A patent1 is given to a novel invention having utility value and does not appear obvious to a person skilled in the art. It is one of the important intellectual properties having tremendous economic potential. It awards economic monopoly (right to produce, sell, licence, import, assign, and use) to the patentee for a limited period of time after which the patent becomes a part of the public domain. The main intention of patenting is to promote innovativeness and research in science and technology to make our lives much more comfortable and easier. As per the WTO guidelines and TRIPS2 every country has right to frame its own patenting laws keeping in mind the ultimate goal of achieving the public reach of those patented inventions once the stipulated period of protection is over. This has utmost significance in the pharmaceutical sector. Availability of affordable drugs and pharmaceuticals along with latest medical care is the need of the hour. Article 31 of the TRIPs also reiterated the same and WTO also has established this fact stating that member countries can frame patent laws and take measures to commercialize the patented technologies in drugs so as to cater to the health-care needs at affordable prices. This gives enough scope for the generic drug production. Generic drug3 is similar to the patented drug (whose term has expired) in all respects but for manufacturing route or packaging etc. Generic drugs possess the same pharmacological significance as the original drugs but have the advantage of cost-effectiveness. The Big pharma companies always want to keep their patents alive by doing minor modifications so as to enjoy the monopoly forever. Such modifications are classified as continuation in part of the original patent or incremental invention. This is called evergreening the patent. This has to be controlled at any cost. Giving licence to generic drugs is not at all detrimental to innovation and incremental inventions since coming out with a generic drug also needs enough research and inventiveness. Generic drugs will come to the rescue of millions of patients who don't have access to the exorbitantly priced patented counterparts of generic drugs. Generic drugs are in no way substandard when it comes to the question of efficacy compared to the patented version of the same. In this connection the case of Indivior Inc Vs Dr. Reddy's over the generic version of sublingual polymeric films for opioid substance deterrence can throw some light on the generic drugs, limitations, how the big pharma companies evergreen their patents and related aspects.
Here the issue is with regard to the US federal court's decision in Indivior Vs Dr. Reddy's Laboratories in the case of marketing the generic version of Suboxone (buprenorphine and naloxone) sublingual film for opioid dependence. It is an ANDA (abbreviated new drug application) litigation over Indivior's suboxone film product, Suboxone®. Basically it is the generic version of Suboxone by Reddy's to supply the prescribed drug at affordable rates compared to the patented drug. It is proved that Dr. Reddy's has not infringed patents held by Indivior and its assignees viz., U.S Patent Nos. 9, 931,305;.8,603,514; 8,017,150; 8,475,832, on rapidly dissolving film formulations containing buprenorphine, and naloxone, that reduce opioid abuse and stop its abuse respectively. These films have an advantage over tablet formulations since they have minimal side effects. But the real task lies in maintaining uniform concentration of the active component in such cases. The films should be possessing homogeneous availability of the active ingredients through out the film. Suitable dosage of the drug is provided by cutting the bigger sheets into smaller units of required size and shape that can be administered to the patient as per the requirement. It is sufficient if the generic version of the particular drug shows the bioavailability of the drug in the blood stream on administration in 24-48 hrs. It need not go through the ordeal of providing animal clinical trial data nor it is required to produce human trial data since the patented compound's drug interactive mechanism has already been established. The ANDA drugs will get immediate approval since they offer cost-effective drugs from the generic version of the patented ones as per the Drug Price Competition and Patent Term Restoration Act of 1984 (known as the Hatch-Waxman Act) in the US.
