United States: Patent Term and Opportunities for Managing IT

Large biopharmaceutical companies are at the forefront of exploring increasingly sophisticated intellectual property strategies for maximizing return on their R&D efforts. These strategies were born out of the recognition that during the next five years, several of the top 15 biopharmaceutical products will come off patent, creating a world market opportunity approximating $20 billion.¹ Add in the fact that R&D productivity dropped 25 percent between the first half 1990s and the second half of the decade² and a recognition of recent legislative efforts to reform the regulatory framework established by the Hatch-Waxman Act, and the reasons for the push to protect these companies’ intellectual property becomes apparent.³ This article provides an overview of proactive patent procurement strategies for creating a value chain framework⁴ aimed at identifying and protecting not only innovations resulting from earlier R&D efforts but also innovations available during the high-profit stages that occur later in the life cycle of a given product.

To illustrate the approach, we will use as an example any development of a new class of moieties along with different available indications, formulations and modes of administration typical in the industry. Figure 1 illustrates a value chain framework as it might be developed for a strategic product platform.⁵

Related drug candidates are often considered during early phases of discovery, prompting multiple provisional patent application filings as research evolves.⁶ As with most new products, in the case of new chemical entities (NCEs), it is advisable to conduct a patent landscape study early on to identify any barriers to patentability or use (e.g., relevant pending or issued patents owned by other entities),⁷ potential competitors and existing or developing competing products. This study will give insight to the available market space. A well crafted and well executed patent landscape study should provoke an interdisciplinary review,⁸ in this example, a review of candidate NCEs, their foreseeable therapeutic applications, regulatory considerations and potential barriers to establish and maximize patent- and non-patent-driven exclusivities. From inception, team focus should be directed to the long-term goal of developing an overall product platform along with the short-term goal of developing a single first product.

Historically, patent applications filed in the earliest stages of portfolio development have disclosed the broadest possible conception of the invention including, in the context of biopharmaceuticals, a broad genus, narrower subgenus(es) and particularly desirable compounds, as well as foreseeable indications, ultimately leading to specific protection of clinical candidates, compositions and their clinical use.⁹ This approach, however, has been reevaluated by many sophisticated entities engaged in biopharma research, reflecting the realization that it may undercut efforts to capitalize on different aspects of the product platform that are not incorporated in the first product selected for clinical development. For example, consider possible chemical modifications of a given NCE, which are ideally suited for later development as subsequent generations products (i.e., downstream on the continuum of Figure 1). The earliest filed application (which will publish 18 months after filing) will often become prior art to later filings covering compounds, compositions or indications that were given broad-brush treatment in the earlier filings. In this situation, applicants may be compelled or even forced to rely on the earliest filings, effectively missing out on potential opportunities that might otherwise be provided by later developments to extend a product life cycle.¹⁰

However, if the ability to obtain meaningful protection of downstream products is to be preserved, careful strategic planning with the objective of balancing the competing needs to protect the broadest inventive concepts in the initial filings against the need to preserve the ability to make (later) filings directed to preferred moieties and additional therapeutic applications is paramount.¹¹ This tension is ideally resolved by a concerted, coordinated effort to coordinate marketing exigencies and research and development resources, as well as business realities, with staggered patent filings and proper disposition of trade-secret assets in an aggressive fashion to create, preserve and capture downstream opportunities.¹²

It is key to align development of first, second and even third-generation versions of a given product under development as soon as they are recognized. Strategic patent filings, tailored to the coordinated development of products within a product platform so as to retain control of the market share, are gaining momentum. At times, it is advisable to file applications focusing on distinct aspects of the different concepts within a core product platform to avoid the effect of omnibus disclosures that might create future patentability problems. In some instances, the breadth of the disclosure for a given invention can and probably should be narrowed in a manner that is consistent with the applicant’s best mode obligation, thereby preserving the ability to procure patent protection for a later-developed subgenus or other permutation. In some circumstances, appreciating and even publicizing¹³ the limitations of a given subgenus is key to setting the stage for later applications seeking to solve an underlying issue now recognized in the art.

