API and IP Newsletter
Contents
DMFs filed in the month of July 2023
We follow DMFs filed by Indian companies. FDA publishes this list every quarter. So, during first week of last month FDA must have published the list of DMF filed in Q3 2023, but we missed to analyse it the last month.
In July 2023, total 56, Type-II DMFs were filed, out of which about 23 DMFs were filed by Indian companies, Cipla and Biphore are at the top of list by filing 3 each in July 2023. Chinese companies are not far behind. Chinese companies filed 18 DMFs in July 2023. In last few quarters there’s increase in DMF filings by Chinese companies.
Some of our product specific observations are as below.
General information
EPO revokes Moderna patent in vaccine dispute with BioNTech
In the pan-European dispute between Moderna and BioNTech over mRNA patents, the patent holder Moderna has now suffered a defeat at the European Patent Office. The Opposition Division has revoked one of the patents-in-suit.
News here.
Following Recent Policy Statement, FTC ‘Disputes’ 100+ Patent Listings in FDA Orange Book
The US Federal Trade Commission (FTC) sent letters on November 7, 2023, accusing 10 companies of improperly listing drug delivery device patents in the US Food and Drug Administration (FDA) Orange Book, stating that the FTC has taken steps to “dispute” these listings.
The FTC’s statements suggest the potential for future antitrust enforcement actions against these companies, as well as for further disputes regarding a “wide array of patent listings.”
News here
Intellectual Property
Rivaroxaban- Netherlands
In Europe patent term extension is called “SPC”. This is Supplementary Protection Certificates (SPCs). An intellectual property right that serve as an extension to a patent right.
This article is not about SPC! We will write about SPC some other time, it is very interesting topic.
This article relates to rivaroxaban and about EP patent ie EP 1845961 (`961). This is the dispute between Bayer and Sandoz in The District Court of The Hague. The composition of matter patent EP1261606 (`606), already expired in December 2020. Dutch SPC on `606 would on 1 April 2024. In short, compound patent would expire in April 2024 along with patent term extension (SPC) in Europe.
Sandoz had plans to market a generic medicine based on the substance rivaroxaban in the Netherlands after the SPC expires in April 2024.
The District Court of The Hague has ruled that Sandoz may not sell its generic version of rivaroxaban in the Netherlands, even after the expiry of an SPC attached to `606 in April 2024.
The court considered the sale of the drug would infringe a valid dosage patent EP 1845961 (`961) for Bayer's original product, Xarelto.
The European Patent Office (EPO) had revoked `961 in the first instance in 2018 due to lack of inventive step, however, the EPO Boards of Appeal reinstated the patent in 2021. Hence, the `961 patent will be valid until January 2026.
Sandoz confirmed to Bayer that it respects `606 patent and does not intend to market its generic product before the patent’s and associated SPC’s expiry in the Netherlands. At the same time, Sandoz filed a nullity action against `961, arguing that the patent is not inventive because the claimed dosage regimen for the subject is obvious in view of cited prior art documents. (prior art references listed at the ends of the article)
In Bayer’s opinion, Sandoz would be infringing the rivaroxaban dosage patent `961, which does not expire until January 2026.
The patent `961 concerns the dosing regimen of rivaroxaban in the treatment of thromboembolic disorders, abbreviated as TEDs.
TEDs are disorders of the blood clotting system that cause blood clots. Blood clots can lead to a blood vessel blockage or embolism, which can cause life-threatening conditions such as stroke, pulmonary embolism or heart attack.
The parties agreed that Kubitza and Harder (prior art references listed at the ends of the article) are the documents from the relevant state of the art that are a realistic starting point for the average skilled person to arrive at the invention.
The court relied on the Harder Poster as the closest state of the art, and therefore as a starting point in assessing the problem-solution approach (PSA). The reason for this is that the Harder Poster was not yet known during the opposition procedure at EPO. Moreover, in the course of the proceedings after the Harder Poster had become known, Sandoz focused its inventive step attack on the Harder Poster and Bayer has not disputed that the Harder Poster is a suitable starting point for the PSA.
In order to assess inventive step in an objective and predictable manner, the so-called problem-solution approach is applied. In the problem-solution approach, there are three main stages:
determining the "closest prior art",
establishing the "objective technical problem" to be solved, and
considering whether or not the claimed invention, starting from the closest prior art and the objective technical problem, would have been obvious to the skilled person.
