API and IP Newsletter
Contents
DMF filings by Indian companies
We analyze DMF filings by Indian companies. FDA recently published a quarterly DMF filing list. This week we analyzed DMFs filed in the month of May 2023. Some of our comments are as follows.
General information
Scientists have discovered a ground-breaking new way to make painkillers like Tylenol and ibuprofen out of a surprising source
Researchers at the University of Bath have developed a way to make these drugs out of waste products from the paper manufacturing industry instead.
The researchers investigated a chemical called beta-pinene, which is derived from pine trees. They then used continuous flow reactors to produce paracetamol, ibuprofen, and precursors to other pharmaceuticals.
News here.
FDA Issues New Nitrosamine Impurities Guidance
On August 4, 2023, the FDA issued a new Guidance to the pharmaceutical industry relating to large molecule drugs left unaddressed in its earlier nitrosamine Guidance publications. (Access the complete Guidance or the abbreviated version.)
News here
Intellectual Property
Federal Circuit affirmed district court’s decision that asserted claims of US 10,130,589 are invalid.
Following patents are listed in OB for Rotigotine. Brand name Neupro.
Neupro (Rotigotine Transdermal System) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease and moderate-to-severe primary Restless Legs Syndrome (RLS).
The technology at issue relates to transdermal therapeutic systems (TTSs), which deliver drugs through the patient’s skin and thus avoid complications with oral treatments. TTSs are usually implemented as skin patches that deliver drugs across the patient’s skin barrier to enter the patient’s bloodstream.
These patches contain drugs in an amorphous, i.e., non-crystalline, form because drugs in crystalline form cannot cross the skin barrier. Consequently, crystallization in patches can reduce the amount of drug leaving the patch and hence reduce a patient’s dose.
Amorphous materials can transition from a non-crystallized (high energy) state to a crystallized (lower energy) state. The temperature at which an amorphous solid change from a rigid state to a flexible, rubbery state is the glass transition temperature (Tg).
Above Tg, molecules are more mobile and more likely to crystalize.
In 2007, UCB invented and marketed Neupro® (original Neupro®), the first USFDA approved patch for treatment of Parkinson’s disease. Original Neupro® contains a dispersion of amorphous rotigotine and polyvinylpyrrolidone (PVP). PVP stabilizes amorphous rotigotine by increasing the Tg and preventing hydrogen bonding between rotigotine molecules, which prevents a clumping of sorts that creates crystallization.
Original Neupro® is covered by several UCB patents, including U.S. Patent Nos. 6,884,434 and 7,413,747 (the Muller patents).
The Muller patents have materially similar specifications and claim priority to an application filed in 1999.
The ’434 Muller patent taught a TTS having rotigotine in an amount effective for treating Parkinson’s disease, with PVP in the range of 1.5% to 5% (w/w).
The ’747 Muller patent taught a TTS with a ratio of 9% rotigotine to 1.5% to 5% PVP by weight.
The Muller patents also described an exemplary process for making a TTS with a rotigotine to PVP weight ratio of 9:3 rotigotine to PVP.
In August 2007, three months after the original Neupro® U.S. launch, it was discovered that a new crystalline form of rotigotine “Form II” occurred when rotigotine was stored at room temperature.
After discussions with the FDA, UCB recalled original Neupro® from U.S. markets in April 2008.
Original Neupro® remained in limited use in the U.S. under a compassionate-use program, while European regulators agreed to continue marketing original Neupro® under cold-chain conditions (i.e., refrigerating original Neupro®), which prevents Form II crystallization.
In 2012, the FDA approved a new version of Neupro® (reformulated Neupro®), which employs a weight ratio of 9:4 rotigotine to PVP.
The reformulated Neupro® exhibits long-term stability at room temperature with a two-year shelf-life. Reformulated Neupro® is bioequivalent to the original Neupro®, and the FDA approved it without new efficacy studies. The Muller patents were listed in Orange Book, as covering reformulated Neupro®.
In 2013, Actavis submitted an ANDA to the FDA for approval of a generic version of a transdermal rotigotine patch. In 2014, UCB filed suit for infringement of the ’434 Muller patent and U.S. Patent No. 8,232,414.
The district court upheld the validity of the challenged claims of the ’434 Muller patent, held some of the challenged claims of the ’414 patent invalid under 35 U.S.C. § 102(a), and granted UCB an injunction preventing approval of Actavis’s ANDA. The injunction expired in March 2021, when the ’434 Muller patent expired.
The interesting twist took place in 2018. In 2018, while UCB was on appeal, UCB filed the patent application that matured into the patent-in-suit, the ’589 patent. The ’589 patent claims priority from a provisional application filed in December 2009. The patent is entitled “Polyvinylpyrrolidone for the Stabilization of a Solid Dispersion of the Non-Crystalline Form of Rotigotine” and discusses both rotigotine Form I and Form II.
The written description explains that PVP is unexpectedly able to stabilize the non-crystalline form of rotigotine and prevent rotigotine from re-crystallization in a solid dispersion thereby imparting sufficient long term storage stability properties to the TTS, preferably at room temperature. The ’589 patent discloses and claims a TTS having a range of rotigotine to PVP ratios by weight of about 9:4 to about 9:6.
