Nano Pharmaceuticals Patents In India: New Hope For Targeted Drug Delivery

"Nanotechnology" refers to the design, production, or modification of structures, devices, or systems at the nanoscale that is less than 100 nm. Human creativity in nanotechnology dates back to ancient times. A Lycurgus cup with colloidal gold and silver incorporated in the glass dates back to the fourth century. It was only in 1981, with the invention of the scanning tunnelling microscope (STM) (1981) and the invention of the atomic force microscope (AFM) (1986), that seeing and manipulating materials at the nanometre scale became a reality. The practical applications of nanotechnology began its journey in many fields, including biotechnology, material science, engineering and nanomedicines.

Advances in nanotechnology lead to an investigation of how the structures engineered with nanomaterials interact with biological systems, like the human body, which opened the emergence of clinical nanomedicine for treating, diagnosing, or preventing historically untreatable diseases through the design and development of pharmaceutical nanoparticles (nanopharmaceuticals) to drive targeted drug delivery. The successful and often-employed approach is to develop a nanomedicine or a novel nanocarrier.

For instance, by therapeutic application of nanotechnology for berberine, curcumin, ellagic acid, resveratrol, curcumin and quercetin through the use of nanocarriers formulated with gold, silver, cadmium sulphide, and titanium dioxide polymeric nanoparticles together with solid lipid nanoparticles, crystal nanoparticles, liposomes, micelles, superparamagnetic iron oxide nanoparticles and dendrimers have been greatly improved. Nanotechnology bridges biological and physical sciences by applying nanostructures and nanophases in nanomedicine and nano-based drug delivery systems.

Patenting Smart Nano Medicines: Size Matters

Inventive activity is dynamic, and inventors continue improving patented inventions to meet the expected standards of their applications, cure drawbacks, and improve efficiency. In pharmaceutical fields, improving therapeutic efficacy is the major concern of the inventor after the lead compound is patented and commercialised. To achieve this, they may make improvements by conjugating, entrapping, or modifying the active agent itself to create smart drug products. For instance, creating pegylated versions of an active agent, reformulating it with a new salt or ester or developing a novel polymorph. Another equally successful and often-employed approach is to develop a nanomedicine or a novel nanocarrier.

For instance, by therapeutic application of nanotechnology for berberine, curcumin, ellagic acid, resveratrol, curcumin and quercetin through the use of nanocarriers formulated with gold, silver, cadmium sulphide, and titanium dioxide polymeric nanoparticles together with solid lipid nanoparticles, crystal nanoparticles, liposomes, micelles, superparamagnetic iron oxide nanoparticles and dendrimers have been greatly improved. The advent of medical nanotechnology made the innovative nanodrugs and smart drug delivery systems queuing up to seek patent protection worldwide.

Smart nanomedicines are useful for diagnosing, treating, and preventing diseases, as well as improving human health compared to traditionally used medicines. Smarter" drug delivery, or smart drug delivery systems (SDDSs), on the other hand, are designed to deliver drugs to specific locations in the body, such as a particular organ or cell type. The primary goal of medicinal nanotechnology is to increase the effectiveness of drugs by enhancing their solubility and bioavailability while reducing their side effects on healthy tissue.

Patent Law and Size of Matter

The patenting of nanopharmaceuticals in drug delivery has its issues and complications. Nanomaterials can be well-defined as materials with sizes ranging between 1 and 100 nm, which influence the frontiers of nanomedicine, starting from biosensors, microfluidics, drug delivery, and microarray tests to tissue engineering. Since inventive nanomaterials are changing the size/ proportion of the known material/substance, it may be seen as the obvious connotation of the prior invention or known material.

The patent eligibility of such material normally hit the obviousness hurdle in all the patent offices as size limitations were insufficient to distinguish such changes over prior art. The primary goal of medicinal nanotechnology is to increase the effectiveness of drugs by enhancing their solubility and bioavailability while reducing their side effects on healthy tissue. The primary reason for the success of nanoparticle-mediated drug delivery is that it increases pharmaceutical concentrations in targeted cells relative to non-targeted cells, thereby decreasing symptoms of unfavourable side effects associated with the administered drug compared to conventional drug delivery methods.