Starting from the Harder Poster, the objective technical problem must then be determined on the basis of the (technical) difference characteristics between the Harder Poster and the invention.
The Harder Poster shows results from a phase I clinical trial of rivaroxaban for the treatment of TEDs. It is reported that some tests show that rivaroxaban has a long-lasting (12 hours and sometimes even 24 hours) effect, indicating its suitability for a once-daily dosing regimen. The Poster also states that rivaroxaban has a half-life of 9-12 hours. The parties agree that the difference between the Harder Poster and the invention is that the claimed invention relates to the medical use of rivaroxaban in the claimed dosage regimen.
Harder concerns a phase I study that shows the PD effects (of different doses) of rivaroxaban on healthy test subjects, but not what the effects are in patients and whether the substance has therapeutic effectiveness (or 'it works'). PD is pharmacodynamics, it is the measure of a compound's ability to interact with its intended target leading to a biologic effect.
The technical effect of the difference measure is that rivaroxaban in the dosing regimen (once a day for at least five days with a rapid release dosage form) is effective and safe for medical use (i.e. in TED patients).
In the court's opinion, it follows from this technical effect that the objective technical problem to be solved is: 'finding an oral dosing regimen of rivaroxaban that is safe and effective against TEDs'.
It must then be assessed whether the invention was obvious to the average skilled person on the priority date, based on this problem definition.
Bayer disputed this, because the professional would have no reasonable expectation of success that the once-daily dosage of rivaroxaban suggested in the Harder Poster would be safe and effective in patients. The professional would not investigate this in a phase II study, because there were contraindications ( pointers away ) that would prevent him from doing so. At the priority date, rivaroxaban (in any dosage regimen) had not yet been approved for medical use in patients.
Sandoz argued, the practitioner seeking a solution to the problem would first look for the known PD and PK effects of various doses of rivaroxaban in phase I studies. The practitioner would consider the suggestion in the Harder Poster to administer rivaroxaban once daily, because some tests performed in that study show that rivaroxaban has a long-lasting PD effect. PK is pharmacokinetics. PK is defined by how a compound is absorbed, distributed, metabolized, and excreted.
Bayer has rightly pointed out, with reference to its expert Haas, that the test referred to in Harder shows a significant fluctuation in the placebo arm, while it should obviously have no relevant (PD) effect as a placebo. This indeed indicates that the test results are not particularly reliable, especially when it is taken into account that the long-lasting effect, according to Harder (and Sandoz), appears to fall within that deviation from the placebo values or is statistically indistinguishable or impossible to distinguish from it.
The Court upheld Bayer’s view. In the court's opinion, the professional would not have a reasonable expectation on this basis that rivaroxaban is safe and effective in patients in a once-daily dose. The Harder Poster does not provide convincing test results for this.
Another reason why the professional from the Harder Poster would not have a reasonable expectation of success is that the suggestion to use rivaroxaban once daily is not based on the half-life of rivaroxaban, but (only) on the PD effects as reported in Harder that apparently lasted a long time.
Sandoz had argued that enoxaparin, a drug known to treat TEDs on the priority date, is administered once daily despite a half-life of 4.5-7 hours.
However, in the court's opinion, this does not mean that it can be concluded that the average professional would have a reasonable expectation that rivaroxaban is safe and effective in patients in a once-daily dose.
The Court held that patent is inventive and therefore valid, so that the court rejected Sandoz's claim.
Decision here
Prior art references cited.
Single Dose Escalation Study Investigating the Pharmacodynamics, Safety, and Pharmacokinetics of BAY 59-7939 an Oral, Direct Factor Xa Inhibitor in Healty Male Subjects ”, Kubitza et. al (exhibits GP16-A: ASH poster and GP16-B: ICT poster).
Multiple Dose Escalation Study Investigating the Pharmacodynamics, Safety, and Pharmacokinetics of BAY 59-7939 an Oral, Direct Factor Xa Inhibitor in Healty Male Subjects ”, Kubitza et. al (exhibits GP15-A: ASH poster and GP15-B).
Effects of Bay 59-7939, an Oral, Direct Factor Xa Inhibitor, on Thrombin Generation in Healthy Volunteers ”, Harder et. al. (exhibit EP26: ASH poster and GP14: ICT poster). Kubitza et. al (exhibit GP16-A: ASH poster and GP16-B: ICT poster).
