Patent Eligibility Of Antivirals?

There are more than 220 viruses that are known to infect humans. Within this field of viruses, RNA viruses dominate the current list of ten global health threats. In this, AIDS caused by the Human Immunodeficiency virus (HIV), influenza, Dengue virus (DENV), and viral diseases caused by the Ebola virus (EBOV) are on the top of the list. Others equality life threating viruses are coronavirus, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-1) and COVID-19, caused by SARS-CoV-2, a coronavirus closely related to SARS-CoV-1. Viruses are known to mutate constantly to evade host immune responses. Combating viral diseases with vaccines and antiviral drugs is a tough challenge.

Drug developers with knowledge of viral action and lifecycle adopt various approaches for curing or treating viral diseases. These approaches include preventing viral adhesion to host cells (inhibitors of host-cell receptors); Inhibiting hemagglutinin-induced membrane fusion; Inhibiting viral escape from endosome (protease inhibitors); Preventing the release of viral particles (blocking neuraminidase); Blocking ion-channels; Blocking RNA packaging; Accelerating capsid assembly; Preventing viral reproduction (blocking integrase or reverse transcriptase); Enhancing intracellular innate immunity; Targeting viral DNA-packaging motors; Inhibiting viral RNA processing (targeting viral polymerase complex); Disrupting viral assembly (nucleoprotein). However, for more than 220 life-threatening viruses known to infect humans, in vivo, treatment through the top ten antiviral tablets is available, as listed below.

Subject Matter Patent Eligibility Considerations

Drug developers looking to capture the antiviral or vaccine medicine market should consider the patent eligibility of the invented drug/invention in many jurisdictions.   The issue of patent eligibility is likely to crop up in countries like India. Section 3(d), in particular, restricts the patentability of derivatives of known compounds if they fail the test of enhanced efficacy. Test of enhanced efficacy as laid down by Supreme Court in Novartis case therapeutic efficacy.

In this case, the Supreme Court looked into the refusal of the patent for the substance that Novartis sought to patent, which was a modification of a known drug, imatinib, publicly disclosed in the 1993 patent application and scientific articles. The Court found that Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib. Therefore, the Court held that the patent office and Intellectual Property Appellate Board properly rejected the patent application.

The case hinged on interpreting the newly introduced amendment in section 3(d) through the amendment of the Patents Act, 1970, in 2005. The original section 3(d) version read as follows: “The mere discovery of any new property or new use of a known substance or the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant.”

This section was amended twice to deal with the patentability of incremental inventions, and the final version of new section 3(d) of Indian patent law now read as

“The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant.

Explanation: For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.” [amended portion shown in bold italics]

In the Novartis case, the Supreme Court clarified that the section 3(d) decision in this case does not put a bar on patent protection for all incremental inventions of chemical and pharmaceutical substances when the Court observed that:

“We have held that the subject product, the beta crystalline form of Imatinib Mesylate, does not qualify the test of Section 3(d) of the Act, but that is not to say that Section 3(d) bars patent protection for all incremental inventions of chemical and pharmaceutical substances. It would be a grave mistake to read this judgment to mean that section 3(d) was amended with the intent to undo the fundamental change brought into the patent regime by deletion of section 5 from the Parent Act. That is not said in this judgment.”

It means that the patent eligibility of derivatives of known antivirals may qualify for a patent if they show enhanced therapeutic efficacy. This patentability requirement is in addition to proving the traditional tests of novelty, inventive step, and application. This new test of enhanced therapeutic efficacy for claims is intended to keep trivial incremental changes to existing drugs outside the scope of the grant of patents under the Patents Act, 1970. In fact, the Supreme Court upheld the view that under the Indian Patent Act, the grant of pharmaceutical patents is subjected to further conditions of enhanced therapeutic efficacy, even if it is novel and inventive.

Pre-grant oppositions on antivirals: Valcyte case

The position under Indian patent law is very clear that an efficacious antiviral can pass the must to be eligible for a grant of a patent. In Valcyte’s case, many generic companies, including patient organisations, filed pre-grant oppositions against the application for powder formulation for the anti-HIV drug Valcyte. The argument against this patent hinges on Roche proving the therapeutic efficacy compared to the known drug.

