In Sickness and In Health: Comparing Patent Protection for Pharmaceuticals and Dietary Supplements

Once composition of matter claims have been obtained for a new compound, or the composition of matter claims for an old compound have expired, what is next? Securing additional patent protection usually entails obtaining claims to methods of treatment, methods of prevention or improvement, methods of maintaining health, and mechanisms of action. These paths diverge depending on whether the compound is being developed as a pharmaceutical (i.e., a drug or biologic) or a dietary supplement.

Use of Pharmaceuticals in Sickness

Patent protection for a pharmaceutical will usually focus on a method of treating a disease or disorder. The elements of dosage, timing and formulation of the composition may be included to narrow a patent’s claims to exactly what the innovator will be manufacturing and how the patient will be instructed to take the drug. Importantly, the claims to a pharmaceutical drug should track the FDA-approved label for the patent to provide the ultimate protection. For example, recently approved IMBRUVICA® is protected by an Orange Book-listed patent with claims to a method of treating. Claim 1 of U.S. Patent No. 10,004,746 reads:

A method for treating chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in an individual who has failed at least one prior therapy for chronic lymphocytic leukemia or small lymphocytic lymphoma comprising administering to the individual once per day about 420 mg of an oral dose of an inhibitor of Bruton’s tyrosine kinase (Btk) having the structure: [ibrutinib].

The FDA-approved label for IMBRUVICA® reads:

IMBRUVICA is a kinase inhibitor indicated for the treatment of patients with: 1) Mantle cell lymphoma (MCL) who have received at least one prior therapy (MCL: 560 mg taken orally once daily (four 140 mg capsules once daily)), 2) Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, 3) Chronic lymphocytic leukemia with 17p deletion, and 4) Waldenström’s macroglobulinemia (WM) (CLL and WM: 420 mg taken orally once daily (three 140 mg capsules once daily)).

Having a patent that mirrors the approved label allows the innovator to keep generic manufacturers at bay, and reduces the burden of proof for the innovator to demonstrate its own label (and therefore the non-innovator’s label) induces infringement by the physician/patient. The FDA requires a generic to be bioequivalent to the innovator’s drug in dosage form, safety, strength, route of administration, stability, quality and performance characteristics. Accordingly, an identical drug label is direct proof of the generic’s intent to infringe the innovator’s patent where the patented claims mirror the FDA-approved label for the product. Where “the proposed label instructs users to perform the patented method . . . the proposed label may provide evidence of [the ANDA applicant’s] affirmative intent to induce infringement.” The contents of the label itself allow a court to infer specific intent to encourage, recommend or promote infringement.

This sounds like a dream come true for the patent owner, right? Well, Congress crashed the wedding by passing a law that allows the generic manufacturer to omit or “carve out” the patented use from its label, a so-called skinny label. 21 C.F.R. § 314.127(a)(7). What effect does this have on the innovator’s well-deserved patent exclusivity? In many states, pharmacists are required to fill prescriptions with “substitutable” generics regardless of intended use, so some consumers will necessarily receive and use a skinny-labeled generic in an infringing manner. Skinny-labeled generics have seemed to get a pass as long as the generic manufacturers stick to the “skinny label” and are careful to promote (to the extent even done by generics) their drugs only for the labeled uses. The Federal Circuit has attempted to restore a bit of the balance, however, by equating labeling with conduct and rejecting the defense that nonspecific label recommendations could not demonstrate specific intent. It does not matter if the labeling contains only general recommendations — what matters is whether the labeling language “would inevitably lead some users to practice the claimed method.” Further proof of the skinny-labeled generics’ inevitable infringement can be found through the bioequivalence rating bestowed by the FDA, published in the Orange Book and promoted by the generic manufacturers. A manufacturer that intends to place a drug on the market knowing it will be used in an infringing manner by some consumers would be liable for inducing infringement, for which the appropriate remedy may be an injunction. It does not matter that the infringing use was mandated by FDA requirements because the manufacturer had other options for avoiding inducement. Irrespective, an attempt to skinny label allows that ANDA applicant to possibly avoid procedural hurdles associated with a paragraph four certification.

