'Add-on Patents': Innovation or Sham?

Once a drug is approved in the United States by the federal Food and Drug Administration (“FDA”) for marketing, the drug owner must provide the FDA with a listing of all patents that cover the approved drug product. The FDA publishes these patents in its “Approved Drug Products with Therapeutic Equivalence Evaluations” publication, otherwise know as the “Orange Book” (so-called because it is actually orange in color). Although the branded pharmaceutical company must certify to the FDA that the patents so submitted cover the approved drug product, allegations of “gaming” the patent system have led the FDA to tighten rules regarding listing of patents in its Orange Book. Such gaming stemmed from branded pharmaceutical companies inappropriately listing patents in the Orange Book.

FDA regulations permit the listing of patents covering the active drug ingredient (eg, the compound which is the active agent), the drug product (eg, a formulation or composition of the active agent), a method of use of the approved product (eg, treatment of a disease or condition) and a drug product made by a particular process. FDA regulations prohibit the listing of patents on intermediates or metabolites, on packaging and processes for making the drug or drug product. Product-by-process patents are listable only if the product made by the particular process is novel. Polymorph patents may be listed provided certain testing requirements are met.

Listed patents serve as a barrier to exclude generic drug companies from entering the market with a competing drug. When seeking approval to market a generic version of a drug, the generic manufacturer must certify to the FDA, one of the following four conditions with respect to the listed patents: 1) there are no listed patents; 2) the listed patents have expired; 3) the listed patents will expire before the generic manufacturer markets its drug; or 4) the listed patents are invalid and/or will not be infringed by the generic drug. If the generic manufacturer certifies that the listed patents are invalid or that the generic drug will not infringe the listed patents, litigation between the branded company and the generic typically ensues.

'Add-on' Patent Approaches

Add-on patents are an approach that branded pharmaceutical companies may seek to offset expiration of patents directed to the base drug or active ingredient. Add-on patents are generally directed to different aspects or properties of the base drug or active agent. Add-on patents include those directed to improved formulations, improved dosing, delivery or bioavailability, derivative compounds, individual isomers of an active agent, stabilized forms of an active agent, a new use of an active agent, and combinations of active agents. These patents are listable in the Orange Book.

Patents directed to improved formulations form one class of common add-on patents. New patentable formulations may increase efficacy and. safety, decrease undesirable side effects, increase shelf life, increase stability of the active ingredient and/or enhance tissue specificity. Specifically, improved formulations may involve changes to excipients or carriers, compounding, or inactive ingredients, such as antioxidants or antimicrobials. For example, paricalcitol (Zemplar'), a vitamin D compound, was originally approved in an intravenous formulation that contained an antioxidant because of its susceptibility to oxidation. The antioxidant had an undesirable yellowing effect. The drug product was reformulated to eliminate the antioxidant as well as certain preservatives or stabilizers having the potentially adverse effect of nephrotoxicity. (See, U.S. Patents 6,136,709 and 6,631,751.) Propofol (Diprivan'), an anesthetic, was originally formulated as a preservative-free. This formulation was susceptible to microbial contamination. A new formulation added edetate as an anti-microbial. (See, U.S. Patent 5,714,520.) Omeprazole (Prilosec'), an inhibitor of gastric acid secretion, as originally formulated was prone to degradation at low pH. A new alkaline formulation eliminated the low pH degradation tendency. (See, U.S. Patents 4,786,505 and 4,853,230.)

Another add-on approach involves improved dosing, delivery or bioavailability. For example, many drugs are marketed in controlled release formulations that provide a more constant blood level of the drug, and may improve in vivo half-life of the active ingredient. Such improved dosing may facilitate better patient compliance by requiring a less frequent dosing or may decrease side effects often associated with spike peak concentrations typically associated with immediate release formulations. For example, human growth hormone (hGH) was originally formulated as a daily injection. It was reformulated as a long-acting hGH, which reduced the frequency of injection. (See, U.S. Patents 5,654,010 and 5,656.297.) Another example is bupropion hydrochloride (Wellbutrin'), an antidepressant, which was originally formulated as an immediate release tablet for treatment of depression. It is now approved and patented in both sustained release (Wellbutrin SR'; see, eg, U.S. Patent 5,763,493) and extended release forms (Wellbutrin XL'; see, eg, U.S. Patent 6,143,327). Venlafaxine hydrochloride (Effexor') is another example of a drug that was originally formulated in an immediate release tablet, and is now approved and patented in an extended release capsule (Effexor XR'; see, eg, U.S. Patents 6,419,958 and 6,444,708).

