

Three lessons follow from the Entresto litigation for design-around practitioners:<\/p>\n\n\n\n

First, a combination patent covering co-administration of two APIs may be the most commercially powerful and the most strategically fragile element of a portfolio. Its breadth makes it attractive to innovators and makes it the primary target for invalidity challenges. If it falls, the rest of the portfolio often lacks the commercial footprint to prevent generic entry.<\/p>\n\n\n\n

Second, solid-state characterization is both the attack and the defense for complex-forming formulations. A patentee who cannot prove through rigorous analytical evidence that an ANDA product contains the claimed complex will not win infringement, regardless of how clearly the complex is described in the patent. Generic manufacturers should invest equally in solid-state characterization to demonstrate that their product does not contain the patented form.<\/p>\n\n\n\n

Third, timing matters. Novartis entered into settlement agreements with several ANDA filers providing for confidential early-entry dates. Those settlements, negotiated in the context of the litigation, represent a form of design-around at the commercial rather than technical level: the generic manufacturer does not need to change its formulation if it can negotiate a launch date that the innovator prefers to the litigation alternative. Understanding the innovator’s commercial calculus \u2014 how much revenue is at stake, what the litigation cost will be, whether the patent is genuinely strong \u2014 informs when to settle versus when to litigate to judgment.<\/p>\n\n\n\n

Case Study 2: Collegium’s Xtampza ER and the Affirmative Design-Around<\/strong><\/h2>\n\n\n\n

Purdue’s OxyContin and the Reformulation Defensive Strategy<\/strong><\/h3>\n\n\n\n

OxyContin (oxycodone extended-release) is the most commercially and legally consequential extended-release formulation in pharmaceutical history. Purdue Pharma’s original OxyContin, launched in 1996, was a hydrophilic HPMC matrix tablet. Following years of abuse \u2014 the matrix could be crushed and the full dose extracted \u2014 the FDA pressured innovators to develop abuse-deterrent formulations (ADFs). Purdue’s reformulation in 2010 used polyethylene oxide (PEO) as the matrix polymer, which made the tablet difficult to crush and caused it to form a gelling mass when dissolved in solvents. Purdue patented this system extensively.<\/p>\n\n\n\n

The reformulation was a commercial and regulatory success: the FDA withdrew approval of the original OxyContin tablet in 2013 on safety grounds, and the reformulated product became the reference listed drug. Any ANDA filer who wanted to reference OxyContin had to reference the PEO-based formulation, which Purdue’s patents protected.<\/p>\n\n\n\n

Collegium’s DETERx Strategy: A New Architecture<\/strong><\/h3>\n\n\n\n

Collegium Pharmaceutical did not try to design around Purdue’s PEO matrix by substituting a different polymer. Instead, it designed a different delivery architecture: a microsphere-in-capsule system using the DETERx platform, in which oxycodone (formulated as the myristate salt, a form that itself carries certain processing advantages) is incorporated into discrete microspheres composed of fatty acids and waxes rather than a hydrophilic polymer matrix [15].<\/p>\n\n\n\n

The DETERx microspheres are approximately 300 micrometers in diameter. When crushed, the wax-and-fatty-acid composition causes the microspheres to smear rather than produce fine particles; when dissolved in water or common solvents, the hydrophobic wax matrix prevents efficient API extraction; when heated for intended IV injection, the melted waxes produce a viscous mass that is difficult and potentially dangerous to inject. The abuse-deterrent properties arise from the physicochemical characteristics of the wax\/fatty acid matrix rather than from the polymer gelling behavior that characterizes the Purdue system [16].<\/p>\n\n\n\n

This is the design-around in its purest form. Collegium did not use Purdue’s PEO matrix. It did not use HPMC. It did not use any hydrophilic polymer at all. It used a lipid matrix system based on fatty acids and waxes. The delivery architecture, the mechanism of abuse deterrence, and the excipient chemistry are all distinct from anything in Purdue’s patent portfolio. Purdue sued Collegium, asserting three patents. Collegium defended successfully: the FDA granted tentative approval in February 2015 and full approval in April 2016 [17]. The 30-month stay triggered by Purdue’s litigation ran and expired without a court finding of infringement.<\/p>\n\n\n\n

The Formulation Science Behind the IP Position<\/strong><\/h3>\n\n\n\n

The Xtampza ER design-around is instructive because Collegium did not merely choose a different polymer and hope for the best. It chose a delivery architecture that was mechanistically distinct from Purdue’s claims in ways that were defensible both scientifically and legally.<\/p>\n\n\n\n

Purdue’s abuse-deterrent claims were built around the properties of a PEO matrix: the polymer’s behavior under crushing, its solubility characteristics, the gelling properties that made extraction difficult. Those claims, necessarily, could only reach formulations that used similar polymer chemistry to achieve similar physical behavior. A lipid matrix, which deters abuse through hydrophobic sequestration and viscosity generation under heat rather than through hydrophilic polymer gelling, operates through a different physical mechanism and is therefore outside the scope of claims that depend on polymer behavior for their operative elements.<\/p>\n\n\n\n

That scientific distinction is not something Collegium discovered during litigation. It was built into the DETERx development program from the outset. The design-around began in the chemistry laboratory, was confirmed through solid-state characterization, and was then validated through in vitro abuse-deterrence testing and in vivo pharmacokinetic studies. By the time Purdue filed its complaint, Collegium had already assembled the scientific record needed to defend its non-infringement position.<\/p>\n\n\n\n

The Regulatory Dimension: FDA’s Abuse-Deterrent Labeling<\/strong><\/h3>\n\n\n\n

A design-around that produces a product technically distinct from the patented formulation still needs FDA approval, and for abuse-deterrent opioids, that approval includes a specific labeling determination. The FDA’s 2015 guidance on abuse-deterrent opioids requires applicants to demonstrate abuse-deterrent properties through in vitro manipulation studies, pharmacokinetic studies in users who have been abusing opioids, and clinical studies. Collegium’s DETERx microspheres were shown to maintain their extended-release pharmacokinetic profile even after crushing and chewing, and the viscous mass formed under extraction conditions reduced the abuse potential for injection and insufflation [18].<\/p>\n\n\n\n

This dual demonstration \u2014 non-infringement of the branded product’s patents, and satisfaction of the FDA’s abuse-deterrence evidentiary standard \u2014 is the complete design-around package. A formulation that avoids the patents but fails the FDA’s performance standard for the reference listed drug’s category cannot be approved. A formulation that meets the FDA standard but infringes the patents faces litigation. Collegium achieved both objectives through deliberate architecture selection, not coincidence.<\/p>\n\n\n\n

Case Study 3: Amarin Vascepa and the Limits of Method-of-Use Design-Arounds<\/strong><\/h2>\n\n\n\n

The Patents and the Challenge<\/strong><\/h3>\n\n\n\n

Vascepa (icosapent ethyl) is purified eicosapentaenoic acid (EPA), a highly refined omega-3 fatty acid derived from fish oil. Amarin received FDA approval in 2012 for severe hypertriglyceridemia and a major cardiovascular risk-reduction indication in 2019 following the REDUCE-IT trial, which showed a 25% reduction in cardiovascular events versus placebo [19]. The core patents on Vascepa were not formulation patents in the traditional excipient sense; they were method-of-use patents claiming specific therapeutic applications of purified EPA.<\/p>\n\n\n\n