The multiple pre-grant oppositions relating to the Roche Valcyte application were successful, as the Controller found that the powder formulation for Valganciclovir had not achieved any technical advancement in the invention. The Controller held that using fumaric acid instead of citric acid, which exhibits a similar stability profile in terms of recovery of Valganciclovir and a number of total impurities, was a choice of alternate organic acid available within the reported pH range. The Roche case lays down that section 3(d) assumes that structurally similar derivatives of a known ‘substance’ will also be functionally similar and hence ought not to be patentable.

Pre-grant oppositions on antivirals: Sovaldi case

However, a patent on Gilead Sciences’ application for the hepatitis C drug sofosbuvir (sold under the brand name Sovaldi in India) was granted by the patent office when it was returned by the High Court for reconsideration. The Controller held that a “Good amount of experimentation would have been required from the common general knowledge available as on the priority before a skilled person could have arrived at the claimed compounds. I find claimed invention inventive and nonobvious.” Rejecting the pre-grant opposition argument on 3(d), the Controller observed that “I am satisfied that claimed compounds have added layer of enhanced efficacy,” and hence, the claimed compounds are outside the prohibition of Section 3(d). Additionally, the applicant was able to convince the Controller that the claimed compound was novel and nonobvious under section 2(1)(j). It means the patent office position on 3(d) is linked to an added layer of therapeutic efficacy.

Enablement and lack of description: Antiviral patent refused in the US

A closer look at the application of US patent statutes 35 USC, sections 102 (novelty), 103 (nonobvious subject matter) and 112 (enablement, written description, and best mode requirements) reveals that they greatly affect the patentability of antivirals. In general, many antiviral patent applications are initially rejected due to the USPTO’s lack of enablement and as being obvious in view of the state of the art. In disputes over the patentability of U.S. Patent No. 7,608,597 between Idenix Pharmaceuticals Llc, Universita Degli Studi Di Cagliari, (Plaintiffs-Appellants) v. Gilead Sciences Inc., (Defendant-Appellee) the Appeal court affirmed district court decision that ‘597 is invalid for lack of enablement. [Idenix Pharm. LLC v. Gilead Scis., Inc., 2018 WL 922125, at *25 (D. Del. February 16, 2018) (“JMOL Opinion”).

Accepting Gilead Sciences Inc.’s (“Gilead”) argument that the patent is also invalid for failure to meet the written description requirement, the appeal court held that the patent is also invalid for lack of written description. This patent was held invalid for lack of written description as well as failing to meet enablement requirements. The ‘597 patent claims a method of treating HCV by administering nucleoside compounds having a specific chemical and stereochemical structure.

Freedom to operate after the expiry of a patent

In the USA, public use of expired patents includes the use of the obvious or patentably indistinct modifications of that invention. In Gilead Sciences, Inc., Hoffmann-La Roche, Inc., F. Hoffmann-La Roche, Ltd., And Genentech, Inc., (Plaintiffs-Appellees), V. Natco Pharma Limited and Natco Pharma, INC., the appeal court reiterated that:

“It is a bedrock principle of our patent system that when a patent expires, the public is free to use not only the same invention claimed in the expired patent but also obvious or patentably indistinct modifications of that invention. ……. In re Longi, 759 F.2d at 892 (“The public should . . . be able to act on the assumption that upon the expiration of [a] patent, it will be free to use not only the invention claimed in the patent but also [any] modifications or variants [thereof] which would have been obvious to those of ordinary skill in the art at the time the invention was made.”). The double patenting doctrine has always been implemented to uphold that principle effectively. Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1372 (Fed. Cir. 2005). That principle is violated when a patent expires, and the public is nevertheless barred from practising obvious modifications of the invention claimed in that patent because the inventor holds another later-expiring patent with claims for obvious modifications of the invention. Such is the case here. The ‘375 patent expires on February 27, 2015. Thus, come February 28, 2015, the public should have the right to use the invention claimed in the patent and all obvious variants of that invention……….. That was the condition upon which the ’375 patent was issued to the inventors.”