This aspect of inventive medical nanotechnology made the innovative nano drugs and smart drug delivery systems queuing up to seek patent protection worldwide. Smart nanomedicines are found to be useful for diagnosing, treating, and preventing diseases, as well as improving human health when compared to traditionally used medicines. Smarter drug delivery, or smart drug delivery systems (SDDSs), on the other hand, are designed to deliver drugs to specific locations in the body, such as a particular organ or cell type. The first smart nano drug patent was granted in 1995 for a formulation of Doxorubicin (DOX) in liposomal nanocarriers (Doxil®).

Doctrine of Inherency and Nanodrug Patent Eligibility

It is well known that every drug has certain inherent properties associated with its form. If a prior art discloses a drug formulation with a broad size range, and nanoscale particles are inherently present within that range, a subsequent patent claim to a nano drug with a similar size range would be considered inherent. Like in the chemicals, the doctrine of inherency in patent eligibility may impact nanodrug claiming only particle size. Inherency refers to a property or characteristic that is inevitably present or inherent in a known drug, even if not explicitly disclosed. In India, section 3(d) particularly put a bar on patenting a new form of a known substance. However, if the new form results in enhanced therapeutic efficacy, it may be eligible for a patent grant.

When a formulation is claimed like Doxil, patent section 3(d) may not apply, but section 3(e) may seek additional information to prove that the substance obtained by mere admixture does not result in aggregating the properties of the known components. We may find additional hurdles under Section 3(i) where the applicant claims a method of treatment as well. These hurdles are in addition to proving novelty and inventive steps. It may be noted that different jurisdictions interpret principles governing patent law in various ways that may impact the patentability of an invention, including India.

For example, the German Federal Supreme Court has invalidated the EPO patent granted to 10x Genomics for 'Compositions and methods for analyte detection" (EP 2794928B1) on the grounds of lack of novelty. This patent was for a selection invention using nanotechnology. [Bundesgerichtshof [BGH] Federal Court of Justice, Inkrustierungsinhibitoren, 2000, 591 GRUR (F.R.G.).

Position in the US

If the invention subject matter merely pertains to changes in size/proportion of the known substance, it may hit the wall of obviousness under US patent law. In re Rose, 220 F.2d 459, 461, 463 (CCPA 1955). where Claims were directed to a lumber package "of appreciable size and weight requiring handling by a lift truck" were not patentable over prior art lumber packages which could be lifted by hand because limitations relating to size were not sufficient to distinguish over prior art. In Troeil, 274 F.2d at 944 (CCPA 1960), the Federal Circuit ruled that "It is well established that the mere change of the relative size of the co-acting members of a known combination will not endow an otherwise unpatentable combination with patentability."

This patent application in question was for a device intended to cover holes or defects in lumber used in structures for pouring concrete. While rejecting this application, the Examiner found that Troiel's invention was a modification of the Spreen patent that combined other patented art in expected ways that would be obvious to those with the relevant skill. Similarly, in re Rinehart, 531 F.2d 1048, 1053 (CCPA 1976), the court held that "[M]ere scaling up of a prior art process...would not establish patentability...".

Again, in re Gardner v. TEC Systems, Inc., 725 F.2d 1338, 220 USPQ 777 (Fed. Cir. 1984), where a claim for a device was found to be not patentably distinct from the prior art as it differs only in terms of relative dimensions (i.e., would not perform differently than the prior art device). In Texas Instruments v. ITC, 805 F.2d 1558 (Fed. Cir. 1986), the court held that "A mere change in size due to improved miniaturisation by technological advance does not in itself save the accused devices from infringement."