Hikma and Dr. Reddy’s Laboratories challenged six of Amarin’s key method-of-use patents in 2019. The district court in Nevada found both infringement and invalidity: the ANDA products infringed the patents’ claims, but all six patents were invalid for obviousness based on prior art teaching that purified omega-3 fatty acids derived from fish oil could be used to treat cardiovascular conditions [20]. GSK’s Lovaza, a prescription omega-3 combination product, was already on the market; the scientific literature on EPA and DHA for cardiovascular benefit was extensive. District Court Judge Miranda Du found that a skilled scientist in the field would have had motivation to use purified EPA specifically, and a reasonable expectation of success, based on the existing body of prior art [21].<\/p>\n\n\n\n

The Skinny Label Strategy<\/strong><\/h3>\n\n\n\n

After the invalidity ruling was affirmed by the Federal Circuit in 2020 and the Supreme Court declined certiorari in 2021, Hikma held an ANDA for generic icosapent ethyl with an FDA-approved label covering only the severe hypertriglyceridemia indication \u2014 the indication whose patents had been invalidated. The cardiovascular indication remained under separate method-of-use patents that Hikma had carved out using a ‘section viii’ carve-out under 21 C.F.R. \u00a7 314.94(a)(12)(iii).<\/p>\n\n\n\n

Amarin then sued Hikma for induced infringement, arguing that even with the cardiovascular indication carved out of Hikma’s label, Hikma’s generic product would be prescribed off-label for cardiovascular risk reduction \u2014 and that Hikma knew this would happen. The Federal Circuit’s August 2024 decision addressed the boundaries of induced infringement through skinny labels [22]. The court found that the combination of Hikma’s carved-out label and its public communications \u2014 press releases, formulary submissions, and statements to physicians \u2014 constituted evidence that Hikma had induced infringing use. The case was remanded for further proceedings on that basis.<\/p>\n\n\n\n

The Design-Around Lesson: Formulation Is Not Enough<\/strong><\/h3>\n\n\n\n

The Vascepa litigation is unusual because the primary barrier was method-of-use, not formulation. Icosapent ethyl is a natural compound (a purified form of a naturally occurring fatty acid) whose composition cannot be patented. There was no polymorph patent to circumvent, no excipient matrix to replace, no delivery architecture to substitute. The only IP barrier was the method of use.<\/p>\n\n\n\n

For design-around practitioners, Vascepa illustrates that a complete freedom-to-operate analysis covers not just formulation claims but method-of-use claims, and that obtaining a skinny label does not insulate a generic manufacturer from induced infringement liability if the manufacturer’s commercial conduct signals awareness of and intent to benefit from infringing uses. The Federal Circuit’s 2024 ruling in Amarin v. Hikma<\/em> makes this point with particular force: marketing communications, formulary strategy, and physician outreach materials are now part of the induced infringement analysis, not just the label itself [23].<\/p>\n\n\n\n

For generic manufacturers designing around method-of-use patents specifically, the relevant protocol is: file a section viii carve-out for the patented indication; ensure that all marketing materials, press releases, and formulary submissions describe only the non-patented indication; and document the internal decision-making that establishes no intent to promote infringing use. This protocol does not guarantee immunity \u2014 the Vascepa case demonstrates that courts will look holistically at the company’s conduct \u2014 but it establishes the foundational non-inducement record.<\/p>\n\n\n\n

Case Study 4: AbbVie Humira and the Patent Thicket That Required a Different Solution<\/strong><\/h2>\n\n\n\n

The Architecture of the Thicket<\/strong><\/h3>\n\n\n\n

Humira (adalimumab) generated $20 billion in annual US revenue at its peak. Since FDA approval in 2002, AbbVie filed hundreds of patent applications covering the biologic’s formulation, manufacturing processes, dosing regimens, and delivery devices. The total patents asserted or available for assertion against biosimilar manufacturers reached over 130 by the time the primary composition patent expired [24]. Between 2013 and 2016 alone, AbbVie filed 85 patents, the vast majority covering formulations, treatment methods, and manufacturing processes. Nearly 90% of Humira’s patents were filed after FDA approval of the original drug. Some formulation patents did not even contain claims reflected in the actual Humira formulation [25].<\/p>\n\n\n\n

This is the patent thicket in its most extreme form. AbbVie patented the commercial formulation, multiple alternative formulations it never commercialized, manufacturing process variations, device components, and dosing regimens. The resulting web of 130-plus patents made it impossible for a biosimilar manufacturer to guarantee clearance of every asserted patent without exhaustive litigation across hundreds of individual patent claims.<\/p>\n\n\n\n

Why Traditional Design-Around Failed<\/strong><\/h3>\n\n\n\n

For small-molecule drugs, a generic manufacturer typically faces a handful of Orange Book-listed patents. A competent design-around analysis can systematically address each patent in turn and identify a product configuration that avoids the relevant claims. For Humira, a biosimilar manufacturer could not design around the formulation patents in isolation because the sheer number of asserted patents made any individual design-around commercially useless: even if formulation patent A was circumvented, patents B, C, D, and E remained asserted, and the cost of litigating all of them simultaneously exceeded the NPV of the biosimilar program for most challengers.<\/p>\n\n\n\n

Boehringer Ingelheim was the only major biosimilar developer that refused to settle and continued litigation. The resulting discovery produced detailed evidence of AbbVie’s patent strategy, including allegations that AbbVie had re-patented processes already in use without disclosing prior use to the USPTO, and that several formulation patents claimed formulations AbbVie had no intention of commercializing [26]. Those allegations, taken together, suggest that the patents were filed not to describe genuine inventions but to increase the cost and complexity of clearing the IP landscape.<\/p>\n\n\n\n

The Commercial Resolution<\/strong><\/h3>\n\n\n\n

AbbVie’s thicket strategy worked as designed. All major biosimilar manufacturers settled, accepting US market exclusivity through January 2023 in exchange for early access to the European market [27]. Without settlements, the cost of litigating 130-plus patents simultaneously \u2014 even if the eventual outcome were favorable \u2014 would have been existential for most biosimilar development programs. The prohibitive litigation cost was the thicket’s operative mechanism, not the strength of any individual patent.<\/p>\n\n\n\n

By the time biosimilars launched in January 2023, AbbVie had used the five-year exclusivity window to reduce Humira’s share of its revenue from approximately 39% in 2022 to a projected 9% in 2025, while Skyrizi and Rinvoq grew from 14% to 43% of revenues. The thicket did not eliminate competition permanently; it bought AbbVie the time to develop a commercially viable post-Humira portfolio [28].<\/p>\n\n\n\n

Policy Response and Its Implications<\/strong><\/h3>\n\n\n\n

The Affordable Prescriptions for Patients Act, proposed in Congress, would cap the number of patents assertable in a biosimilar lawsuit at 20 in the initial litigation phase. The FTC’s delisting campaign against device and component patents in the Orange Book is a parallel effort to reduce patent barriers in the small-molecule context. Neither initiative eliminates the thicket problem for biologics, but both reduce the scale of legal exposure that inhibits challenge.<\/p>\n\n\n\n