Another approach for improved delivery, successful for some biologics (eg, proteins), is pegylation. Pegylating is a method by which a biologic or drug is conjugated with polyethylene glycol. Pegylation has been noted to improve absorption and bioavailability of some poorly absorbed and poorly bioavailable drugs. For example, peginterferon alfa-2a (see, eg, Pegasys') has a significantly higher proportion of virological response compared to conventional interferon-2a (see, eg, Intron A').

Still another add-on approach involves seeking patents on individual isomers of a racemic drug. Most drug molecules exist as two mirror-image forms, only one of which is active. New separation techniques have been developed to isolate and discard the non-active isomer, enabling the manufacture of essentially the same drug with greater potency and/or fewer side effects. This strategy has generated a number of single isomer versions of drugs, including Prozac', Losec' and Claritin'.

Seeking patents on compounds derived from an active ingredient is yet another add-on approach. Modifications to drug molecules may increase efficacy, or decrease side effects. This approach is probably used less than other add-on approaches because the changing of the chemical structure of a drug generally requires new toxicity and efficacy studies. Until recently, related compounds such as metabolites could be listed in the Orange Book. While such compounds can no longer be listed, the case of loratadine and desloratadine illustrates the derived compound approach. Loratadine (Claritin'), a tricyclic antihistamine, (see, eg, U.S. Patent 4,282,233) had many adverse side effects, eg, arrhythmias, fatigue, dry mouth, and gastrointestinal distress. Desloratadine (Clarinex'), the active metabolite of loratadine, avoids adverse side effects caused by loratadine metabolic bi-products. (See, U.S. Patents 4,804,66 and 6,100,274.)

Patents on stabilized forms of an active agent can also provide another add-on approach. A certain purity profile or a new crystalline form may improve stability for handling and formulating the active agent. For example, calcipotriol or calcipoltriene (Dovonex') is a vitamin D compound that is marketed in a solution or ointment for topical administration for the treatment of psoriasis. Calcipotriol, as an anhydrous crystal, however, had poor stability in certain solutions, particularly in creams and gels. Moreover, the anhydrous form is not easily used in the milling process utilized to obtain a suitable small and uniform particle size. In fact, during the wet milling process, the anhydrous form developed a stable foam. A crystalline monohydrate was developed that is readily useable in a wet milling process for obtaining suitable particle size, and that permitted the manufacture of crystal suspension formulations. (See, U.S. Patent 5,763,426.)

Yet another approach is to develop a new use for an existing drug. This approach requires efficacy and toxicity testing. Bupropion hydrochloride, as noted above, was originally approved and patented as a treatment for depression. Burpropion hydrochloride (Zyban') is also approved and patented for smoking cessation. (See, U.S. Patent 5,763,493.)

Combination therapies involve combinations of active agents that are co-administered. The action of one drug supplements and complements the pharmaceutical action of the other drug, and the unexpected complementary action can form the basis for new patents. Such combinations may improve efficacy, or treat multiple symptoms of a disease. For example, an ACE inhibitor has been combined with L-carnitine, in which the ACE inhibitor treats high blood pressure and the carnitine treats other cardiovascular symptoms. (See, U.S. Patent 5,861,434.) Combination therapies are especially common in treatment of hyperproliferative diseases, eg, cancers. For example, a paclitaxel/cisplatin combination is approved for advanced ovarian carcoma and non-small cell lung cancer. A combination of fluoxetine hydrochloride, an antidepressant, and olanzapine, an antipsychotic, (Symbyax') is approved as a treatment of bipolar depression. (See, U.S. Patent 5,945,416.)

Challenging 'Add-ons'

While add-on patents can appropriately meet the standards for patentability, they are, as noted above, viewed in some quarters as suspect, addressing insignificant aspects of a drug. Nonetheless, add-on patents are favored for challenge by generic drug manufacturers, either because of their limited coverage or suspect validity. Indeed, litigation over add-on patents forms the majority of actions brought pursuant to the Drug Price Competition and Patent Term Restoration Act of 1984 (also known as the Hatch-Waxman Act), the law that was designed to reward innovation at major pharmaceutical companies and protect intellectual property while at the same time, lowering the costs by making it easier for generic drug manufacturers to reach the U.S. marketplace. Generics have prevailed in a significant number of these cases.

Conclusion

Pharmaceutical companies desire a robust, defensible proprietary position. Despite the risk of challenge, add-on patents are integral to a company's patent life cycle management and portfolio planning, providing an important avenue for maximizing patent term and market exclusivity.

Some recent estimates suggest that by 2007 brand name pharmaceutical companies will lose more than $80 billion in drug sales because of patent term expirations. Patent term expirations, of course, usher the entry of generic drugs into the marketplace. On average, the market share for branded products decreases by 15% to 30% when a first generic version reaches the market, and as much as 75% to 90% when subsequent generics launch. Such significant losses provide incentive to extend patent life and maximize the period of market exclusivity for a patented drug.