In the preclinical stage, further characterization of the biochemical properties of a NCE often leads to the selection of a defined NCE candidate. Crystals, stereoisomers,¹⁴ polymorphs,¹⁵ hydrates, solvates, new processes (e.g., synthetic or semisynthetic), biological mode(s) of action¹⁶ and possibly key intermediates¹⁷ are also often identified at this stage.

Consistent with the need to avoid statutory bars and to preserve absolute novelty, secondary patent applications should be critically timed to maximize patent life value upstream and downstream along the value chain continuum. The decision of when to file secondary patent applications should be carefully weighed in view of practical considerations, including disclosures necessary for financing, regulatory purposes and the need to protect innovation from leaking outside the company. The clear case for simultaneous filing is presented by those aspects of an inventions integral to a product selected for clinical development and regulatory approval or strictly necessary to create a barrier to entry in the market space of the product in clinical trials. In this context, the patentability of structurally related moieties, including prodrugs, esters and salts should be carefully evaluated¹⁸ to identify opportunities for future development. This evaluation should be done by the innovator company as well by others seeking to enter the market under development.¹⁹ Research tools are often identified during this stage of development and are an integral part of the overall strategy, providing additional openings for extracting value and inhibiting competitors²⁰ (e.g., creating platform technologies).

A critical consideration is whether and when to list a patent²¹ in the Orange Book,²² thus providing a modicum of exclusivity and notice under controlling provisions. Under the current law, innovators are required to inform the U.S. Food and Drug Administration (FDA) of each NCE, composition, formulation or use (but not process) patent covering the product for which the innovator is seeking approval. The FDA then lists the patents identified by the innovators in the Orange Book.²³ Recently adopted changes to the Hatch-Waxman Act, which defines the Abbreviated New Drug Application (ANDA) framework, effectively limit brand-name drug manufacturers to one FDA 30-month stay of competition in a patent infringement suit against a generic drug applicant, providing a strong incentive to obtain issued patents for listing in the Orange Book as early as possible. Thus, one former strategy, the systematic listing of patents²⁴ to delay generic development by continually restarting the 30-month stay, is no longer available. However, additional later-available patents may still provide further valuable barriers for competitors’ entry into the market.²⁵

Notably, patent applications directed to different crystal forms often encounter patentability hurdles absent evidence that each crystal is patentably distinguishable (e.g., evidence of superior properties).²⁶ Patents directed to specific stereoisomers present similar challenges. However, patent protection is likely to be available upon establishing clinical or other practical significance (e.g., improved purity and/or effectiveness) of a particular crystal form, stereoisomer, polymorph, product obtained by a new process (e.g., synthetic or semisynthetic) and, possibly, a key intermediate, potentially providing an additional Orange Book listing and barrier to entry for competitors. Metabolites present a more difficult situation requiring a case-by-case analysis in light of patentability considerations (e.g., inherency) and the controversial issue as to whether they cover the "approved product."

Later stages in clinical development often bring to light more information leading to the identification and elucidation of prodrugs, degradation products, new formulations, drug delivery devices, additional uses and indications, mode and timing of administration, treatment regimens, specific dosing and multiple-drug interactions. Again, patentability assessment, portfolio design considerations and, foremost, Orange Book listing opportunities will dictate the form and timing of filings to extend patent protection in time and scope to cover these additional developments. Often by this time, manufacturing considerations are under development and scale-up processes are delineated. To take advantage of that reality, production method patents (e.g., scale up) ideally should be drafted to capitalize on specific process aspects²⁷ relating to the product under approval. Whenever feasible, these cases should be filed separately from and, if possible, subsequent to the filing of the NCE patent application to provide additional patent protection following expiration of primary patent filings. Under certain circumstances, competitors will have access to the drug itself, but will not have the right to manufacture it according to the patented and approved methods. Clearly, this strategy is more attractive for so-called biologics than with traditional drugs (e.g., small molecule) because of the complexity and process-of-making interdependency inherent to macromolecular entities.²⁸ In addition to the intellectual property harvesting examples mentioned above, downstream innovations include active chemical modification, purified forms and reformulation, as well as combinations of these approaches. Design protection for package and dosage forms should be considered as well.