Chain of Events
Reckitt Benckiser developed Suboxone sublingual film using MonoSol Rx's PharmFilm technology. In December 2014, Reckitt Benckiser de-merged its pharmaceuticals business as Indivior of UK. The US Food and Drug Administration (USFDA) approved Suboxone film in four different strengths of Indivior's American establishment, Indivior Inc. In June, 2017 the USFDA approved Dr. Reddy's Buprenorphine and Naloxone Sublingual Film, in four strengths including 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and 12 mg/3 mg, for sale in the US market. In June, 2017 Indivior Inc filed an infringement suit against Dr. Reddy's in the district court of Delaware and got injunction orders under the Hatch-Waxman act. In August 2017, Judge Richard Andrews (D. Del.) held that Indivior failed to meet its burden of showing that Dr. Reddy's generic Suboxonefilm infringed the '514 patent. On 5th April, 2018, Indivior Inc., filed patent lawsuits against Dr. Reddy's, and 3 others for infringing U S Patent No. 9,931,305 (having priority to US32886801P, issued on April 3rd, 2018) which is a continuation in part of U.S. Patent No. 8603514 ( due to expire on 2022-02-14) to obtain temporary injunction against the generic version of the invention by Dr. Reddy's. in New Jersey court.4-11
Indivior approached the court of appeals for the Federal Circuit Court in November, 2018. The Circuit court upheld the district court's decision and vacated the preliminary injunction order given earlier since, the '305 patent is indistinct from U.S. Patent No. 8603514.12
On Feb 22, 2019, Dr. Reddy's Laboratories relaunched its generic version of Suboxonesublingual film in the U.S. Indivior's plea to stay a lower courts' order was refused by the Supreme Court which finally paved the way for Dr. Reddy's generic sublingual films for opioid deterrence.
Why the courts decided in favour of generic films by Dr. Reddy's?
The patents held by Indivior that are pitted against Dr. Reddy's included patents viz., U.S. Patent No. 8603514, 8017150 and 8475832.
US patent No.860351413 disclosed rapidly dissolving thin film drug delivery compositions for the oral administration of active components. The active components are provided as taste-masked or controlled-release coated particles uniformly distributed throughout the film composition. The compositions may be formed by wet casting methods, where the film is cast and controllably dried, or alternatively by an extrusion method
But, Indivior's claims of patent infringement are found baseless and the Federal court concluded that the '514 patent has opposed the sole use of topical air drying of the film and the film was subjected to bottom drying by microwaves. Dr. Reddy's generic film is dried by conventional top air drying and hence 514' has not been infringed, Federal Circuit went against the lower courts decision and vacated the injunction order.
Things that went in favour of Dr. Reddy's
The explicit limitations that formed the basis of '514 patent included practical difficulties in achieving drug content uniformity in the film form, viscosity of the matrix in order to maintain non-self-aggregating uniformity of the pharmaceutically active species, and amenable matrix for drying with out disturbing the uniformity of such active species. To overcome these issues, "the specification disclosed controlled drying processes that differ from conventional techniques , which consisted of controlled bottom drying or controlled microwave drying. Though Indivior disclosed conventional methods in the description, it has restricted itself to have bottom microwave drying as a compulsory condition for achieving the uniformity with no more than 10% loss of the active ingredient.
Dr. Reddy's has used only top drying of the film hence no infringement to this extent with regard to patent '514.
US Patent 801715014 disclosed non-self-aggregating, uniform heterogeneous film products by controlled drying or other mechanisms. The films contained a polymer matrix of polyethylene oxide optionally blended with hydrophilic cellulosic polymers. The films contained a pharmaceutical and/or cosmetic active agent with up to 10% variance of the pharmaceutical and/or cosmetic active agent per unit area of the film. Dr. Reddy's Labs substituted polyvinyl pyrrolidone for hydrophilic cellulosic polymer for preparing generic sublingual films for the treatment of opioid addiction. Patent '150 did not claim any thing about polyvinylpyrrolidone (PVP) but disclosed the same in the description .Hence these embodiments are in the public domain (according to the District Court). Hence no right will accrue to the present patent holder Indivior and '150 patent claims will not come under Indivior's doctrine of equivalents contentions.
US patent 890049715disclosed rapidly evaporating flowable polymer matrix to prepare a. visco-elastic film having uniform distribution of components using a solvent, Such film having at least one active component that can be used to prepare individual unit doses of equal size not varying by more than10% . It did not claim the combination of the two drugs and hence no infringement.