Use of Dietary Supplements in Health

In contrast, method of use patent protection for a dietary supplement focuses on methods of maintaining a person’s health. The elements of dosage, timing and formulation of the composition may be included to narrow the patent claims to exactly what the innovator will be manufacturing. However, unlike pharmaceutical drugs, the FDA will not allow the label of a dietary supplement to state that the product can be used for diagnosis, cure, mitigation, treatment or prevention of a condition or disorder; such a statement will prompt a warning letter from the FDA. For health claims to be acceptable to the FDA, the innovator must prove, with supporting scientific evidence, that the dietary supplement is intended to affect some structure or function in humans. Acceptable structure/function claims include the following: (1) a statement that claims a benefit related to a classical nutrient deficiency disease and that discloses the prevalence of such disease in the United States; (2) a statement that describes the role of a nutrient or dietary ingredient intended to affect the structure or function in humans, or characterizes the documented mechanism by which a nutrient or dietary ingredient acts to maintain such structure or function; or (3) a statement that describes the general well-being from consumption of a nutrient or dietary ingredient. 21 U.S.C. 343(r)(6). For example, Bausch & Lomb sells the dietary supplement OCUVITE®.

The product label states: “OCUVITE helps replenish essential nutrients to help protect the health of your eyes. Lutein supports macular health by helping filter harmful blue light.” While the Ocuvite label states the product is for replenishing essential nutrients for eye health, the patent marked on the product, U.S. Patent No. 6,660,297, claims:

A method for stabilizing visual acuity loss in persons with early age-related macular degeneration comprising: administering a daily dosage of not less than approximately 420 mg and not more than approximately 600 mg vitamin C, not less than approximately 400 IU and not more than approximately 540 IU vitamin E, approximately 0.04 mg to 40 mg lutein-zeaxanthine combination, not less than approximately 60 mg and not more than approximately 100 mg zinc and at least 1.6 mg and not more than approximately 2.4 mg copper.

Assuming the preamble of the claim is a limitation (which could be the subject of a completely separate article), it is not clear how another product with identical ingredients and an identical label would infringe this claim, since the label fails to mention “stabilization of visual acuity loss” or for use in persons with “early age-related macular degeneration.” While this claim may be entirely suitable and enforceable in the pharmaceutical context, this type of claim may be more difficult to assert in the Dietary Supplement Health and Education Act environment.

Claims to dietary supplements have been relatively easy to attain in the past, but the honeymoon may be coming to an end. The dreaded ineligible subject matter hurdle may be causing some problems for the validity of dietary supplement patents. A Southern District of California court recently invalidated a patent directed to a method of regulating hydronium ion concentrations in human tissue, saying it claimed patent-ineligible subject matter. Nat’l Alts. Int’l, Inc. v. Allmax Nutrition, Inc., 258 F. Supp. 3d 1170 (S.D. Cal. 2017). Claim 1 of National Alternatives International, Inc.’s U.S. Patent 5,965,596 reads:

A method of regulating hydronium ion concentrations in a human tissue comprising: providing an amount of beta-alanine to blood or blood plasma effective to increase beta-alanylhistidine dipeptide synthesis in the human tissue; and exposing the tissue to the blood or blood plasma, whereby the concentration of beta-alanylhistidine is increased in the human tissue.

The court held that the principle that ingesting beta-alanine, a natural substance, will increase carosine concentrations in a tissue, and thereby aid in regulating the hydronium ion concentration in the tissue, was directed to a law of nature. Interestingly, in response to the plaintiff’s argument that the claims were directed to eligible subject matter, the court stated that the plaintiff failed to adequately explain how or why the method increases the carosine content in the tissue through a non-natural process and stated that nothing in the claim requires the carosine concentration achieved by the method be at unnatural levels. Is this a glimmer of hope? Could claims directed to methods for using dietary supplements be patent-eligible if they include how an increase of a molecule in a tissue is occurring through a non-natural process or if the levels achieved are at unnatural levels? The court also leaves us with some additional hope: If the method claim requires that the compounds used come from non-natural sources, it could be patent-eligible. This is certainly unsettled law; the plaintiff may appeal its case to the Federal Circuit, which might create a precedent for lower courts. We will have to wait and see who wins this fight.

For Richer or Poorer

With that said, how do the courts view infringement of method of use claims? Demonstrating a manufacturer’s infringement of dietary supplement method of use patents may be difficult because manufacturers are not required to list the same benefits on their labels. This omission may make it more difficult for the innovator of a dietary supplement to stop a competitor from using only a method of use patent.