For biosimilar developers, the Humira case establishes that a portfolio capable of asserting 130-plus patents against a single challenger cannot be designed around at the formulation level. The viable strategies are: early settlement for geographic market access; IPR petitions targeting the highest-value patents in the thicket on invalidity grounds; regulatory pressure through FTC and FDA to delist improperly listed patents; and antitrust litigation asserting that the thicket as a whole constitutes unlawful monopoly maintenance under Section 2 of the Sherman Act. Design-around, in the formulation science sense, is a necessary but not sufficient element of biosimilar strategy when the patent count exceeds what any single litigation program can address.<\/p>\n\n\n\n

The Legal Framework for Executing a Design-Around<\/strong><\/h2>\n\n\n\n

Non-Infringement Analysis: The Three-Step Process<\/strong><\/h3>\n\n\n\n

A defensible design-around rests on a formal non-infringement opinion from qualified patent counsel. That opinion follows a three-step process: claim construction, literal infringement analysis, and doctrine of equivalents analysis.<\/p>\n\n\n\n

Claim construction determines what each limitation in each asserted claim means, reading the claim language in light of the specification and the prosecution history. This is a question of law \u2014 courts decide claim construction independently and are not bound by the parties’ positions. The Supreme Court’s 2005 decision in Phillips v. AWH Corp.<\/em> established that claims are to be construed from the perspective of a person having ordinary skill in the relevant art at the time of the invention, with the specification serving as the most important intrinsic guide to meaning. For formulation patents, this means that technical terms like ‘hydrophilic matrix,’ ‘amorphous solid dispersion,’ ‘nanoparticulate,’ and ‘extended-release’ carry the meanings understood by a trained pharmaceutical scientist, not their colloquial meanings.<\/p>\n\n\n\n

Literal infringement analysis then applies the construed claims to the proposed formulation element by element. If any element of an independent claim is absent from the proposed formulation \u2014 if the claim requires HPMC and the formulation uses ethyl cellulose, or if the claim requires a particle size below 2000 nm and the formulation uses particles averaging 3500 nm \u2014 there is no literal infringement. This analysis is binary: either the element is present or it is not.<\/p>\n\n\n\n

Doctrine of equivalents analysis addresses whether the proposed formulation is ‘substantially similar’ to the claimed invention in function, way, and result even though it does not literally read on the claims. The three-part function-way-result test asks whether the substitute element performs substantially the same function (sustained drug release), in substantially the same way (diffusion through a polymer matrix), to achieve substantially the same result (once-daily dosing with the specified dissolution profile). Prosecution history estoppel limits this doctrine: if the patentee narrowed a claim to overcome prior art, equivalents are foreclosed for the surrendered subject matter.<\/p>\n\n\n\n

The Written Description and Enablement Challenges<\/strong><\/h3>\n\n\n\n

The most powerful invalidity tool against broad formulation patents is the written description requirement of 35 U.S.C. \u00a7 112. A patent claim must be supported by a written description that shows the inventor actually possessed what was claimed. Broad functional claims that attempt to capture all compositions achieving a particular result, without describing enough representative species to support the claim’s full scope, are vulnerable under post-Amgen v. Sanofi<\/em> doctrine [29].<\/p>\n\n\n\n

In Amgen v. Sanofi<\/em> (2023), the Supreme Court unanimously invalidated Amgen’s broad antibody claims because the claims were directed at all antibodies that ‘bind to PCSK9’ and block its interaction with LDL receptors, but the specification only disclosed two specific antibodies from that functional genus. The Court held that a patentee cannot claim the entire class of things that achieve a result if the patent only enables a fraction of that class [30]. This ruling applies directly to formulation patents that claim ‘a composition comprising [drug X] in a sustained-release matrix that releases at least 80% of the drug within 12 hours’ without describing all the formulation approaches that could achieve that release profile.<\/p>\n\n\n\n

In the fiscal year 2024, IPR institution rates for bio\/pharma petitions were approximately 73%, and of those instituted, a substantial fraction resulted in cancellation of at least some challenged claims [31]. For generic manufacturers whose design-around analysis reveals a potentially invalid primary patent, IPR provides a faster and cheaper path to invalidity than district court litigation, with institution to final written decision running approximately 18 months.<\/p>\n\n\n\n

The 30-Month Stay and First-Filer Advantage<\/strong><\/h3>\n\n\n\n

Under the Hatch-Waxman Act, filing a Paragraph IV certification \u2014 which certifies that a listed Orange Book patent is invalid, unenforceable, or not infringed by the ANDA product \u2014 entitles the first ANDA filer to 180 days of marketing exclusivity. If the patent holder sues within 45 days of receiving notice of the Paragraph IV certification, the FDA must stay ANDA approval for up to 30 months while litigation proceeds. This stay does not apply to design-arounds filed with Paragraph III certifications (which certify that the patent is not infringed because it will expire before the proposed launch date) or section viii statements (which certify that no method-of-use patent is applicable to the proposed product).<\/p>\n\n\n\n

A successful design-around typically supports a Paragraph IV filing (asserting non-infringement) rather than a Paragraph III filing (acknowledging the patent’s validity and waiting for expiry) because the design-around argument is precisely the non-infringement argument. The 30-month stay is triggered by the Paragraph IV filing, which means that a strong design-around position must be capable of withstanding 30 months of litigation before its commercial value is realized. This timeline should be built into any design-around program’s commercial planning from the outset.<\/p>\n\n\n\n

Freedom-to-Operate Opinions and Their Limitations<\/strong><\/h3>\n\n\n\n

A freedom-to-operate (FTO) opinion from patent counsel is not a guarantee against infringement claims. It is an assessment of infringement risk based on the claims in force at the time of the analysis, the known prosecution history, and the technical configuration of the proposed product. It does not protect against newly issued continuation patents filed after the opinion date, against re-examination or IPR outcomes that change claim scope, or against claim constructions adopted by courts that differ from the construction used in the opinion.<\/p>\n\n\n\n

For this reason, FTO opinions for design-around programs should be updated regularly throughout the development process, particularly at each milestone where the product configuration is finalized. They should cover not just the primary composition patent but every formulation patent, method-of-use patent, and process patent listed in the Orange Book for the reference listed drug, plus any continuation or continuation-in-part applications visible in the prosecution history that may issue with updated claims after the initial opinion date.<\/p>\n\n\n\n

The Design-Around Workflow: A Practitioner’s Playbook<\/strong><\/h2>\n\n\n\n

Phase 1: Patent Intelligence Gathering (Weeks 1-4)<\/strong><\/h3>\n\n\n\n

The design-around process begins with comprehensive patent intelligence gathering. The objective is to build a complete map of every patent that could be asserted against a proposed product, along with the technical requirements those patents impose on the product’s design space.<\/p>\n\n\n\n

Start with the Orange Book listing for the reference listed drug. Pull every listed patent number and cross-reference it against the USPTO full-text patent database and DrugPatentWatch’s litigation intelligence to identify all related continuations, divisionals, and continuation-in-part applications. Some of the most commercially important patents in a portfolio are continuation applications that do not appear on the original Orange Book listing because they issued after the original NDA but before the ANDA filing. These are often drafted specifically to address design-around attempts the patentee anticipated based on the ANDA applications already in the pipeline.<\/p>\n\n\n\n

