API and IP Newsletter
Contents
Recent P-IV filings
We follow generic companies' P-IV filings. In the last two to three months, three ANDAs with P-IV certificates have been filed.
The details and our observations are as below.
General information
Orexo resolves Zubsolv US patent dispute with Sun Pharma
Orexo has reached a settlement agreement with India’s Sun Pharmaceutical Industries to resolve the patent litigation regarding Zubsolv (buprenorphine and naloxone) sublingual tablet (CIII), for the treatment of opioid use disorder in the USA.
News here
Advancing continuous manufacturing with FDA support
Compelling data from companies already adopting CM, reporting a "50% reduction in operating costs, a 33% reduction in waste and an 80% reduction in manufacturing and testing cycle time," with some companies experiencing "up to a 66% reduction in time from testing to release
News here
Intellectual Property
Novartis Vs MSN
In 2015, the FDA approved Novartis’s New Drug Application (“NDA”) for Entresto, a combination therapy of valsartan and sacubitril.
Entresto is indicated to reduce the risk of cardiovascular death and hospitalisation due to heart failure in adult patients.
Novartis seeks to prevent MSN Pharmaceuticals from launching its generic version of Entresto®, which Novartis claims would infringe U.S. Patent 11,096,918.
The ’918 patent, owned by Novartis and set to expire on November 8, 2026, pertains to an amorphous solid form of trisodium valsartan sacubitril, or “TVS.”
The patent contains two claims, which recite:
An amorphous solid form of a compound comprising anionic [valsartan], anionic [sacubitril], and sodium cations in a 1:1:3 molar ratio.
A pharmaceutical composition comprising the amorphous solid form according to claim 1 and at least one pharmaceutically acceptable excipient.
Because the ’918 patent is not Orange Book-listed, the filing of Novartis’s complaint did not trigger a statutory stay barring the FDA from approving any ANDAs filed by drugmakers seeking to manufacture and sell generic versions of Entresto.
In 2019, MSN and others submitted their ANDA for Entresto. Novartis sued all ANDA filers, asserting that each manufacturer’s generic product would infringe the ’918 patent due to the presence of amorphous TVS.
At claim construction, the parties disputed the meaning of only a single claim term: “an amorphous solid form of a compound.”
Novartis contended that the term did not necessitate any interpretation, while MSN claimed that the term refers to "a substantially pure amorphous solid form of a compound.”
The parties disputed the amount of amorphous TVS in the compound compared to any other non-amorphous TVS component (e.g., crystalline TVS) required by the claim.
The court determined that Novartis’s assertion that any presence of amorphous TVS in a solid form would fall within the claims' scope conflicted with the prosecution’s history, which established that amorphous and crystalline TVS display different properties and are easily distinguishable.
It thus interpreted “an amorphous solid form of a compound” to mean a solid form of a compound in which the amorphous form predominates. An amorphous solid form is mutually exclusive to a crystalline solid form but not necessarily mutually exclusive to a partially crystalline form.
On 24 July 2024, the FDA granted final approval of MSN’s ANDA, paving the way for an at-risk launch of MSN’s valsartan-sacubitril product, which MSN asserts contains crystalline TVS, or “Form-S.”
Novartis responded by filing a motion in district court to preliminarily enjoin MSN from launching its product.
In its motion, Novartis contended that it was likely to succeed in proving that MSN’s generic product contains the claimed amorphous TVS, and thus infringes claim 1 of the ’918 patent.
Novartis contended that testing by its expert, Dr. Matzger, indicated that, contrary to MSN’s depiction of its product as crystalline TVS, the product is, in fact, a physical mixture of crystalline valsartan and crystalline sacubitril, along with regions of amorphous TVS formed during the manufacturing process.
In Novartis’s view, Form-S is not crystalline TVS at all; it is merely a physical mixture of separate crystalline components.
MSN argued that Novartis is unlikely to prove that MSN’s product contains any amorphous TVS.
After reviewing the evidence and testimonies from both sides, the district court determined that Novartis had not fulfilled its obligation to demonstrate that it is likely to succeed in proving that MSN’s ANDA product includes amorphous TVS.
The district court’s order stated that even if Novartis was correct in claiming that Form-S is a physical mixture of crystalline valsartan and crystalline sacubitril, it did not sufficiently demonstrate that the amorphous regions of MSN’s product identified by Dr. Matzger are indeed amorphous TVS.
The district court determined that Novartis had not adequately shown it would suffer irreparable harm without an injunction.
Novartis promptly appealed the district court’s decision to the Court of Appeals for the Federal Circuit (CAFC).
The CAFC observed that the district court stated, “MSN notes that Dr. Matzger did not compare the spectra he obtained from MSN’s API to the Form-S reference spectra,” and that “MSN asserts that when the comparison is made between MSN’s API spectra and the Form-S reference spectra, the peaks in MSN’s API spectra that Dr. Matzger points to as proving the presence of amorphous TVS more closely match the peaks in MSN’s Form-S reference spectra than those in the amorphous reference spectra.”
The CAFC generally agreed with Novartis’s assertion that this comparison would not be decisive in the ultimate infringement inquiry, which requires demonstrating that MSN’s final product includes amorphous TVS.
However, a closer record review shows that MSN did not argue to the district court that Novartis had failed to compare the spectra obtained from MSN’s API with a Form-S reference spectrum. Instead, it argued that Novartis had failed to compare the spectra Dr. Matzger obtained from MSN’s final product with a Form-S reference spectrum.
CAFC did not find an apparent error in the district court’s analysis and evaluation of the evidence. MSN countered Novartis’s argument by presenting evidence to show that the alleged amorphous TVS regions identified by Dr. Matzger in the final product were actually indicative of crystalline TVS.
MSN achieved this with the help of its expert, Dr. Steed, who compared the spectra obtained by Dr. Matzger from the final product to a Form-S reference spectrum and determined that they align closely.
The CAFC said this raises considerable doubt about Dr. Matzger’s testing and implies that further testing should have been performed to ascertain whether crystalline or amorphous materials were present in MSN’s ANDA product.
The CAFC upheld the district court’s determination that Novartis failed to prove that the accused product contained any amorphous TVS.
Decision here
