The storyline of patent protection incentivizing the invention of new drugs has come under scrutiny. In the field of HIV, a closer look at the drugs in the pipeline reveals that rather than being new chemical entities, the majority of the most salient pipeline drugs represent incremental changes to existing drugs. These incremental innovations, which often result from routine practice or obvious adjustments, are not breakthrough inventions. Yet the market monopolies awarded to these drug companies can pose barriers to the ability of patients and governments to access medicines. In this article, we flesh out this story of the HIV antiviral pipeline in order to showcase the drawbacks of the current patent system and provide a prescription for a healthier innovation regime
What’s in the HIV Drug Pipeline? Advocating for a Healthier Innovation System
by Jimmy Pan* and Priti Radhakrishnan**
Initiative for Medicines, Access & Knowledge (I-MAK.org)
THE HIV DRUG PIPELINE
ANTI-RETROVIRAL THERAPY (ART)
Background
Why are new anti-retrovirals needed if so many already exist? First, drugs that employ new biochemical pathways to combat the HIV virus may be more efficacious than existing drugs. These new pathway drugs may also be used in combination with existing drugs in order to create a multi-pronged attack that is less likely to succumb to viral resistance. Secondly, while prices of first-line regimens have fallen due to increased generic production worldwide, many patients become resistant to these treatments. These patients need either new drugs or new combinations. Third, updated versions of existing treatments may provide additional benefits, e.g. less toxicity.
When the public imagines drug innovation, it typically conjures up the laboratory researcher discovering new compounds with new, unexpected mechanisms of actions. The question that we sought to resolve was whether this image reflects reality, e.g. if the HIV pipeline of medicines is comprised of new chemical entities, or whether the HIV drug pipeline is a collection of incremental changes to existing compounds.
Incremental Innovation
Incremental innovation is prevalent in medicine patenting, including the patenting of new forms of known compounds and combinations of older compounds. New forms of known compounds include the creation of derivative compounds, salts, polymorphs, prodrugs, formulations etc. Combinations are created when two or more known drugs are combined into a single treatment. Often, incremental innovations demonstrate a benefit that is not therapeutic in nature, such as increased stability of a drug product. Stabilization involves improving the stability of the drug in various environmental conditions, such as improving heat stability or shelf-life.
The unifying theme between the different types of incremental innovation is their routine nature: they are usually generated via commonly practiced pharmaceutical techniques. For example, the lab processes employed to create salts of known compounds are regular practice and are well known to the pharmaceutical community. That is not to posit that these drugs have no worth, but we do propose that this sort of routine practice does not warrant a new twenty-year term of market exclusivity, because it does not result from the type of inventiveness that warrants such a monopoly.
Countries are beginning to recognize the routine nature of incremental innovation. As an example, India has rejected combinations of known HIV drugs, as well as the heat-stabilized version of ritonavir/lopinavir. Brazil also recently rejected a patent application for a salt derivative of the already-known drug tenofovir.
PIPELINE SUMMARY
Ideally, the patent system ought to provide sufficient incentive to create new chemical entities. Yet, an analysis of the pipeline for upcoming HIV drugs reveals that the patent system is not meeting this promise.
We analyzed the eleven upcoming HIV drugs in the pipeline (The Roadmap: The HIV Drug Pipeline and its Patents), which hold the most relevance for low- and middle-income countries. These drugs were selected based on a review of the latest available information from scientific and public health experts. Our scientific and legal team compared these pipeline drugs against existing drugs and analyzed the quality and strength of these patents.
Eight of the eleven drugs analyzed were found not to be new chemical entities with new mechanisms of action. Instead, many of these pipeline drugs were new forms of known substances or combinations.
To provide a few key examples from our findings:
CMX157 and tenofovir alafenamide fumarate (TAF) are merely new forms of the existing HIV drug tenofovir, which are likely be found to be obvious or non-inventive given existing pharmaceutical practices.
Complera (tenofovir disoproxil fumarate +emtricitabine + rilpivirine) and Stribild (tenofovir disoproxil fumarate +emtricitabine + elvitegravir + cobicistat) are both merely combinations of various existing HIV drugs. These combinations offer no increase in therapeutic efficacy over the individual drug components.
Cobicistat is merely an analog of the HIV drug ritonavir (which comes off patent in the near future) with no clinical benefit offered over ritonavir.
Etravirine is structurally similar to and is a derivative of known compounds already disclosed in the prior art.