For each patent, obtain the complete prosecution history from the USPTO Patent Center. This is free and publicly available. Assign each patent to a claim type category: composition-of-matter, formulation (excipient), formulation (solid state), formulation (manufacturing process), formulation (dosage form), and method-of-use. Build a matrix showing, for each patent, the critical claim limitations, the prosecution history restrictions on equivalents, the expiry date, and the existing litigation outcome data from DrugPatentWatch’s database.<\/p>\n\n\n\n

Identify the three to five patents most likely to be asserted based on expiry date (still in force at anticipated launch), claim type (formulation or composition), and litigation history (previously asserted against other ANDA filers). These are the patents that require the deepest design-around analysis.<\/p>\n\n\n\n

Phase 2: Technical Design Space Analysis (Weeks 4-12)<\/strong><\/h3>\n\n\n\n

With the patent map complete, pharmaceutical scientists can begin the design space analysis. For each high-priority patent, the objective is to identify the boundaries of the claims in technical formulation terms and then map the available design space outside those boundaries.<\/p>\n\n\n\n

The design space analysis for an HPMC matrix extended-release patent, for example, would identify: the claimed polymer type and concentration range; the claimed drug-to-polymer ratio; the claimed processing approach; and the claimed performance parameters (dissolution rate, dissolution profile shape). For each claimed element, the analysis identifies the design alternatives available from formulation science \u2014 different polymers, different concentration ranges, different architectures \u2014 and plots those alternatives against the patent boundary.<\/p>\n\n\n\n

Formulation development at this stage is preliminary and should be structured around feasibility rather than optimization. The question is whether a non-infringing formulation can achieve the dissolution profile required for FDA bioequivalence approval, not whether it can be manufactured efficiently at commercial scale. The feasibility work should generate three to five candidate formulations that sit clearly outside the identified patent boundary while meeting the basic performance criteria for bioequivalence.<\/p>\n\n\n\n

Phase 3: Legal Validation and FTO Opinion (Weeks 8-16)<\/strong><\/h3>\n\n\n\n

Legal validation runs in parallel with technical development. Patent counsel reviews the candidate formulations against the patent map, construes the relevant claims, and provides an initial assessment of the non-infringement position for each candidate. This iterative process \u2014 candidates developed by formulation scientists, reviewed by patent counsel, modified based on legal feedback, and resubmitted for review \u2014 is the core of the design-around workflow.<\/p>\n\n\n\n

The FTO opinion produced at this stage should be detailed enough to support a Paragraph IV certification filing, meaning it should contain a complete claim-by-claim non-infringement analysis for each asserted patent, a prosecution history analysis, and an opinion on the doctrine of equivalents for each claim limitation that is relevant to the non-infringement position. This opinion will be reviewed by the patent holder’s counsel if litigation is filed, so quality and rigor are not optional.<\/p>\n\n\n\n

If the legal analysis reveals significant infringement risk for all candidate formulations, the output of Phase 3 may be a decision to pursue IPR petitions against the highest-priority patents rather than a design-around. An IPR petition filed on strong prior art grounds can stay district court litigation and, if instituted, proceeds to final written decision in approximately 18 months. A successful IPR that cancels the primary infringement barrier may be faster and cheaper than a fully developed design-around program.<\/p>\n\n\n\n

Phase 4: Formulation Development and Bioequivalence (Months 4-24)<\/strong><\/h3>\n\n\n\n

Once a legally validated formulation configuration is identified, full-scale development begins. For an oral solid dosage form, this typically involves systematic optimization of the identified non-infringing excipient system, scale-up from laboratory to pilot scale, and pivotal bioequivalence studies. The bioequivalence standard for FDA approval requires that the 90% confidence intervals for the Cmax and AUC ratios (test\/reference) fall within the 80-125% acceptance criteria.<\/p>\n\n\n\n

A critical and often underweighted consideration in design-around bioequivalence programs is food effect management. Many extended-release formulations were designed to minimize food effects \u2014 the change in pharmacokinetic profile when the drug is taken with food versus fasted. A design-around formulation using a different excipient system may have a different food effect even if the fasted-state profile is bioequivalent. The FDA requires bioequivalence demonstration under both fasted and fed conditions for most extended-release products. A design-around that achieves fasted bioequivalence but shows a clinically significant food effect difference will not be approved.<\/p>\n\n\n\n

Phase 5: ANDA Filing and Litigation Management<\/strong><\/h3>\n\n\n\n

ANDA filing with a Paragraph IV certification triggers the 45-day litigation window and, if the patent holder files suit, the 30-month stay. The ANDA filing marks the point at which the design-around transitions from a technical and legal exercise into an active litigation management challenge. The technical and legal work done in Phases 1-4 directly informs the litigation strategy: the formulation differences identified in Phase 2 become the factual basis for the non-infringement expert opinions, and the prosecution history analysis from Phase 3 becomes the legal argument for prosecution history estoppel against equivalents claims.<\/p>\n\n\n\n

The median duration of Hatch-Waxman patent litigation from complaint to trial is approximately 27 months, which aligns with the 30-month stay period in a way that is not coincidental. Congress calibrated the stay to provide enough time for litigation to reach conclusion. Cases that do not reach a court decision within 30 months typically result in either ANDA approval (if the stay expires without a court ruling) or settlement. Many design-around cases settle well short of trial because the patent holder’s assessment of the non-infringement position, once they have seen the proposed formulation and the legal opinion, leads to a negotiated launch date preferable to the litigation outcome.<\/p>\n\n\n\n

Using Patent Data Tools Strategically: The Role of DrugPatentWatch<\/strong><\/h2>\n\n\n\n

What the Database Provides<\/strong><\/h3>\n\n\n\n

Patent intelligence for design-around work requires aggregating data from multiple public sources: the Orange Book, the USPTO full-text database, the USPTO Patent Center (prosecution histories), PTAB proceedings, federal district court PACER filings, and the FDA’s paragraph IV certification database. Doing this aggregation manually for a single drug product can take weeks. Commercial databases compress that timeline substantially.<\/p>\n\n\n\n

DrugPatentWatch aggregates Orange Book patent listings, tracks continuation and divisional applications tied to NDA patents, monitors PTAB proceedings for pharmaceutical patents, and provides litigation outcome data for resolved ANDA cases. For design-around practitioners, the litigation history function is particularly valuable: it shows how courts have construed specific claim limitations in patents you are analyzing, which ANDA filers made Paragraph IV certifications against those patents, and what the outcomes were. If a court has already construed a critical claim limitation in a patent you are designing around, that construction is highly persuasive in subsequent litigation and should be the basis for your design-around analysis rather than a fresh interpretation.<\/p>\n\n\n\n

The formulation intelligence functionality addresses what DrugPatentWatch describes as a fundamental asymmetry in pharmaceutical IP strategy: most pharma professionals treat patents as countdown clocks; a smaller number read them as detailed technical disclosures that reveal competitor strategy. For design-around practitioners, this means using patent data not just to track exclusivity timelines but to extract the specific formulation parameters, excipient systems, and manufacturing approaches that define the technical landscape you are working in.<\/p>\n\n\n\n

