Recent trends in cancer chemotherapy treatments indicates that employing effective drug combinations in optimal doses are more effect. Same is true for variety of medical conditions where it is found that single-agent therapies are not very effective. In fact, the difficult to cure disease conditions such as AIDS, tuberculosis, leprosy, cancer, malaria, diabetes do respond well to the combination therapies. Basic trend in such combination normally point towards pushing the dose content of each combination to get best results. These combinations at times results into falling short of providing optimal efficacy due to the manner in which the drugs components interact. However, encouraging results are forthcoming particularly in cancer therapy where cytotoxic drugs are found to be most effective when given in combination to achieve additive or synergistic effects.
Combination therapy and patent eligibility
These possibilities in combination therapies opened a new area of drug development for targeted therapy and looking for possible patent grants for such combination drugs. Combination drugs for examples gefitinib and Erlotinib (useful for non-small-cell lung cancer patients with EGFR mutations), panitumumab and cetuximab (useful for metastatic colon cancer, vemurafenib for patients with melanomas harboring BRAF mutations), and crizotinib (useful for lung cancer patients with EML4-ALK translocations) are found to have effective response in reducing tumour size with reduced toxic effects. Other examples include combination therapy using metformin and repaglinide for treatment of noninsulin-dependent diabetes mellitus. Innovative drug developers see the possibility in obtaining patents in this niche space. But they may have to cross certain hurdles in obtaining drug combination patents. One effective patent strategy is to demonstrate synergistic effect of such combination with supportive studies disclosed in the specification and another approach could be to establish novelty /non obviousness in the combination. In the combination drug area, patent examiners invariably seek evidence of additive effect /synergistic effect before he ventures into other patentability issues.
Entry of synergism in combination patents
"Synergism," is deliberately coined and variously-defined term in patent law. It refers to the combined action of two or more elements/integers producing an effect greater than the sum of the several effects taken separately. It remained a handy tool for obtaining the combination product patents. Though synergism was not accepted as standard of patentability, yet it finds its useful application in obtaining combination patents. Non-obviousness, not synergism, is the sole mandated test in patent law which vouch for patentability of a novel and useful invention, whether the invention comprises a combination of old elements or not. Concept of synergism (added property of known integers) was not known in mechanical inventions. In 1969, in Anderson's Black Rock v. Pavement Co. infringement case for the first time the term ‘synergistic result’ appeared for evaluation of mechanical combination of two machines patent for "Means for Treating Bituminous Pavement." This patent sought to solve the problem of a cold joint on "blacktop" paving by combining known elements, a radiant-heat burner, a spreader, and a tamper and screed, on one chassis. In this case it was argued by patentee that “ A combination of elements may result in an effect greater than the sum of the several effects taken separately.” However, US SC invalidated the patent on finding that “ No such “synergistic result” is argued here.” The Court further jinxed the argument “that the combination filled a long felt want and has enjoyed commercial success.” , on the suggestion that those matters "without invention will not make patentability."
Mechanical combinations: functional interaction
Technically speaking, combination patents in mechanical cases do saw a sea change as the aggregation of old integers/elements was not considered patent eligible without the functional interaction between the old elements/parts since the first known case of invalidation of mechanical combination patent for pencil with eraser. A synergism test, which looks exclusively to the functioning of the individual components after combination, was based on the assumption that it is always obvious to take known elements and combine them. This proposition however, was latter disregarded by courts by suggesting that it may be the act of selecting the elements for combination which is itself non-obvious and therefore the invention. It is also pertinent to note that the ‘synergism test’ is applied exclusively on the performance of the elements after the combination is made disregarding the obviousness or non-obviousness of making the combination.
Arrangement and rearrangement of known integers
Delhi High Court in Standipack Private Limited & ... vs M/S. Oswal Trading Co. Ltd. rejected the argument of the inventor that adding of thickness to the layers of pillow pouch is inventive and concluded that “thickness of the plastic film/layer depends upon the tolerance of the contents in the pouch. Thus the same is merely an arrangement and re-arrangement of the mixture of the material and cannot be termed as a novel concept and does not have any novelty.” The court also relied on the ruling of the of Bishwanath Prasad Vs. Hindustan Metal Industries and stated that “In the said decision the Supreme Court held that in order to be patentable an improvement on something known before or a combination of different matters already known, should be something more than a mere workshop improvement; and must independently satisfy the test of invention or 'inventive step'. It was further held that mere collection of more than one integers or things, not involving the exercise of any inventive faculty, does not qualify, for the grant of a patent. The Supreme Court has categorically held that in order to be patentable, the new subject matter must involve invention producing new result or a new article or better or cheaper article.” Thus, in India courts basically rely on the test laid down by the Bishwanath Prasad Vs. Hindustan Metal Industries case for invents involving arrangement and rearrangement of intergers/elements.
Synergism vs obviousness
The non-obviousness standard in every patent law jurisdiction requires that if the differences between the combination of known elements sought to be patented and the prior art is such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains the patent may be denied. This requirement match with the provision of section 2(1)(ja) of Indian patent act which was added in in the patent law in 2005. Accordingly, the “inventive step” in Indian patent law context means “ a feature of an invention that involves technical advance as compared to the existing knowledge or having economic significance or both and that makes the invention not obvious to a person skilled in the art;” This provision was further strengthen by adding the definition of the ‘New invention’ in section 2(1) (l) through 2005 amendments. Accordingly, the ‘new invention’ means “any invention or technology which has not been anticipated by publication in any document or used in the country or elsewhere in the world before the date of filing of patent application with complete specification, i.e., the subject matter has not fallen in public domain or that it does not form part of the state of the art;”. The latter provision does reflect the universal principle of keeping the inventions in public domain out of the bounds for the inventors for obtaining a patent.
Revisiting patenting strategy
The element of obviousness in synergistic combinations will have a significant impact on combination drugs patenting. Competition to find more effective combination drugs that fall within the same functional group is stiff but fierce. In order to find favour with patent examiner the best possible approach could be to prove that a specific combination achieves superior results as compared to the whole class in general. Mere demonstration of a superior synergistic effect may not suffice in crowded similar combination drugs groups as it may raise the issue of enablement at a later stage when there is dispute. To avoid any such dispute in the future, expert opinion and strategy will be essential for drafting and prosecution of such application. Extra care and caution must be applied to show why certain combinations are not obvious to cross statutory cliff of patenting.