Other examples can be found in The Roadmap: The HIV Drug Pipeline and its Patents.
PROBLEM DESCRIPTION
Our purpose in assessing the HIV drug pipeline was to highlight one of the issues central to the patent system: that patents on incremental innovation can prevent access to needed treatment.
First, the ability to obtain patents on incremental, non-innovative changes may be detrimental to innovation of new therapies, rather than positive. It is well documented that companies regularly file incremental applications in order to extend the life of their existing patents and lengthen the effective patent term. This allows companies to retain market exclusivity without requiring them to innovate truly new medicines after their existing drug patents expire. Empirical evidence reveals that the rate of innovation has indeed started to slow down.
This market exclusivity permits companies to keep prices out of reach. For example, Ukraine is currently paying 10.13 times the lowest generic price for the pipeline HIV drug raltegravir, $6843 per person per year (pppy) versus $675 for the generic. Similarly, Argentina is paying 10.86 times the lowest generic price for the first-line drug atazanavir, $2912 pppy versus $268 pppy. These prices make it difficult or infeasible for governments to procure treatment for patients in low- and middle-income countries.
Second, the use of incremental patents as “blocking patents” can prevent the development of new technologies. In these cases, generic ART manufacturers are denied the ability to combine existing drugs into new combination therapies. This inability to produce new combinations generically is exacerbated by the refusal of many originators to voluntarily license their drugs to be used in combination therapies.
LEGAL SUMMARY
Another factor to consider is whether and where these pipeline drugs are being patented. We know from our patent searches that patent applications have been filed for all pipeline drugs analyzed for The Roadmap. Our preliminary patent landscaping in middle-income countries shows that patents on these compounds have been filed extensively in Argentina, Brazil and Ukraine, among others. Whether these applications are granted or denied depends on the patent regime of the individual country.
The law in the US, EU, and many other jurisdictions are favorable to patents on new forms of known substances, new uses and combinations. In these jurisdictions, several of the patent applications on these eight drugs have already been granted.
The negative impact of a granted patent in these countries might not be felt immediately (as a number of these drugs are still awaiting regulatory approval), but several implications are nevertheless clear. Most immediately, the newly granted patents may be used in litigation as blocking patents to block entry of generic combination therapies or other modified, similar forms of known drugs. By blocking entry of generic competition, the patentees retain the market power to keep drug price high, even after the patents for the older compounds expire.
In contrast, the patent policy in countries such as India, Argentina, and the Philippines is to impose stricter standards for obtaining patents for incremental innovation.
In India, for example, applications for new forms of known compounds must demonstrate increased efficacy in order to qualify for a patent. The 2013 Indian Supreme Court judgment Novartis v Union of India clarified that the law requires a demonstration of increased therapeutic efficacy. This means that pharmaceuticals may obtain patents on incremental changes if and only if they can demonstrate that the change provides real improvement to patients. This “increased therapeutic efficacy” requirement requires applicants to submit scientific data demonstrating improvement in patient health; in US/EU-like patent regimes, applicants are not required to demonstrate an improvement in therapeutic efficacy, but merely that there is some unexpected advantage, which does not have to be therapeutic, and is a much lower bar. Under India’s legal standard, our review indicates that these eight pipeline ARVs should not be granted.
There are many benefits to the approach India and other countries are adopting. The immediate impact is to free manufacturers to create new combination therapies, variations on existing drugs, or generic versions of off-patent medicines. This benefit cannot be understated for patients who have developed resistance against existing first- and second-line HIV therapies.
This approach also ensures long-term sustainability for the patent system, where patent rights are given only to genuinely innovative creations, as opposed to permitting the system to bloat with a surfeit of marginally innovative patents.
FIXING THE PROBLEM
PATENT OFFICE
Patent examiners play an important role on access to essential medicines, especially for the upcoming HIV pipeline drugs.
In most countries, examiners should strongly consider rejecting these patents for lack of inventive step since many of the techniques employed are routine and obvious to those skilled in pharmaceutical practice.
In offices that operate under the India/Argentina/Philippines patentability standard, examiners should evaluate these pipeline drug applications for what they are: secondary, incremental improvements to known drugs, rather than genuinely new medicines.
HEALTH MINISTRIES
Each health ministry, in order to improve domestic public health, should increase monitoring efforts to understand the impact of the country’s patent system on treatment access. For example, our own analysis indicates that patents on pipeline ARVs may prevent generic production and make drugs unaffordable for government procurement programs.