Competitive Intelligence Applications<\/strong><\/h3>\n\n\n\n

Beyond the immediate design-around context, formulation patent analysis provides competitive intelligence about a competitor’s R&D priorities, development timeline, and commercial lifecycle strategy. A company that files 20 continuation applications for a drug three years before the composition patent expires is signaling that it expects intense generic competition and is constructing a secondary patent barrier. A company that files a single formulation patent for an extended-release product two years before composition expiry, with claims limited to a specific polymer and concentration range, may have a vulnerability to a design-around that the filing company has not fully considered.<\/p>\n\n\n\n

Natural language processing tools applied to pharmaceutical formulation patents can automate extraction of specific data elements from large patent corpora: excipient identities and concentration ranges from the detailed description, API-to-polymer ratios from examples, stability data from tables, and dissolution profiles from experimental results sections [32]. This automated analysis enables a design-around team to process dozens of patents simultaneously rather than reading each one individually, which changes the scope of what is practically achievable within a competitive intelligence program.<\/p>\n\n\n\n

The Patent Cliff Context: Why 2025-2030 Is the Most Active Design-Around Period in History<\/strong><\/h2>\n\n\n\n

The Revenue at Risk<\/strong><\/h3>\n\n\n\n

Over 190 drugs face loss of exclusivity between 2024 and 2030, representing approximately $300 billion in cumulative annual revenues. This is the most concentrated patent expiry event in the history of the pharmaceutical industry by revenue at risk [33]. The top of the list includes drugs with formulation patent portfolios that extend beyond the composition expiry: pembrolizumab (Keytruda, $29.5 billion in 2024 revenue, IV formulation key patents expiring approximately 2028, but Merck’s subcutaneous formulation development creates a new exclusivity pathway); apixaban (Eliquis, $13 billion, facing generic entry from April 1, 2028 as one of the first ten drugs subject to Inflation Reduction Act price negotiations); ustekinumab (Stelara, biosimilar entry began in the US in 2023 with multiple biosimilars now launched); and ibrutinib (Imbruvica, approximately $10 billion, facing LOE around 2027).<\/p>\n\n\n\n

Bristol-Myers Squibb faces the steepest proportional revenue exposure: by 2030, an estimated 47% of BMS revenues are at risk from patent expirations, with Eliquis and Opdivo together representing approximately 45% of total revenues and a combined growth gap \u2014 the difference between expiring revenue and new product revenue \u2014 that analysts estimate at roughly $38 billion [34]. For generic manufacturers and biosimilar developers, this pipeline represents the largest design-around opportunity in history.<\/p>\n\n\n\n

The Regulatory Shifts That Change the Calculus<\/strong><\/h3>\n\n\n\n

Several regulatory and legal developments between 2023 and 2025 altered the design-around landscape in ways that favor challengers.<\/p>\n\n\n\n

The FTC’s Orange Book delisting campaign removed hundreds of device and component patents that had been improperly listed to trigger 30-month stays. The December 2024 Federal Circuit ruling against Teva requiring delisting of five inhaler patents, followed by Teva’s agreement to remove over 200 listings and pay a $35 million settlement, established that pharmaceutical device patents must claim the ‘drug product’ as defined in the statute, not peripheral components [35]. For ANDA filers targeting inhaler, auto-injector, and combination drug-device products, this reduces the pool of patents they must address in their Paragraph IV certifications.<\/p>\n\n\n\n

The Amgen v. Sanofi<\/em> written description standard, applied to formulation patents, creates new invalidity arguments against broad functional claims that attempt to capture all formulations achieving a performance result without providing enabling disclosure for the full scope of the claim. These arguments are most powerful against first-in-class drugs where the patentee wrote broad claims in the absence of prior art, knowing that the patent examiner had limited technical basis for rejection.<\/p>\n\n\n\n

The IRA’s drug price negotiation program adds another dimension: drugs subject to IRA negotiation will have their US prices set by CMS negotiations, reducing the economic incentive for lengthy litigation by both innovators (reduced revenue to protect) and generic manufacturers (reduced generic market opportunity at the negotiated price). The net effect on design-around investment is unclear, but the IRA’s focus on high-revenue drugs whose formulation portfolios are the primary protection is creating a new analytical variable in design-around program NPV calculations.<\/p>\n\n\n\n

Practical Considerations for Investors and Portfolio Managers<\/strong><\/h2>\n\n\n\n

Reading Formulation Patent Portfolios as Asset Valuation Inputs<\/strong><\/h3>\n\n\n\n

For institutional investors evaluating pharmaceutical assets, formulation patent portfolio analysis is a component of NPV modeling that is frequently underweighted relative to primary patent analysis. The relevant framework from DrugPatentWatch’s patent strategy guidance identifies three structural portfolio indicators [36]:<\/p>\n\n\n\n

A strong portfolio lists Orange Book patents expiring across multiple years through 2035 or later, with multiple claim types covering composition, formulation, and method of use. This structure makes design-around difficult because circumventing the formulation patents does not clear the method-of-use patents, and vice versa. Eliquis had this structure until the IRA negotiations changed the commercial calculus.<\/p>\n\n\n\n

A vulnerable portfolio concentrates all Orange Book patent expiries within a 12-month window, suggests that the lifecycle management program is underdeveloped, and indicates that a generic manufacturer who resolves the formulation design-around question will face minimal residual IP barriers. When all Orange Book patents expire simultaneously, generic entry will be rapid and total, with multiple ANDA approvals occurring within months of each other.<\/p>\n\n\n\n

A deceptively vulnerable portfolio has a large number of Orange Book-listed patents but concentrations in device components, method-of-use claims for minor indications, or formulation claims on dosage forms the reference product no longer actively promotes. The FTC’s delisting actions and the 2024 Federal Circuit inhaler rulings are the direct result of innovators over-listing precisely this type of portfolio to deter ANDA filings. Post-2025, this strategy carries regulatory and litigation risk that was not present before the FTC’s enforcement actions.<\/p>\n\n\n\n

Identifying Design-Around Opportunities in a Target Portfolio<\/strong><\/h3>\n\n\n\n

Investors doing diligence on a branded pharmaceutical asset, or on a generic company whose pipeline depends on design-around success, should request the following analyses from their technical advisors:<\/p>\n\n\n\n

A claim type breakdown of the Orange Book-listed patents: what percentage cover composition, formulation, and method-of-use, and when does each cluster expire? A portfolio where formulation patents expire eight years after the composition patent represents a longer exclusivity window than nominal analysis suggests. A portfolio where all listed patents are method-of-use claims is vulnerable to skinny label carve-outs.<\/p>\n\n\n\n

A prosecution history review for the highest-revenue formulation patents: what prior art did the examiner cite, what arguments did the applicant make to distinguish that prior art, and what does the prosecution history estoppel mean for the doctrine of equivalents? This review is what distinguishes a sophisticated IP diligence opinion from a simple patent summary.<\/p>\n\n\n\n