Here is the representative Claim 1 of `589: 1. A method for stabilizing rotigotine, the method comprising providing a solid dispersion comprising polyvinylpyrrolidone and a non-crystalline form of rotigotine free base, wherein the weight ratio of rotigotine free base to polyvinylpyrrolidone is in a range from about 9:4 to about 9:6.
The table 3 of the patent explains that no crystals were observed at room temperature for up to 24 months for sample 5 with the PVP to rotigotine weight ratio of 9:4.
The ranges of rotigotine to PVP ratios disclosed in the Muller patents and the ’589 patent overlap from about 9:4 to 9:5 and include the ratio in reformulated Neupro®.
In March 2019, about a year before UCB’s injunction expired, UCB again filed a lawsuit against Actavis, accusing Actavis’s same ANDA of infringement. This time, UCB asserted the ’589 patent, which would delay FDA approval of a generic for nine additional years, until the ’589 patent expires in December 2030. UCB asserted that Actavis infringed claims 1–3, 7, and 10–12 of the ’589 patent. Actavis conceded that, if the ’589 patent is valid, then its ANDA would infringe.
In July 2019, in response to Mylan Technologies, Inc. seeking to market its own generic version of Neupro®, UCB also filed a lawsuit against Mylan alleging infringement of the ’589 patent and U.S. Patent No. 10,350,174. This appeal consolidates both cases.
In March 2021, the month UCB’s injunction expired, the district court ruled on Actavis’s invalidity defences. Let us discuss obviousness arguments in this write-up.
Obviousness.
The district court held the asserted claims obvious based on two separate grounds, including that: (1) the claimed range of weight ratios of rotigotine to PVP overlap with that disclosed in the Muller patents and UCB failed to rebut this prima facie case of obviousness; and (2) the prior art’s 9:2 and 9:3 TTS examples as modified by Muller’s teachings of a range of 1.5% to 5% PVP render the claims obvious.
UCB challenged the district court’s holdings on both grounds.
Here, it is undisputed that the range claimed in the ’589 patent overlaps with the ranges taught by the Muller patents. Thus, Actavis established a prima facie case of obviousness.
On appeal, UCB contends that the Muller patents do not reflect the state of the art at the time of the invention because they precede Form II of rotigotine and, as such, their disclosed range cannot render the claimed range obvious.
UCB contended that a different prior art reference U.S. 2009/0299304 (Tang) is actually the closest prior art because, unlike the Muller patents, Tang addresses the stability problem.
UCB further contended that Tang teaches away from the claimed range, thus establishing nonobviousness of the claimed range. Tang is directed to TTSs with a therapeutic agent in a stable amorphous form.
It teaches the importance of the weight ratio of the polymeric stabilizer to the therapeutic agent in stabilizing the therapeutic agent. Specifically, Tang taught that if a therapeutic agent has a low Tg, the weight ratio of the polymeric material to the amorphous form of a therapeutic agent is 2 or greater.
And if the therapeutic agent has a high Tg, the ratio is 0.5 or greater. Tang focused on working examples of scopolamine, which is used to treat motion sickness.
None of Tang’s working examples include rotigotine as the active ingredient. And Tang does not disclose the Tg of rotigotine.
The district court found that the claimed range did not produce new and unexpected results. The court determined that results obtained in the alleged invention and those in prior art, like the ’747 Muller patent, are similar in kind with similar levels of stability (i.e., lack of crystallization).
CAFC read the district court’s finding of similar levels of stability as a finding that any differences in stability between the claimed range and prior art is one of degree. Dr. Prausnitz’s expert testimony, cited by the court, explains that adding slightly more PVP increased stability, but that such a change is one of degree; there would be no new properties.
The court relied on other evidence to support its finding that a person of ordinary skill would expect the claimed rotigotine to PVP weight ratio range and the range disclosed in the prior art to provide stability in a similar way.
For example, the district court cited to prior art and expert testimony showing that PVP was the most effective crystallization inhibitor tested.
Further, the court found that a person of ordinary skill would expect that increasing the concentration of PVP in a TTS would increase the stability of the amorphous drug. In support of its finding, the court relied on UCB’s expert, Dr. Myerson, who testified that, as a general principle, increasing PVP should increase the stability, although one would need experiments to verify how much the stability increases.
The district court also found that a person of ordinary skill in the art would know that only minor changes to the amount of PVP were needed to address crystallization of original Neupro® given the success with cold-chain storage.
The court cited Actavis’s expert, Dr. Rogers, who testified that cold storage helps reduce crystallization of amorphous materials (which occurs when molecules bond to each other), because the cold reduces the mobility of molecules.
The court also leaned on Actavis’s expert, Dr. Prausnitz, who testified that the lack of crystallization at cold temperatures for the 9:2 patch suggests that a fundamental change in the patch design isn’t needed and, instead, increasing PVP is going to be something that can get over this hurdle of crystallization and increase the stability.
Based on above facts the CAFC concluded that the district court’s finding that the claimed range did not produce new and unexpected results is not clearly erroneous. OB listed patent US 10130589 was invalidated.
Decision here