One approach for brand name pharmaceutical companies is to develop so-called “add-on” patents to those for existing drugs. Add-on patents typically address different aspects or new uses of an existing drug. These add-ons are also referred to as “second-generation patents,” “secondary patents” or “late-filed patents.” Some critics refer to add-on patents as sham patents, claiming that they often address insignificant elements of a drug, having less to do with any improved patient benefits and more to do with maintaining profits.

Patents and Approvals

Once a drug is approved in the United States by the federal Food and Drug Administration (“FDA”) for marketing, the drug owner must provide the FDA with a listing of all patents that cover the approved drug product. The FDA publishes these patents in its “Approved Drug Products with Therapeutic Equivalence Evaluations” publication, otherwise know as the “Orange Book” (so-called because it is actually orange in color). Although the branded pharmaceutical company must certify to the FDA that the patents so submitted cover the approved drug product, allegations of “gaming” the patent system have led the FDA to tighten rules regarding listing of patents in its Orange Book. Such gaming stemmed from branded pharmaceutical companies inappropriately listing patents in the Orange Book.

FDA regulations permit the listing of patents covering the active drug ingredient (eg, the compound which is the active agent), the drug product (eg, a formulation or composition of the active agent), a method of use of the approved product (eg, treatment of a disease or condition) and a drug product made by a particular process. FDA regulations prohibit the listing of patents on intermediates or metabolites, on packaging and processes for making the drug or drug product. Product-by-process patents are listable only if the product made by the particular process is novel. Polymorph patents may be listed provided certain testing requirements are met.

Listed patents serve as a barrier to exclude generic drug companies from entering the market with a competing drug. When seeking approval to market a generic version of a drug, the generic manufacturer must certify to the FDA, one of the following four conditions with respect to the listed patents: 1) there are no listed patents; 2) the listed patents have expired; 3) the listed patents will expire before the generic manufacturer markets its drug; or 4) the listed patents are invalid and/or will not be infringed by the generic drug. If the generic manufacturer certifies that the listed patents are invalid or that the generic drug will not infringe the listed patents, litigation between the branded company and the generic typically ensues.

'Add-on' Patent Approaches

Add-on patents are an approach that branded pharmaceutical companies may seek to offset expiration of patents directed to the base drug or active ingredient. Add-on patents are generally directed to different aspects or properties of the base drug or active agent. Add-on patents include those directed to improved formulations, improved dosing, delivery or bioavailability, derivative compounds, individual isomers of an active agent, stabilized forms of an active agent, a new use of an active agent, and combinations of active agents. These patents are listable in the Orange Book.

Patents directed to improved formulations form one class of common add-on patents. New patentable formulations may increase efficacy and. safety, decrease undesirable side effects, increase shelf life, increase stability of the active ingredient and/or enhance tissue specificity. Specifically, improved formulations may involve changes to excipients or carriers, compounding, or inactive ingredients, such as antioxidants or antimicrobials. For example, paricalcitol (Zemplar'), a vitamin D compound, was originally approved in an intravenous formulation that contained an antioxidant because of its susceptibility to oxidation. The antioxidant had an undesirable yellowing effect. The drug product was reformulated to eliminate the antioxidant as well as certain preservatives or stabilizers having the potentially adverse effect of nephrotoxicity. (See, U.S. Patents 6,136,709 and 6,631,751.) Propofol (Diprivan'), an anesthetic, was originally formulated as a preservative-free. This formulation was susceptible to microbial contamination. A new formulation added edetate as an anti-microbial. (See, U.S. Patent 5,714,520.) Omeprazole (Prilosec'), an inhibitor of gastric acid secretion, as originally formulated was prone to degradation at low pH. A new alkaline formulation eliminated the low pH degradation tendency. (See, U.S. Patents 4,786,505 and 4,853,230.)

Another add-on approach involves improved dosing, delivery or bioavailability. For example, many drugs are marketed in controlled release formulations that provide a more constant blood level of the drug, and may improve in vivo half-life of the active ingredient. Such improved dosing may facilitate better patient compliance by requiring a less frequent dosing or may decrease side effects often associated with spike peak concentrations typically associated with immediate release formulations. For example, human growth hormone (hGH) was originally formulated as a daily injection. It was reformulated as a long-acting hGH, which reduced the frequency of injection. (See, U.S. Patents 5,654,010 and 5,656.297.) Another example is bupropion hydrochloride (Wellbutrin'), an antidepressant, which was originally formulated as an immediate release tablet for treatment of depression. It is now approved and patented in both sustained release (Wellbutrin SR'; see, eg, U.S. Patent 5,763,493) and extended release forms (Wellbutrin XL'; see, eg, U.S. Patent 6,143,327). Venlafaxine hydrochloride (Effexor') is another example of a drug that was originally formulated in an immediate release tablet, and is now approved and patented in an extended release capsule (Effexor XR'; see, eg, U.S. Patents 6,419,958 and 6,444,708).