A competitive design space analysis: how many alternative formulation approaches exist outside the literal and equivalents scope of the primary formulation patents? If the answer is ‘several viable alternatives with established scientific literature,’ the formulation patent cluster is less durable than its face value suggests. If the answer is ‘the patented form is the only commercially viable approach,’ the formulation protection is genuinely strong.<\/p>\n\n\n\n

Common Mistakes in Design-Around Programs<\/strong><\/h2>\n\n\n\n

Mistake 1: Optimizing the Product Before Completing the Legal Analysis<\/strong><\/h3>\n\n\n\n

The most common and costly mistake in design-around programs is allowing formulation scientists to optimize their preferred formulation before patent counsel has completed the freedom-to-operate analysis. This produces a beautifully optimized formulation that infringes the primary patent and requires a complete restart of the development program. The legal analysis must precede and constrain the technical development, not follow it.<\/p>\n\n\n\n

Mistake 2: Ignoring Continuation Applications<\/strong><\/h3>\n\n\n\n

Orange Book listings show only the patents listed at the time of the most recent NDA update. Patent families with pending continuation applications can produce newly issued patents after the ANDA filing that are specifically drafted to capture the proposed design-around formulation. The most sophisticated innovator IP teams monitor ANDA filings and, when they identify a Paragraph IV certification based on a non-infringement argument, file continuation applications with claims drafted to cover the proposed design-around before it can be commercially launched. Design-around analysis must include a thorough review of all pending continuation and continuation-in-part applications in the relevant patent families, not just the issued patents.<\/p>\n\n\n\n

Mistake 3: Treating Doctrine of Equivalents as a Binary Question<\/strong><\/h3>\n\n\n\n

Doctrine of equivalents analysis is not binary \u2014 it is probabilistic. Courts differ in how they apply the function-way-result test, and different judges on the Federal Circuit have different analytical approaches. A non-infringement opinion that simply states ‘the proposed formulation does not infringe under the doctrine of equivalents’ without addressing the specific claim limitations and the prosecution history for each, without acknowledging the range of possible judicial outcomes, and without providing a probability assessment of each outcome, is not an adequate basis for a design-around commercial decision.<\/p>\n\n\n\n

Mistake 4: Underestimating the Analytical Work Required for Solid-State Patents<\/strong><\/h3>\n\n\n\n

Polymorphic form, co-crystal, and amorphous solid dispersion patents require solid-state analytical characterization of both the patented form and the proposed alternative. XRPD, solid-state NMR, DSC, and hot-stage microscopy are required for a complete characterization. The Entresto ‘918 patent litigation shows that even the patentee can fail to adequately prove which solid-state form is present in an ANDA product. A generic manufacturer who has not rigorously characterized its own product’s solid-state properties cannot mount an effective non-infringement defense on these patents.<\/p>\n\n\n\n

Key Takeaways<\/strong><\/h2>\n\n\n\n

1. Formulation patents protect the delivery architecture, not the molecule.<\/strong> A composition-of-matter expiry does not clear the portfolio. Every formulation, process, and method-of-use patent listed in the Orange Book represents a separate infringement exposure that requires individual analysis. Sophisticated design-around programs address all three patent layers, not just the composition patent.<\/p>\n\n\n\n

2. The prosecution history is the claim boundary.<\/strong> The claims define what the patentee argues is protected; the prosecution history defines what a court will hold is actually protected. Design-around analysis without a thorough prosecution history review is legally incomplete and risks a doctrine of equivalents attack on your non-infringement position.<\/p>\n\n\n\n

3. The six design-around vectors are independent of each other.<\/strong> Alternative excipients, alternative solid-state forms, alternative release architectures, alternative salt and co-crystal forms, alternative particle engineering, and alternative routes of administration each offer a distinct IP escape route. A drug with a dense formulation portfolio may still have one or two open vectors that a skilled formulation scientist can exploit.<\/p>\n\n\n\n

4. Collegium, MSN, and Hikma prove the model works.<\/strong> The DETERx microsphere system for Xtampza ER circumvented Purdue’s PEO matrix patents through architectural substitution. MSN’s generic Entresto launched in July 2025 after successfully challenging Novartis’s ‘659 combination patent. Hikma’s icosapent ethyl generic launched in 2020 after the obviousness invalidation of Amarin’s method-of-use patents. Each case followed a different technical path but the same analytical framework.<\/p>\n\n\n\n

5. The $300 billion patent cliff through 2030 is the largest design-around opportunity in pharmaceutical history.<\/strong> Keytruda, Eliquis, Stelara, Opdivo, and dozens of other blockbusters face formulation patent portfolios that can be systematically analyzed for design-around opportunities. The companies that invest in this analysis now \u2014 before the ANDA queues form \u2014 will capture the first-filer 180-day exclusivity advantage and the NPV lead over reactive competitors.<\/p>\n\n\n\n

6. Policy changes favor challengers.<\/strong> The FTC’s delisting campaign removed hundreds of improperly listed device and component patents. The Amgen v. Sanofi<\/em> written description standard creates new invalidity arguments against broad functional formulation claims. The Federal Circuit’s 2024 inhaler delisting rulings set clear limits on what can legitimately trigger a 30-month stay. The legal terrain for design-around programs is more challenger-friendly in 2026 than it was in 2020.<\/p>\n\n\n\n

7. No design-around is complete without a qualified FTO opinion.<\/strong> Technical creativity in formulation science does not create legal safety. Every design-around program requires a claim-by-claim non-infringement analysis from qualified patent counsel, including a prosecution history estoppel analysis and a doctrine of equivalents assessment, before the product is finalized and certainly before an ANDA is filed.<\/p>\n\n\n\n

\n\n\n\n

Frequently Asked Questions<\/strong><\/h2>\n\n\n\n

Q1: How does a design-around differ from a Paragraph IV invalidity challenge, and when should a generic manufacturer choose one over the other?<\/p>\n\n\n\n

A design-around is a non-infringement strategy: you change the formulation so it falls outside the patent claims, then file a Paragraph IV certification asserting that the patent is not infringed by your product. An invalidity challenge \u2014 whether in district court litigation or through an IPR petition at the PTAB \u2014 attacks the patent itself, arguing that it should never have been granted because the invention was not novel, not non-obvious, or not adequately disclosed. The two strategies are not mutually exclusive. Most Paragraph IV certifications include both a non-infringement argument and an invalidity argument. The choice depends on the relative strength of each argument for a specific patent. If the patent covers a genuinely innovative formulation with strong prior art support and a well-constructed prosecution history, invalidity arguments may be weak, and a design-around is the more reliable path. If the patent was granted over weak art or with claims that stretch well beyond the examples in the specification, invalidity through IPR may be faster and cheaper than developing an alternative formulation. When both options have merit, run them in parallel: develop the design-around while filing the IPR, and let the outcomes of each inform the overall launch strategy.<\/p>\n\n\n\n

Q2: What is the biggest misconception about bioequivalence and design-around formulations?<\/p>\n\n\n\n