For a dietary supplement to infringe the method claims of a pharmaceutical drug patent, the dietary supplement would have to promote its product as being useful for treating the disease. This behavior would not only lead to an infringement suit, but also trigger FDA warning letters and enforcement actions and possibly detention and destruction of the infringing products, under the theory that the FDA has not evaluated the dietary supplement as being safe and effective in the manner being deceptively promoted by the supplement manufacturer. While not in the context of dietary health supplements, in an analogous context, the FDA recently announced that it would be reviewing and taking action against the deceptive marketing practices of manufacturers of “vaginal rejuvenation” devices, which have not been properly evaluated by the FDA.

Further, a dietary supplement that does not instruct a consumer to take the product for the treatment of disease will not be found to infringe a pharmaceutical drug method patent. Infringement questions surrounding method of use patents may hinge on the interpretation of the phrase “a subject in need thereof.” Are patients to be treated and consumers maintaining health both considered “subject[s] in need thereof”? The court addressed this question in Jansen. Jansen owned U.S. Patent No. 4,945,083, directed to:

A method of treating or preventing macrocytic-megaloblastic anemia in humans which anemia is caused by either folic acid deficiency or by vitamin B₁₂ deficiency which comprises administering a daily oral dosage of a vitamin preparation to a human in need thereof comprising at least about 0.5 mg. of vitamin B₁₂ and at least about 0.5 mg. of folic acid.

Rexall markets an over-the-counter dietary supplement that contains folic acid and vitamin B₁₂ for maintenance of proper blood homocysteine levels. Janssen argued that the phrase “in need thereof” encompasses a person who does not know that his/her serum levels of folic acid and vitamin B₁₂ are adequate. In contrast, Rexall argued that the same phrase encompasses someone either suffering from macrocytic-megaloblastic anemia or at risk of developing such a condition. Rexall only marketed its product for the regulation of blood homocysteine levels. The court agreed with Rexall, stating that use of an over-the-counter product like Rexall’s is quite different from the use of a product pursuant to a prescription from a medical doctor. In the latter case, a prescription is evidence of a diagnosis and a knowing need to use the product for the stated purpose. Janssen did not have evidence of such use in this case. Rexall’s product was provided with a label stating that the product can be used for maintenance of blood homocysteine levels, and purchasers do not necessarily know that they are in need of preventing or treating macrocytic-megaloblastic anemia. The court also emphasized that the claim’s preamble is not merely a statement of effect that may or may not be desired or appreciated. Rather, it is a statement of the intentional purpose for which the method must be performed. In other words, administering the claimed vitamins in the claimed doses for some purpose other than treating or preventing macrocytic-megaloblastic anemia is not practicing the claimed method because Janssen limited its claims to treatment or prevention of that particular condition in those who need such treatment or prevention.

In Good Times and in Bad

Is the marriage of treatment claims and mechanisms of action made to last, or destined for divorce? Does reciting a compound’s mechanism of action in a claim strengthen and support the claim’s validity? Practitioners may add the mechanism of action to a method claim to circumvent the prior art or to narrow the limitation of the claims to a specific function of the compound or narrow the scope for enablement purposes. But is the mechanism of action an inherent property of that molecule? The Federal Circuit suggests that the mechanism of action of a compound may not always be seen as an inherent characteristic. For example, Alcon’s claims 1-3 and 5-7 of U.S. Patent No. 5,61,805 were found obvious over the prior art, while claims 4 and 8 were found valid. Representative claim 1 of the ‘805 patent reads:

A method for treating allergic eye diseases in humans comprising stabilizing conjunctival mast cells by topically administering to the eye a composition comprising a therapeutically effective amount of 11-(3-dimethylaminopropylidene)-6, 11-dihydrodibenz(b,e) oxepin-2-acetic acid or a pharmaceutically acceptable salt thereof.

This case focuses on the phrases “stabilizing conjunctival mast cells” and “therapeutically effective amount.” Apotex argued, and the court affirmed, that claiming olopatadine’s mechanism of action (stabilizing conjunctival mast cells) cannot impart patentability to the all of the claims of the ‘805 Patent because it is an inherent property of olopatadine. In contrast, Alcon argued that mast cell stabilization is not an inherent property of olopatadine because only some concentrations stabilize mast cells to a clinically relevant extent. In other words, the therapeutically effective range was construed to be the range wherein the conjunctival mast cells were stabilized, as described in claims 4 and 8.