Another approach for improved delivery, successful for some biologics (eg, proteins), is pegylation. Pegylating is a method by which a biologic or drug is conjugated with polyethylene glycol. Pegylation has been noted to improve absorption and bioavailability of some poorly absorbed and poorly bioavailable drugs. For example, peginterferon alfa-2a (see, eg, Pegasys') has a significantly higher proportion of virological response compared to conventional interferon-2a (see, eg, Intron A').

Still another add-on approach involves seeking patents on individual isomers of a racemic drug. Most drug molecules exist as two mirror-image forms, only one of which is active. New separation techniques have been developed to isolate and discard the non-active isomer, enabling the manufacture of essentially the same drug with greater potency and/or fewer side effects. This strategy has generated a number of single isomer versions of drugs, including Prozac', Losec' and Claritin'.

Seeking patents on compounds derived from an active ingredient is yet another add-on approach. Modifications to drug molecules may increase efficacy, or decrease side effects. This approach is probably used less than other add-on approaches because the changing of the chemical structure of a drug generally requires new toxicity and efficacy studies. Until recently, related compounds such as metabolites could be listed in the Orange Book. While such compounds can no longer be listed, the case of loratadine and desloratadine illustrates the derived compound approach. Loratadine (Claritin'), a tricyclic antihistamine, (see, eg, U.S. Patent 4,282,233) had many adverse side effects, eg, arrhythmias, fatigue, dry mouth, and gastrointestinal distress. Desloratadine (Clarinex'), the active metabolite of loratadine, avoids adverse side effects caused by loratadine metabolic bi-products. (See, U.S. Patents 4,804,66 and 6,100,274.)

Patents on stabilized forms of an active agent can also provide another add-on approach. A certain purity profile or a new crystalline form may improve stability for handling and formulating the active agent. For example, calcipotriol or calcipoltriene (Dovonex') is a vitamin D compound that is marketed in a solution or ointment for topical administration for the treatment of psoriasis. Calcipotriol, as an anhydrous crystal, however, had poor stability in certain solutions, particularly in creams and gels. Moreover, the anhydrous form is not easily used in the milling process utilized to obtain a suitable small and uniform particle size. In fact, during the wet milling process, the anhydrous form developed a stable foam. A crystalline monohydrate was developed that is readily useable in a wet milling process for obtaining suitable particle size, and that permitted the manufacture of crystal suspension formulations. (See, U.S. Patent 5,763,426.)

Yet another approach is to develop a new use for an existing drug. This approach requires efficacy and toxicity testing. Bupropion hydrochloride, as noted above, was originally approved and patented as a treatment for depression. Burpropion hydrochloride (Zyban') is also approved and patented for smoking cessation. (See, U.S. Patent 5,763,493.)

Combination therapies involve combinations of active agents that are co-administered. The action of one drug supplements and complements the pharmaceutical action of the other drug, and the unexpected complementary action can form the basis for new patents. Such combinations may improve efficacy, or treat multiple symptoms of a disease. For example, an ACE inhibitor has been combined with L-carnitine, in which the ACE inhibitor treats high blood pressure and the carnitine treats other cardiovascular symptoms. (See, U.S. Patent 5,861,434.) Combination therapies are especially common in treatment of hyperproliferative diseases, eg, cancers. For example, a paclitaxel/cisplatin combination is approved for advanced ovarian carcoma and non-small cell lung cancer. A combination of fluoxetine hydrochloride, an antidepressant, and olanzapine, an antipsychotic, (Symbyax') is approved as a treatment of bipolar depression. (See, U.S. Patent 5,945,416.)

Challenging 'Add-ons'

While add-on patents can appropriately meet the standards for patentability, they are, as noted above, viewed in some quarters as suspect, addressing insignificant aspects of a drug. Nonetheless, add-on patents are favored for challenge by generic drug manufacturers, either because of their limited coverage or suspect validity. Indeed, litigation over add-on patents forms the majority of actions brought pursuant to the Drug Price Competition and Patent Term Restoration Act of 1984 (also known as the Hatch-Waxman Act), the law that was designed to reward innovation at major pharmaceutical companies and protect intellectual property while at the same time, lowering the costs by making it easier for generic drug manufacturers to reach the U.S. marketplace. Generics have prevailed in a significant number of these cases.

Conclusion

Pharmaceutical companies desire a robust, defensible proprietary position. Despite the risk of challenge, add-on patents are integral to a company's patent life cycle management and portfolio planning, providing an important avenue for maximizing patent term and market exclusivity.