A health ministry may observe, for example, that tenofovir alafenamide fumarate (TAF) is granted a patent in its jurisdiction. It can then note that the TAF patent would have been rejected under an India/Argentina/Philippines-like patent regime, or if the examiner had employed stricter inventive step standards. If the patent has been improperly granted (e.g. TAF in India), the health ministry should intervene by law where permitted, e.g. by filing a Section 64 revocation action in India.
The ministry can concomitantly monitor the increased cost to government procurement that ensues from restricting generic production of TAF, and keep track of the number of patients which are subsequently denied access to TAF. Only by keeping such tabulation on essential-medicine patent grants can a national health ministry make a meaningful assessment of the public health impact of its own patent laws. Health ministries can utilize this evidence to demonstrate the need for national patent reform in the interest of improving treatment access. They can push for stricter patentability standards which require new forms of known substances to improve therapeutic efficacy, or simply standards which exclude routine derivatives wholesale. They can also flag to the patent offices that inventiveness should be examined more closely, especially for pharmaceutical development.
PATENT REFORM
The majority of countries lack higher patent requirements for incremental improvements to known drugs. This limits the ability of patent examiners to exclude those applications which are not truly innovative. The inability to reject incremental patents can be observed, for instance, by noting the expansive patent clusters (over a hundred patents in the U.S.) surrounding the HIV drug Kaletra.
To provide those tools to examiners, legislators should amend patent regimes to provide examiners with the ability to screen out incremental patents, particularly for medicinal compounds essential to health - requiring applicants to make a showing of therapeutic improvement. Some countries have taken steps to amend their laws in this fashion. Brazil, for example, has introduced proposals to adopt patent requirements similar to India’s higher requirements for new uses of known compounds.
If the first step towards strengthened patent examination is higher standards for patentability, then the second is third party participation in patent hearings. Several countries allow for this form of “citizen review,” including the Australia, Brazil, Argentina, Indonesia, Vietnam, Pakistan, India, Thailand, and the Philippines. In these countries, third parties are permitted to submit scientific evidence to the patent examiners prior to the granting of the patent, rather than attempt to invalidate the patent after the grant. Some of these countries allow third parties to participate in the examination of the patent, while others, like India, also allow a hearing prior to the grant. Pre-grant citizen review helps set out evidence for rigorous patent examination that the examiner may not otherwise be exposed to. Citizen review in India has helped examiners to make more informed decisions about the ingenuity of the claimed products, leading to the rejection of several non-inventive patent applications. Yet the US and EU continue to restrict third party participation worldwide by introducing provisions into their bilateral trade agreements with other countries, which prohibit these procedures. Countries should resist this external pressure, and adopt the ability to have pre-grant citizen review.
CONCLUSION
Our analysis of pipeline HIV drugs reveals that the next wave of drugs is the result of incremental changes which are routine practice. Eight of eleven pipeline drugs should be denied patents to ensure that the next generation of HIV medicines reaches patients who need them and that the integrity of the patent system remains intact.
In this light, we hope that patent offices and legislators worldwide can develop evidence-based reforms to the patent regime. If countries set higher standards for incremental innovation patenting, and permit citizen or third-party review of patents before and after examination, then we will likely see increased generic competition in the ART market, new combination therapies, and lower ART prices. In the longer term, higher inventiveness standards will help clear the patent thicket to allow new products to develop, and push industry towards genuine innovations. The HIV pipeline illustrates why patent reform is necessary in order to improve treatment availability for patients across the world. Citizens, examiners, and health officials alike should resist the patenting of the derivative pipeline drugs, so People Living with HIV (PLHIV) have access to all treatments.
For further information, please visit The Roadmap: The HIV Drug Pipeline and its Patents.
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*Jimmy Pan is an staff attorney and public health professional at I-MAK. Prior to his transition into law, he contributed to HIV research as a laboratory scientist. All I-MAK research is available at www.i-mak.org.
**Priti Radhakrishnan is Co-Founder and Director of Treatment Access of Initiative for Medicines, Access & Knowledge (I-MAK), a team of lawyers and scientists increasing access to affordable medicines by making sure the patent system works. Prior to founding I-MAK, she served as the Senior Project Officer of the Lawyers Collective HIV/AIDS Unit in India. Most recently, Priti was awarded the National South Asian Bar Association’s Public Interest Achievement Award and was named to the Good 100, a selection of the 100 most innovative individuals changing the world.