Position in EPO

In the European patent office, the patenting of inventions relating to nanotechnology is also guided by the issues related to size. For a patent examiner, size is not a sufficient condition to establish the novelty of an invention. If the claimed invention involves nanoscale formulations of previously disclosed chemical compounds, structures and materials, it will create a prima facie impression that this invention is not patentable. This issue can be resolved if the applicant can provide data relating to nanoscale inventions to show that they exhibit properties that are, in some measure, unanticipated or different from those found in larger-scale prior art.

Novelty Issues

In the European Patent Office, the novelty issue relating to nanotechnology was resolved by EPO Boards of Appeal in BASF v Orica Australia, [T-0547/99 (8 January 2002). In this case, the opposition to granting EP 0 389 179 to Orica Australia was filed by BASF. The novelty hitch, in this case, was settled by the Board stating that in "selection inventions" like this, if the overlap is narrow relative to the larger prior art range and it is sufficiently far removed from the larger range, it is indicative of an invention only if exhibit a new or unexpected effect that occurs only within the selected sub-range." The Board held that the subject matter of the opposed patent was novel, inter alia, because none of the citations disclosed sterically stabilised dispersions of particles having a maximum average diameter of 100 nm and/or a method for their preparation comprising a polymerisation initiation temperature of under 40 C.

This clearly suggests the applicability of selection invention criteria to nanotechnology-related patents. In fact, Borad applied in Smithkline Beecham Biologicals v Wyeth Holdings Corporation, and the EPO's TBA applied this rationale. In this case, the question was whether Smithkline's patent application on a Hepatitis B vaccine adjuvant lipid measuring 60-120 nms lacked novelty in light of a prior patent on a similar adjuvant with particles measuring 80-500 nms. The TBA found that Smithkline's patent was novel because the overlap was:

• narrow - only 10% of the larger range in the earlier patent;
• at the extreme lower end of the prior art range and
• exhibited significantly improved adjuvant – the smaller particles resulted in an unexpected and favourable shift in the immune response.

The Board, in this case, also found that the prior art gave little guidance on how to prepare the smaller particles and observed that a skilled person who followed the vaccine supplier's protocol would have produced particles of between 115 and 951 nms. Therefore, the technical teachings in the prior art were not considered relevant to Smithkline's patent application.

Position in India

The position in the Indian patent office is not different from that of its counterpart in the USPTO in terms of the size and scale of the invention. As a general rule, size is not a sufficient condition to establish the novelty of an invention. In this context, we found that IPAB refused patents for different sizes of disposable syringes. However, where nanopharmaceutical inventions involve nanoscale formulations of previously disclosed chemical compounds, structures and materials, the Patent office checks the applicability of section 3(d), where claims recite only nano form of known drug or section 3(e) where claims recite use of nano carries from known drugs. It may be noted that the selection invention is patentable in India for the same reason as the EPO ruling in Smithkline Beecham Biologicals v Wyeth Holdings Corporation.

Inventive Step Hurdle

Like in EPO and other jurisdictions, examiners in India would also look for inventive steps in view of the closest prior art, even where the novelty hurdle is crossed. If we relook at the decision of the Boards of Appeal of the EPO in BASF v Orica Australia, [T-0547/99 (8 January 2002)] discussed above, we will find that the Board held that the subject matter was also considered to involve an inventive step. This stand was taken by the Board as the state of the art did not suggest the claimed solution of the technical problem existing with respect to the closest prior art as represented by D3, i.e. the provision of dispersions having good rheological properties at high solids content suitable for the preparation of high gloss coatings.

Dismissing the appeal in BASF v Orica Australia, Boards of Appeal of the EPO, [T-0547/99 (8 January 2002)] held that Orica's smaller particles exhibited remarkably improved technical properties, resulting in a glossier coat compared to the larger particles protected under the prior patent. Therefore, the difference in properties was held to be sufficient to impart novelty to inventions. Normally, for the Examiner, even the slightest overlap is sufficient to destroy novelty. However, this case culled out the exceptions that can be liberally applied to nanoscale inventions by the EPO Board of Appeal in future cases. In the absence of any case law in India, we may hope that the Examiner may go EPO ways when the question of inventive step is posed for deciding patentability inventions involving nanotechnology.