US patent 847583216 disclosed pH maintaining Sublingual and buccal film compositions containing polymeric carrier matrix for the treatment of narcotic dependence in a user. Narcotic dependency minimizers can be selected from buprenorphine or naloxone or their pharmaceutically acceptable salts and it did not claim their combination. Invalidation of claim nos.15-18 is irrelevant in this regard since the invention disclosed in- vivo profiling of the active components on administering. In no way it can affect the film casting which is the bone of contention in this case. It is reflected in the decision of the Federal court which vacated the invalidity of the claims of '832 as decided by the PTAB review and held them valid.
Dr. Reddy's Labs cited three prior art references of U.S. Patent Nos. 4, 849, 24617; 6, 552, 02418; and 5,881,47619 at trial to invalidate the claims by Indivior. The '246 patent disclosed methods for making pharmaceutical films and nothing explicitly expressed about the uniform nature of the film thus obtained, as asserted by Indivior. The '024 patent taught top-air drying pharmaceutical films and nothing was disclosed about bottom drying using microwaves (the crux of the patents held by Indivior). US Patent No.5881476 disclosed a method and device for controlling the moisture or coating quantity profile in a paper- web, which in no way related to the sublingual polymeric films for the treatment of opioid addiction.
The District Court felt that the patents '246 and '024 have not disclosed anything about the films possessing uniform drug content which is a requisite of the claimed invention of Indivior and at the same time nothing was disclosed regarding the nature of the pharmaceutical films. Since the '476 patent is not at all related to pharmaceutical film, the court could not combine the said patents to nullify the non-obviousness of Indivior's patents and upheld the validity of its patents.
In the meanwhile, Indivior changed the terms "drying/dried" of 9, 931, 30520 patent to "continuously produced self-supporting film during the manufacturing process." It is clear that '305 patent is a continuation of the '514 patent and lacked special novelty over its parent patent and indistinct from it but for the casting method. '305 patent disclosed selection of suitable polymer like polyethylene oxide so as to maintain non-self-aggregating uniform heterogeneity, and the edible-film thus formed by hot-melt extrusion. The absence of additional solvent during the manufacturing process ensured the release of the taste-masked or controlled-release, coated active agent. It also claimed a multilayered individual dosage unit containing at least one active component, The terminal disclaimer on the '305 patent was filed to overcome patenting rejection due to indistinctiveness over the '514 patent. The Federal Circuit concluded that the specification disclaimer and claim preclusion revealed non-infringement by Dr. Reddy's. Finally Dr. Reddy's launched its Suboxone generic-film product the same day that the FDA approved its ANDA .
Patent protection always promotes innovations. But ever-greening by minor modifications and claim reconstruction to enjoy monopoly are not welcome gestures. Generic drugs can definitely change the pharmaceutical scenario by providing affordable medicines with the same efficacy and bioequivalence as their patented counterparts. If big countries like the US can offer its people affordable drugs by way of ANDA route, there is nothing wrong if India provides the same by way of avoiding ever-greening of patents, under section 3(d) of the Indian Patent Act, (in consonance with the WTO guidelines and TRIPS provisions)!
This is Dr. T. Bhavani, IP consultant, Technical Specialist, Lifeintelect Consultancy Pvt.,Ltd., from Bangalore. Doctorate in Chemistry (IICT), IN/PA-1295, PGDIPRL (NLSIU), Worked with BrainleagueIPServices (presently BananaIPsolution), published papers in reputed journals. Contributed to the Question Corner, The Hindu. Paper on e-waste management published in the IIFM-abstracts.
9. https://asia.nikkei.com : Business : Companies : Dr.-Reddy-s-restarts-Sub
12. Indivior Inc. v. Dr. Reddy's Labs. S.A., No. 2018-2167, 2018 U.S. App. LEXIS 32776 (Fed. Cir. Nov. 20, 2018
13. US Patent No.8603514
14. US Patent No.8017150
15. US Patent No.8900457
16. US Patent No.8475832
17. US Patent No.4849246
18. US Patent No.6552024
19. US Patent No.5881476
20. US Patent No.9931305
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