Chemical modification of a compound changes the underlying chemical structure creating an NCE and requiring a full NDA process, which is expensive. However, a timely filed patent application covering the modified compound adds value by extending the life cycle of these drugs. Chemical modifications of lead compounds of several biopharmaceutical companies have resulted in new compounds that have improved pharmacological profiles and which replace the original approved drug (e.g., desloratadine, or CLARINEX®, an active metabolite designed to supplant loratadine, or CLARITIN®, as it shifted to the over-the-counter market). A particular type of chemical modification involves identifying desirable compositions that combine an existing drug product with other active pharmaceutical ingredients.

Optically pure forms of known compounds are gaining considerable attention as clever opportunities to expand a product platform. Well-timed chiral switching can offer enhanced therapy and further profitability as means of product line extension for profitable racemic drugs facing expiring patent protection. A recent study highlighted the opportunities presented by drugs that have been approved as racemates or as mixtures of diastereomers (e.g., epimers) but have been developed later as single enantiomers, or even single enantiomers that have been redeveloped as paired enantiomers.²⁹ In commercial terms, perhaps the most significant example of the successful use of chiral switching is offered by AstraZeneca PLC’s drug, omeprazole (PRILOSEC®), which is a racemate biologically acting as a prodrug. A chiral switch was affected before expiration of the patents covering the racemate and also before the incursion of the respective generic drugs onto the market, effectively converting the market share to the optically pure form known as esomeprazole magnesium, or NEXIUM®. In contrast, efforts to affect a chiral switch of fluoxetine HCl or PROZAC®, which had been developed and sold as a racemate, were unsuccessful. Clinical trials using a single enantiomer of PROZAC® as a second generation SSRI antidepressant drug were aborted following reports of adverse effects, which would have delayed approval. The delay allowed generic versions of PROZAC® to reach and capture the market, severely limiting any future market for the second-generation product.

Reformulation strategies may generate significant value in life-cycle management. This stems from the considerably lower developmental costs and complexities³⁰ as compared to de novo chemical modifications of an approved drug. Also, because changes in the formulation often improve pharmacokinetic properties or patient compliance, they are generally patentable.

Improved bioavailability forms (e.g., forms associated with increased solubility or permeability) provide further downstream opportunities for patent filings. Technologies for improving bioavailability range from traditional coating approaches to nanoparticle approaches (e.g., RAPAMUNE® by Wyeth Pharmaceuticals Inc.). Forms such as sustained release (SR) or the converse, immediate release (IR), also fall within this category. Pharmacokinetic advantages inherent to the availability of SR or IR forms may create a "new intellectual property space" for an existing drug already on the market.³¹ Alternative routes of administration may also define a proprietary playing field in downstream endeavors. Successful examples include nasal delivery of existing oral forms for more rapid absorption into the blood stream and avoiding first pass hepatic elimination (e.g., making IMITREX® by GlaxoSmithKline available for nasal administration to treat migraines). Another example includes attempts to develop inhalation administration technologies applicable to large molecules traditionally requiring peripheral or parenteral administration. Others include a garden variety of administration approaches applied to known drugs already on the market to improve efficacy and/or patient compliance using osmotic devices such as patches or depot injections, to mention but a few. Such delivery methods are themselves the focus of considerable research (e.g., oral administration of peptides and peptidic entities).

A well developed patent portfolio strategy is essential for protection of biopharma assets and investments. A patent filing strategy, however, is only as good as the research generating new products. In today’s competitive environment, it is especially important that R&D focus on developing innovations that extend a new drug’s life cycle via second and third-generation products utilizing different formulations, alternative modes of administration, useful for new indications and the like. A patent portfolio strategy that keeps pace with evolving business objectives and R&D progress can maximize the life span of patent protection for lead products and provide formidable advantage over competitors. More and more, a sophisticated biopharmaceutical firm will focus its patenting strategies on protecting a technology platform that covers all of its core technologies, processes and services by making strategic, staggered patent filings throughout the process of product development, including defensive filings when feasible and continuation applications where necessary. Strategically filed independent applications covering various aspects of an evolving product will enable a company to achieve market dominance and competitive advantage by supplementing patent coverage of core technologies and extending patent life cycles in reaction to changes in the market and technology. By filing for patent applications, represent the fruits of ongoing R&D efforts over a staggered period of time, a new patent covering some aspect of a drug may issue as an old patent nears expiration, allowing continuing patent protection and maximization of market exclusivity.

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