Do mechanism of action claims require the subjective recognition and intent on the part of the doctor administering the drug, i.e., that the patient would benefit from the particular mechanism? If intent is part of the claim, then can it be infringed? The Supreme Court has affirmed that direct patent infringement remains a strict liability offense that does not require a showing of intent and that, as a result, “a defendant’s mental state is irrelevant.” Accordingly, the interpretation (i.e., claim construction) of the intent component of a mechanism of action claim is quite relevant. Unfortunately, there is no clear answer. Such an analysis received opposing answers in two co-pending cases against AstraZeneca by different judges in the same court.

In the first case, a representative claim of U.S. Patent No. 6,511,800, owned by MUSC, was directed to:

A method of treating a nitric oxide or cytokine mediated disorder in a cell, comprising administering a biologically effective amount of at least one induction suppressor of an inducible nitric oxide synthase or a cytokine, wherein said induction suppressor is an inhibitor of mevalonate synthesis, an inhibitor of the farnesylation of Ras, an antioxidant, an enhancer of intracellular cAMP, an enhancer of protein kinase A (PKA), an inhibitor of NF-k.beta. activation, an inhibitor of Ras/Raf/MAP kinase pathway, an inhibitor of mevalonate pyrophosphate decarboxylase or an inhibitor of farnesyl pyrophosphate.

In this case, the parties agree that the terms require an intent to treat a nitric oxide or cytokine mediated disorder. MUSC Found. for Research & Dev. v. AstraZeneca Pharms. LP, Nos. 2:13-cv-2078-RMG (D.S.C. Nov. 25, 2014). However, the parties disagreed on whether the intent must be held by a treating medical professional and whether the intent must be specific. The MUSC court concluded that no specific knowledge or recognition was required:

Nothing in the plain language requires that the person practicing the invention know that the disorder she is treating is a nitric oxide mediated disorder or a cytokine mediated disorder. Holding that such knowledge is required also creates a perverse incentive for treating doctors to remain ignorant; a person skilled in the art could avoid infringement by remaining ignorant of the cellular biology underpinning a particular disorder. Therefore, the Court construes the preamble to require that “the person practicing the method must intend to treat a nitric oxide or cytokine mediated disorder in a cell but need not recognize that the disorder he or she is treating is a nitric oxide or cytokine mediated disorder.”

In the second case, a representative claim of U.S. Patent No. 6,465,516, owned by Palmetto, was directed to:

A method of treating a nonhyperlipidemic subject who would benefit from increased Nitric Oxide production in a tissue comprising: administering to the nonhyperlipidemic subject in need of such treatment a Hmg-CoA reductase inhibitor in an amount effective to increase Nitric Oxide production in said tissue of the subject.

During claim construction, Palmetto asserts that the preamble of claim 1, in combination with the phrase “subject in need of such treatment,” requires that “the person practicing the method must intend to treat a subject who is at risk for cardiovascular disease conditions and adverse events.” Palmetto Pharms. LLC v. AstraZeneca LP, No. 2:11-cv-00807-SB (D.S.C. Nov. 30, 2015). AstraZeneca asserts that the preamble, in combination with the phrase “subject in need of such treatment,” requires a “subject having a recognized need for increased nitric oxide production in a tissue” and further requires intent by the treating medical professional (i.e., “method for treating a non-hyperlipidemic subject with the intentional purpose of increasing nitric oxide production in the subject’s tissue”). The court found that the focus of the intent is to treat a non-hyperlipidemic subject to increase nitric oxide production in the tissue of the subject. In other words, the Hmg-CoA reductase inhibitor must be administered to a non-hyperlipidemic subject with a recognized need for an increase in nitric oxide production with the intent to increase nitric oxide production.

Adding clauses focused on mechanism of action could provide additional protection in inducement situations. However, having claims with and without a mechanism of action may be the best protection, and let the good times roll.

For as Long as We Both Shall Live…Or at Least Until Our Patents Expire

For long and successful patent exclusivity, an innovator’s patent strategy, whether a pharmaceutical drug or a dietary supplement, should focus on crafting narrow claims that encompass the product’s label to ensure coverage of would-be infringers. Additionally, innovators should carefully craft their patents to include claims with and without a mechanism of action to prove inducement, should it become necessary.