The biggest misconception is that bioequivalence approval by the FDA means the design-around product cannot infringe a formulation patent. The FDA evaluates products on pharmacokinetic performance; it does not evaluate patent infringement, which is a legal question determined by courts. A product can be fully FDA-approved as bioequivalent \u2014 same Cmax, same AUC, within the 80-125% confidence interval for both \u2014 and still infringe a formulation patent. The Cmax and AUC measurements do not reveal whether the product contains HPMC or ethyl cellulose, whether the particles are crystalline or amorphous, or whether the release mechanism is matrix diffusion or membrane-controlled osmosis. Those structural distinctions are what patent claims cover. Bioequivalence gets you approved. Patent clearance \u2014 through non-infringement analysis, invalidity arguments, or license negotiation \u2014 keeps you in the market after launch.<\/p>\n\n\n\n

Q3: How does the ‘obvious to try’ doctrine apply to formulation patents, and when does it succeed?<\/p>\n\n\n\n

The ‘obvious to try’ doctrine, developed in the post-KSR era following the Supreme Court’s 2007 decision in KSR International v. Teleflex<\/em>, applies when the prior art identifies a problem, offers a finite set of known candidate solutions, and pursuing any of those candidates would involve routine experimentation rather than inventive work. Courts have found this argument particularly effective against formulation patents when the toolkit of available excipients and delivery approaches is well-established. The argument works when three conditions are present: the prior art must identify the specific technical problem the patentee solved (e.g., poor aqueous solubility of a BCS Class II compound); the prior art must suggest a finite, predictable set of solutions (e.g., HPMC matrices, amorphous solid dispersions, nanoparticles, lipid formulations); and the patentee’s specific choice within that set must have been predictable in outcome rather than surprisingly better. The argument fails when the patentee can demonstrate unexpected results: if the claimed formulation achieves a 70% improvement in bioavailability while the closest prior art example achieves only 20%, the unexpectedness of that result is evidence that a skilled formulator would not have predicted the outcome, defeating the ‘obvious to try’ challenge. Preparing this evidence proactively \u2014 before filing the application \u2014 is standard lifecycle management practice for innovators. Identifying whether an innovator did this, and how strong their unexpected results data actually is, is a key step in design-around invalidity analysis.<\/p>\n\n\n\n

Q4: Can an innovator company patent a design-around of its own product to block a generic’s strategy?<\/p>\n\n\n\n

Yes, and it happens regularly. When an innovator identifies a likely design-around approach from monitoring ANDA filings and Paragraph IV certifications, it can file continuation applications with claims specifically drafted to capture the design-around formulation. This practice is legal under current patent law: an inventor who discloses a broad genus of formulations in the original specification can prosecute continuation claims covering specific species within that genus for as long as a parent application with the same disclosure remains pending. The practical counter-strategy for generic manufacturers is to file ANDA applications early, because an issued patent cannot reach back to capture an ANDA filed before the continuation’s issue date under the Hatch-Waxman first-to-file analysis. Monitoring the continuation prosecution of all pending applications in the relevant patent family is a mandatory component of any design-around program that extends beyond 18-24 months from the initial FTO analysis.<\/p>\n\n\n\n

Q5: What do the Inflation Reduction Act’s drug price negotiation provisions mean for design-around program economics?<\/p>\n\n\n\n

The IRA’s Medicare drug price negotiation program compresses the economic incentive for both innovators and generic manufacturers in the affected drug categories. For drugs selected for negotiation \u2014 the first 10 included Eliquis, Enbrel, Jardiance, Januvia, Farxiga, and others \u2014 the IRA sets a ‘maximum fair price’ at which Medicare Part D must cover the drug. This price reduction reduces the revenue that the innovator is defending with its patent portfolio, which in turn reduces the economic value of every year of additional exclusivity that a formulation patent or design-around fight is protecting. For generic manufacturers, the reduction in brand revenue translates to a reduction in generic revenue at market entry: if the brand is already selling at IRA-negotiated prices substantially below its unregulated price, the generic price at which a competitor can enter profitably is also reduced. The net effect on design-around investment decisions is case-specific. For drugs where the IRA negotiation produces a 50-60% price reduction, the NPV of a design-around program that accelerates market entry by three years may be materially lower than it would have been under the pre-IRA pricing structure. Financial modeling for design-around programs targeting IRA-negotiated drugs should explicitly account for the negotiated price in the generic market entry revenue projections, not the historical brand WAC price.<\/p>\n\n\n\n