Additionally, the Court clarified:

“Note that we address only obvious variants of an invention, not separately patentable improvements. The public’s ability to practice an invention claimed in an expired patent may be further restricted by, for example, an overlapping patent covering patentably distinct subject matter. But the point of the double patenting doctrine is to protect the public from attempts by inventors to effectively extend their patent term through a later-expiring patent claiming patentably indistinct subject matter.”

Thus, in the Gilead Sciences, Inc., V. Natco Pharma Limited appeal case, the dispute relates to two United States Patent Nos. 5,763,483 and 5,952,375, for antiviral compounds and methods for their use held by Gilead Sciences, Inc. (“Gilead”) was resolved by the Court by looking into the principles of double patenting. The appeal court, in this case, found that:

Gilead currently enjoys the benefits of the ’375 patent, including an earlier priority date and the specific exclusivity provided by the scope of its claims. The expiration of the ’375 patent triggers the public’s right to use the invention claimed in it and all obvious modifications of that invention. When the ’375 patent expires, however, the public will not be free to do so because (as we assume) the ’483 patent claims some of those obvious variants of the invention in the ’375 patent and expires twenty-two months later. Therefore, if it does indeed claim obvious variants of the invention claimed in the ’375 patent, the ’483 patent would violate the doctrine against double patenting. Accordingly, the district court erred in concluding that the ’483 patent could not be invalid for double patenting because the ’375 patent could not qualify as an obviousness-type double patenting reference. We therefore  vacate the judgment of the district court and remand for further proceedings consistent with this opinion.”

Combination of drugs

It is not uncommon to come across viral infections that do not respond to one regimen. In such cases, multiple antiviral drug combinations are used. This treatment is termed as Antiretroviral therapy (ART). In this treatment, people infected with human immunodeficiency virus (HIV) were treated using anti-HIV drugs. It consists of a combination of drugs that suppress HIV replication.

This treatment is known as “Highly Active Antiretroviral Therapy” (HAART). There is no statutory bar on the patentability of combination drugs in any patent jurisdiction. However, such a combination should be not only novel but also inventive. Additionally, such a combination should not be a mere admixture resulting in the aggregation of the properties of the individual drug.

Cipla Antiretroviral combination rejected in India

The Indian Patent Office denied a patent for an Antiretroviral Combination HIV drug comprising “ritonavir” and “darunavir“. (1399/MUMNP/2010 by Cipla limited). This patent application was refused on the grounds of lack of inventive step in view of the prior published documents as well as based on Section 3(d) of the Patents Act in the absence of any surprising effect of this drug combination. The Controller held that the claims in the present application related to a new layered form of a known combination of the prior art and thus were not patentable under Section 3(d).

Combination of antivirals in US and EPO: Sofosbuvir/Velpatasvir

Gilead has filed a number of patent applications on the combination of antivirals, including a combination of sofosbuvir and velpatasvir. USPTO allowed patents on the combination formulation of two antiviral compounds in many cases. It may be noted that a patent on the sofosbuvir and velpatasvir combination is allowed in the US and EPO. For example, US14/168,340_(2014-01-30), US15/282,128 (2016-09-30) US 15/670,283_2017-08-07. Similarly, EPO patent [EP2950786B1] on a combination of antivirals comprising amorphous ledipasvir dispersed within a polymer matrix formed by copovidone and sofosbuvir in a crystalline form, and the composition for use in the treatment of HCV has been granted.

Combination Antiviral Therapy Refused by the EPO Board

The appeal question before the EPO Board was on the patent application filed by Gilead Sciences, Inc., for a co-formulation of Coviracil (FTC) and Viread (Tenofovir Disoproxil Fumarate (TDF) and refused by the opposition board. The invention in this application was for a pharmaceutical co-formulation in the form of a tablet comprising tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) for the treatment or prevention of the symptoms or effects of an HIV infection. The pharmaceutical composition was so designed by Gilead to provide a “one pill, once daily” dosage regimen.

