December 1, 2013 (Vol. 33, No. 21)

Proving Nonobviousness is Essential to Obtaining Patent Protection

Combination therapies are often used to treat a variety of medical conditions that have proved difficult to cure with single-agent therapies including tuberculosis, leprosy, cancer, malaria, and AIDS. In cancer therapy, it is now believed that cytotoxic drugs are most effective when given in combination to achieve additive or synergistic effects.

The rationale for combination chemotherapy is that co-administering drugs that work by different molecular mechanisms can increase cancer cell killing, while reducing the likelihood of drug resistance, and minimizing overlapping toxicity.

Patent protection is vital for the development of any new drug, including new combination therapies, because creating a new therapy often requires years of extremely costly research and clinical testing for drug developers. The Federal Circuit’s decision in Novo Nordisk A/S v. Caraco Pharmaceutical Labs. Ltd., however, indicates that patent protection for combination therapies will likely be significantly more difficult to obtain in the future.

The patent at issue in Novo Nordisk was directed at the treatment of noninsulin-dependent diabetes mellitus using a novel combination of repaglinide (marketed as Prandinlin in the United States) and metformin (sold under the trade name Glucophage). Repaglinide is an “insulin secretagogue,” which works by stimulating insulin release from pancreatic beta cells. Metformin is an “insulin sensitizer” that reduces insulin resistance by acting on the liver to reduce glucose production, thereby improving insulin sensitivity in muscle and fat tissues.

Novo Nordisk scientists discovered that the combination of the two drugs was significantly more effective than their “hypothetical additive effect,” that is, the combination has a synergistic effect. However, the Federal Circuit held that the combination was obvious despite evidence of synergistic effect of the two drugs.

Judith L. Toffenetti, Ph.D.

The Court’s Reasoning

The decision primarily hinged on the fact that combination therapy using metformin and another secretagogue, glyburide, was well known in the art to produce beneficial and even synergistic results.

Repaglinide and glyburide belong to two different subtypes of insulin secretagogues, and these subtypes differ in molecular structure, profile of action, and excretion mechanism. Citing these facts, Novo Nordisk argued (in vain) that the synergistic effect seen with the glyburide/metformin combination was not readily transferrrable to the repaglinide/metformin combination.

Nonetheless, the Federal Circuit held that the claimed combination was obvious because repaglinide (claimed invention) and glyburide (prior art) share a general mechanism of action—that is, they both stimulate the pancreas to release insulin.

Cynthia Chen, Ph.D.

Revising Patent Strategies

This decision will likely have a significant impact on patenting combination cancer therapies in the future. Synergy between different classes of cancer drugs has been investigated based primarily on their known mechanisms of action. For example, the synergistic effects have been investigated for certain alkylating agents and purine analogs (cyclophosphamide and fludarabine), platin-and-antimetabolite combinations (cisplatin and fluorouracil; cisplatin and gemcitabine), and dual-antimetabolite combinations (gemcitabine and capecitabine).

These studies likely have created a high bar for patenting combination therapies using other cytotoxic drugs that fall within the same functional classes. In the future, new patent strategies will need to be applied to show why certain combinations are not obvious.

One possible patent strategy is to show that a specific combination achieves superior results as compared to the whole class in general. However, demonstrating a superior synergistic effect could force an enablement issue. For example, if synergistic effect is derived from in vitro data, it may not be deemed as sufficient by the U.S. Patent and Trademark Office (even though technically, in vivo data are not required for patentability).

Cite in Vivo Results

In the biotechnology area, patent examiners increasingly request evidence of in vivo efficacy, citing various publications or failed clinical trials as evidence that in vitro results are not predictive of in vivo efficacy. For example, in cancer therapy, it has been reported in the scientific literature that cancer cells may respond differently in lab conditions, where cancer cells are generally tested in the absence of any supporting neighboring cells, as compared to in animal studies where cancer cells interact with normal cells of the body.

These kinds of reports are often relied upon by patent examiners as a basis for rejecting claims that are supported only by in vitro studies, requiring patent applicants to undertake animal studies, which may cause a significant delay in the issuance of the patent.

As newer models are being developed to better mimic the cancer microenvironment, drug developers who want to file a patent application at the earliest possible date should consider conducting a survey of available in vitro and in vivo models in the field beforehand, and select those models that are recognized as giving fewer false positives.

Focus on Patient Subpopulations

Another useful patent strategy is to demonstrate synergy and/or reduced drug resistance in a selected population of cancer patients. Today, many cancer patients are treated with targeted therapy, using cytotoxic drugs that inhibit specific genetic mutations that give rise to the growth and spread of cancer cells. Patients having specific genetic mutations often respond well to the targeted therapies and experience high rates of response (that is, reduction in tumor size) and reduced toxicity.

Examples of targeted therapy include gefitinib and erlotinib for non-small-cell lung cancer patients with EGFR mutations, panitumumab and cetuximab for metastatic colon cancer, vemurafenib for patients with melanomas harboring BRAF mutations, and crizotinib for lung cancer patients with EML4-ALK translocations.

Specify Dose Ratios

Finally, patent claims directed to combination therapy can be supported by showing optimal drug ratios, for example. Current cancer chemotherapy treatments typically employ drug combinations in which the dose of each agent is pushed to the brink of unacceptable toxicity. However, emerging evidence indicates that this approach may not be providing optimal efficacy due to the manner in which the drugs interact.

It has been reported that certain ratios of combined drugs can be synergistic while other ratios of the same agents may be antagonistic, implying that the most efficacious combinations may be those that utilize certain agents at specific dose ranges. Such evidence may be used to claim combination therapy based on an optimal dosage—or a range of effective doses—for each drug. However, one should be mindful to include all clinically meaningful doses, if possible, to avoid easy design-around by competitors.

Judith L. Toffenetti, Ph.D., is a partner and Cynthia Chen, Ph.D. ([email protected]), is an associate in the law firm of McDermott Will & Emery LLP.

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