\n\n\n\n

References<\/strong><\/h2>\n\n\n\n
    \n
  1. Fish & Richardson. (2025, October 27). Lessons for biopharma from the battle of Entresto.<\/em> Fish Richardson IP Law. https:\/\/www.fr.com\/insights\/thought-leadership\/blogs\/lessons-for-biopharma-from-the-battle-of-entresto\/<\/li>\n\n\n\n
  2. Amgen Inc. v. Sanofi, 598 U.S. 594 (2023).<\/li>\n\n\n\n
  3. Congressional Research Service. (2026, January 21). Patent listing in FDA’s Orange Book<\/em> (Report No. IF12644). Congress.gov. https:\/\/www.congress.gov\/crs-product\/IF12644<\/li>\n\n\n\n
  4. DrugPatentWatch. (2026, March 22). ANDA litigation: The complete playbook for pharmaceutical patent litigators, IP teams, and institutional investors.<\/em> DrugPatentWatch. https:\/\/www.drugpatentwatch.com\/blog\/anda-litigation-strategies-and-tactics-for-pharmaceutical-patent-litigators\/<\/li>\n\n\n\n
  5. DrugPatentWatch. (2026, March 22). Drug patent strategy: The definitive guide for pharmaceutical IP teams, R&D leads, and institutional investors.<\/em> DrugPatentWatch. https:\/\/www.drugpatentwatch.com\/blog\/optimizing-your-drug-patent-strategy-a-comprehensive-guide-for-pharmaceutical-companies\/<\/li>\n\n\n\n
  6. DrugPatentWatch. (2026). Drug patent formulation intelligence: The definitive guide to decoding competitor strategy.<\/em> DrugPatentWatch. https:\/\/www.drugpatentwatch.com\/blog\/cracking-the-code-using-drug-patents-to-reveal-competitor-formulation-strategies\/<\/li>\n\n\n\n
  7. Crystal Pharmatech. (2024). Crystal’s perspective: Polymorph patent landscape of 28 FDA-approved small molecule drugs in 2024.<\/em> Crystal Pharmatech. https:\/\/www.crystalpharmatech.com\/crystals-perspective-polymorph-patent-landscape-of-28-fda-approved-small-molecule-drugs-in-2024.html<\/li>\n\n\n\n
  8. Noonan, K. E. (2024, August 7). Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc. (Fed. Cir. 2024).<\/em> Patent Docs. https:\/\/www.patentdocs.org\/2024\/08\/amarin-pharma-inc-v-hikma-pharmaceuticals-usa-inc-fed-cir-2024.html<\/li>\n\n\n\n
  9. DrugPatentWatch. (2026, March 29). Pharma patent filing strategies that maximize exclusivity: The complete IP playbook.<\/em> DrugPatentWatch. https:\/\/www.drugpatentwatch.com\/blog\/filing-strategies-for-maximizing-pharma-patents\/<\/li>\n\n\n\n
  10. D Young & Co. (2018, October 12). Pharmaceutical patenting.<\/em> D Young & Co. https:\/\/www.dyoung.com\/en\/knowledgebank\/articles\/pharmaceuticalpatenting0213<\/li>\n\n\n\n
  11. Fish & Richardson. (2025). Lessons for biopharma from the battle of Entresto<\/em> (see [1]).<\/li>\n\n\n\n
  12. DeepCeutix. (2026, February 2). $300 billion in pharma revenue loses patent protection by 2030.<\/em> DeepCeutix Strategic Briefings. https:\/\/deepceutix.com\/insights\/patent-cliff-reformulation<\/li>\n\n\n\n
  13. DrugPatentWatch. (2023, March 23). A strategic guide to patenting drug combinations.<\/em> DrugPatentWatch. https:\/\/www.drugpatentwatch.com\/blog\/successfully-patenting-drug-combinations-strategies-and-challenges\/<\/li>\n\n\n\n
  14. Novartis. (2023, July 7). Novartis will appeal to U.S. Court of Appeals to uphold validity of Entresto combination patent.<\/em> Novartis Media Releases. https:\/\/www.novartis.com\/news\/media-releases\/novartis-will-appeal-us-court-appeals-uphold-validity-entresto-combination-patent-maintains-2023-guidance-and-mid-term-outlook<\/li>\n\n\n\n
  15. Collegium Pharmaceutical. (2015, February 26). Collegium Pharmaceutical announces notice of allowance for U.S. patent covering DETERx, an abuse-deterrent, extended-release, technology platform<\/em> [Press release]. GlobeNewswire. https:\/\/www.globenewswire.com\/news-release\/2015\/02\/26\/710145\/10122088\/en\/<\/li>\n\n\n\n
  16. Pergolizzi, J., et al. (2018). Review of opioid abuse-deterrent formulations: Impact and barriers to access.<\/em> National Institutes of Health, PubMed Central. https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC11162618\/<\/li>\n\n\n\n
  17. Medscape. (2016). FDA gives final approval to abuse-deterrent Xtampza ER.<\/em> Medscape Medical News. https:\/\/www.medscape.com\/viewarticle\/862662<\/li>\n\n\n\n
  18. Anderson, N. P., et al. (2020). Use of a long-acting opioid microsphere formulation to overcome difficulties in swallowing pain medication.<\/em> Journal of Pain Research.<\/li>\n\n\n\n
  19. Petrie-Flom Center. (2021, September 23). Fatty acids, skinny labels: Fish oil patent battle back in court.<\/em> Harvard Law Petrie-Flom Center. https:\/\/petrieflom.law.harvard.edu\/2021\/09\/23\/fish-oil-patent-battle\/<\/li>\n\n\n\n
  20. BioSpace. (2020). Amarin’s Vascepa loses patent protection in court battle, shares plunge.<\/em> BioSpace. https:\/\/www.biospace.com\/amarin-shares-plunge-following-ruling-in-vascepa-patent-lawsuit<\/li>\n\n\n\n
  21. Pharmaphorum. (2020). Amarin hit hard as generics loom for fish oil drug Vascepa.<\/em> Pharmaphorum. https:\/\/pharmaphorum.com\/news\/amarin-hit-hard-as-generics-loom-for-fish-oil-drug-vascepa<\/li>\n\n\n\n
  22. Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc., No. 21-2071 (Fed. Cir. Aug. 2024).<\/li>\n\n\n\n
  23. Fierce Pharma. (2022, March 31). Amid US patent defeat for Vascepa, Amarin makes strides in EU for fish-oil-derived heart drug.<\/em> Fierce Pharma. https:\/\/www.fiercepharma.com\/marketing\/amid-us-patent-defeat-vascepa-amarin-makes-strides-eu-fish-oil-derived-heart-drug<\/li>\n\n\n\n
  24. STAT News. (2018, November 7). Behind the patent thicket: Tactics AbbVie allegedly used to thwart biosimilar versions of Humira.<\/em> STAT News. https:\/\/www.statnews.com\/pharmalot\/2018\/11\/07\/abbvie-biosimilars-humira-patents\/<\/li>\n\n\n\n
  25. DeepCeutix. (2026). $300 billion in pharma revenue loses patent protection by 2030<\/em> (see [12]).<\/li>\n\n\n\n
  26. Petrie-Flom Center. (2021, January 6). AbbVie wins first round in Humira antitrust lawsuit.<\/em> Harvard Law Petrie-Flom Center. https:\/\/petrieflom.law.harvard.edu\/2021\/01\/06\/abbvie-humira-antitrust-patent-thicket\/<\/li>\n\n\n\n
  27. Mintz. (2020, June 18). AbbVie’s enforcement of its ‘patent thicket’ for Humira under the BPCIA.<\/em> Mintz Levin. https:\/\/www.mintz.com\/insights-center\/viewpoints\/2231\/2020-06-18-abbvies-enforcement-its-patent-thicket-humira-under<\/li>\n\n\n\n
  28. DeepCeutix. (2026). $300 billion in pharma revenue loses patent protection by 2030<\/em> (see [12]).<\/li>\n\n\n\n
  29. DrugPatentWatch. (2026). Drug patent challenges: The complete strategic playbook for IP teams and portfolio managers.<\/em> DrugPatentWatch. https:\/\/www.drugpatentwatch.com\/blog\/when-science-meets-law-the-art-and-strategy-of-challenging-drug-patents\/<\/li>\n\n\n\n
  30. Amgen Inc. v. Sanofi, 598 U.S. 594 (2023) (see [2]).<\/li>\n\n\n\n
  31. DrugPatentWatch. (2026). Drug patent challenges: The complete strategic playbook<\/em> (see [29]).<\/li>\n\n\n\n
  32. DrugPatentWatch. (2026). Drug patent formulation intelligence<\/em> (see [6]).<\/li>\n\n\n\n
  33. DrugPatentWatch. (2026). Drug patent strategy: The definitive guide<\/em> (see [5]).<\/li>\n\n\n\n
  34. DeepCeutix. (2026). $300 billion in pharma revenue loses patent protection by 2030<\/em> (see [12]).<\/li>\n\n\n\n
  35. Congressional Research Service. (2026). Patent listing in FDA’s Orange Book<\/em> (see [3]).<\/li>\n\n\n\n
  36. DrugPatentWatch. (2026). Drug patent strategy: The definitive guide<\/em> (see [5]).<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    A practitioner’s guide for IP teams, generic manufacturers, and pharmaceutical investors who need to decode what a competitor’s formulation patent […]<\/p>\n","protected":false},"author":1,"featured_media":38842,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_lmt_disableupdate":"","_lmt_disable":"","site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[10],"tags":[],"class_list":["post-38837","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-insights"],"modified_by":"DrugPatentWatch","_links":{"self":[{"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/posts\/38837","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/comments?post=38837"}],"version-history":[{"count":1,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/posts\/38837\/revisions"}],"predecessor-version":[{"id":38843,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/posts\/38837\/revisions\/38843"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/media\/38842"}],"wp:attachment":[{"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/media?parent=38837"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/categories?post=38837"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.drugpatentwatch.com\/blog\/wp-json\/wp\/v2\/tags?post=38837"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}