Patents on Nano Drugs Granted in the USA

The question of when the first nanodrug was patented remained a mystery or rather a matter of debate as most of the nanotechnology patents were filed under broader categories. However, some notable early patents related to pioneers of nano drugs are listed below:

Patents in US

Position in India

The patentability of the nanodrugs was subjected to the exception under Sections 3(d) and 3(e). However, many nano drug patents were allowed in India as well. The earliest reported patent for a Nanoparticle-based delivery system for the anti-cancer drug Paclitaxel" was granted in 2013 to Dr Reddy's Laboratories Ltd. Some of the other examples of nanodrug patents are listed below.

Drafting of Nanomedicine Patent

We know that the doctrine of inherency in patent eligibility plays a significant role in the examination of patent applications in general, including inventions relating to nanomedicines. For patent examiners in all jurisdictions, inherence means a property or characteristic that is inevitably present or inherent in a known or newly discovered compound, even if it is not explicitly stated in prior art reference. For instance, particle size or surface properties of the claimed drug are considered inherent to the known compound. However, novel or unique properties or characteristics not inherently present in prior art references can be claimed. The Examiner, in such cases, looks for supporting data to prove surprising or unexpected results.

Thus, to demonstrate unexpected results, the applicant must show that the claimed nanodrug exhibits unexpected benefits or performance characteristics compared to prior art references. The patent specification should explicitly highlight specific nanoscale features/structures not inherently present in prior art references. Close scrutiny of the refusal of a nano drug patent reveals that a nano drug patent is rejected due to the inherent properties of a known compound. In these cases, the patent examiner has determined that the claimed nanodrug properties are inherently present in the prior art compound, and therefore, the nanodrug invention is not novel or non-obvious. This situation can be saved by drafting the patent specifications, including the claims, to support and demonstrate the unexpected and surprising results claimed by the inventor.

Looking Forward

If we see patents granted around the world, we will find that nanotechnology has diverse applications like nanomedicine in the medical field, ranging from novel diagnostic instruments, imagery and methodologies, targeted medicinal products, pharmaceutical products, biomedical implants, and tissue engineering. According to the market reports, the nanotechnology products and services market is expected to reach the $3 trillion target. It is not surprising to find that the patenting activity in nanotech medicine and service products has increased over fifty times since the first patent was granted in 1995. A close look at the granted therapeutic patents worldwide reveals that a large majority of such patents are focused on drug delivery systems, highlighting the importance of nanoparticles in making smart drugs as nano-based drugs have the ability to allow superior drug absorption, controlled drug release and reduced side-effects, as compared to traditional drug delivery systems.

Nanoparticle-based patents are not limited to nanomedicine alone. We find multiple patents on nanoemulsions, nanogels, liposomes, nanofibers, dendrimer technology and polymers, which provide opportunities for diverse applications of nanotechnology for obtaining such patents in other jurisdictions, including India. In the last twenty years, the emergence of nanopharmaceuticals patents such as micelles, nanoemulsions, quantum dots, liposomes, dendrimers, polymeric nanoparticles, magnetic nanoparticles, carbon nanotubes, metallicnanoparticles, and likes have made revolutionary changes in drug delivery as well as advance medical service system.

With nanotechnology, it is now possible to achieve efficient targeting and movement of drugs across many barriers. All this makes patenting inventions in this field a leading, profitable commercial venture. The scope for obtaining patents on nanomedicine ranges from the medical applications of nanomaterials and biological devices to nanoelectronics biosensors and future applications of molecular nanotechnology such as biological machines. Expert advice to counter Sections 3(d) and 3(e) and inherency challenges in India may help and navigate successfully through the patent law hurdles even in India.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.