The applicant claimed the inventive combination provided a physically acceptable, chemically stable and effective composition. The opposition board refused the combination patent for lack of inventive steps in view of document No. 24. The EPO board found that document (24), which relates to providing a co-formulation for the same purpose as the patent in suit and its content, would be considered by the skilled person. The Board ruled that “The selection tablet form and of a weight ratio of TDF to FTC within 1:10 to 10:1 is thus the result of the routine approach taken by the skilled person when formulating a pharmaceutical composition comprising these two actives. No inventive step can be acknowledged.” [T 0725/11 dated 13-03-2017)

Position of sofosbuvir and velpatasvir combination patent in India

Gilead patent application no 201627008488 on the combination of Sofosbuvir and Velpatasvir is pending examination in India. Pre-grant opposition is also filed on this application. It will take some time for us to know the patentability of this application in India. However, all the combinations of drugs are subjected to the exceptions on patent eligibility under section 3(e), which reads “a substance obtained by a mere admixture resulting only in the aggregation of the properties of the components thereof or a process for producing such substance”. It clearly means that mere aggregation of properties is insufficient for cross-section 3(e) bar. The applicant must prove the existence of a synergist effect in the combination of antivirals on the therapeutic effect of each drug if taken separately.

Looking Forward

Though the position under Indian patent law is very clear that an efficacious antiviral can pass muster to be eligible for a grant of a patent yet, many generic companies, including patient organisations, do file a pre-grant opposition against such antiviral patent applications. The success in such opposition depends and instead hinges on the applicant proving the therapeutic efficacy compared to the known drug. Patents on Remdesivir, Favipiravir and Tocilizumab were granted in India. The list of antiviral Patents is growing in India, and so is the concern about their patent eligibility in many cases.

The growth of patents on antivirals remained slow and steady in the US and many other jurisdictions. In India, many such applications are pending examination. In the USA, around 800 patents have been granted since 2021. However, the grant of patents to antiviral and ongoing US litigation also reflects concerns regarding their patentability. In the US, the patents on antivirals suffered invalidation attacks as well. In India, sofosbuvir was subjected to a series of pre-grant and post-grant opposition, and this patent application was refused. The Sovaldi case on remand by the High Court found favour with the patent office, and the Controller held that the claimed compound was novel and nonobvious under section 2(1)(j).

The Controller ruled that “I am satisfied that claimed compound has added layer of enhanced efficacy,” hence, the claimed compounds are outside the prohibition of Section 3(d). The multiple pre-grant oppositions relating to India’s patent for powder formulation for the anti-HIV drug Valcyte was successful, and the patent was denied to Roche on the ground that the powder formulation for Valganciclovir has not achieved any technical advancement in the invention. So far, the combination patent for two or three antivirals is concerned.

The Indian patent office checks the applicability of section 3(e), and the chances of the patentability rests on the applicant showing and proving synergistic /surprising effects of the combination relating to treatment results. In the Cipla case, the antiretroviral combination of ritonavir” and “darunavir” was rejected on the grounds of lack of inventive step in view of the prior published documents as well as based on Section 3(d) of the Patents Act for lack of surprising effect. The patent eligibility of antivirals depends on the type of inventive compound or combination. The results from the patent prosecution in India and elsewhere have shown that there is no statutory restriction on the patentability of antivirals.

However, where applicants seek patents for derivatives or a combination of antivirals, the provisions of section 3(d) and section 3(e) are applied by controllers in India. The Gilead Sciences, Inc. V. Natco Pharma Limited case highlights how a later patent with obvious variants of the invention in the earlier patent will be hit by the obviousness-type double patenting doctrine in the US. In India, such patents may fall under section 2(1)(j) and section 3(d). Expert advice in filing patent applications for antiviral would be useful in seeking a patent grant in India.

Author: DPS Parmar

First Published By: Mondaq Here