API and IP Newsletter
Contents
DMFs filed by Indian companies
We follow DMFs filed by Indian companies. FDA uploaded list of DMFs for Q4 2023 in the first week of January 2024. This week we analysed DMFs filed by Indian companies in October 2023. Our analysis of November 2023 and December 2023 will follow next weeks.
Total 59 DMFs filed in October 2023 and maybe first time Chinese companies had overtaken DMF filings by Indian companies. Total DMFs filed by Indians are 24 whereas Chinese DMFs are 25!
Some of our observations are as below.
General information
Eagle Pharmaceuticals Provides Update on Bendamustine Intellectual Property Portfolio
On January 16, 2024, the United States Court of Appeals for the Federal Circuit affirmed the previously announced decision by the United States District Court for the District of Delaware finding that the 505(b)(2) drug applications referencing BELRAPZO® filed by Slayback Pharma Limited Liability Company (“Slayback”) and Apotex Inc. and Apotex Corp. (“Apotex”) did not infringe Eagle’s previously issued ‘483 patent. Slayback, Apotex, and Baxter Healthcare Corporation (“Baxter”) launched their respective products in December of 2022.
News here.
The FDA Goes After Homeopathic Eye Drops
Throughout the year 2023, the U.S. Food and Drug Administration (FDA) has had over-the-counter (OTC) ophthalmic products in its crosshairs. In April 2023, and after an 11-day inspection that had begun in February, the FDA found that the Global Pharma Healthcare facility in India did not follow proper protocol to prevent bacterial contamination of its eye products. The company recalled its Artificial Tears Lubricant Eye Drops, distributed by EzriCare and Delsam Pharma, even before the FDA’s inspection was completed. Yet, the Centers for Disease Control and Prevention (CDC) reported four deaths and 14 instances of eye loss after their use
News here
Intellectual Property
Rucaparib camsylate/PFIZER Vs Hexal AG
T 1126/19 (Rucaparib camsylate/PFIZER)
Rucaparib, sold under the brand name Rubraca, is a PARP inhibitor.
It was approved by European Commission (EC) on 20 November 2023 and has granted marketing authorization for a first-line maintenance treatment for all women with advanced ovarian cancer
The patent under dispute is EP 2534153 was issued to Pfizer and was opposed by Hexal AG.
The decision under appeal is the opposition division's interlocutory decision rejecting Pfizer’s main request (patent as granted) and finding that EP 2534153 as amended in the form of auxiliary request 1 met the requirements of the EPC.
The amended version of the patent held allowable by the opposition division contained four independent claims, namely claims 1, 9, 10 and 13. They read as follows:
"1. A camsylate salt of Rucaparib, wherein the salt is crystalline and has a powder X-ray diffraction pattern comprising peaks at diffraction angles 12.2±0.2, 14.8±0.2 and 22.4±0.2, wherein said powder X-ray diffraction pattern is obtained using copper K-alpha1 X-rays at a wavelength of 1.5406 Angstroms."
"9. A pharmaceutical composition comprising the salt of any of claims 1-8."
"10. The salt of any of claims 1-8 or the pharmaceutical composition of claim 9 for use in a method of treating a mammalian disease condition mediated by poly(ADP-ribose) polymerase activity, the method comprising administering to a mammal in need thereof a therapeutically effective amount of said salt or said pharmaceutical composition."
"13. A process for the preparation of a salt of any one of claims 1-8."
The claim 1 is directed to a crystalline rucaparib camsylate salt.
In this write-up we will cover discussions about inventive step.
The following documents are referred to in the present decision related to inventive step discussions:
D1 US 2006/0074073 A1
D30 Declaration of J.B. Etter dated 16 November 2017
D33 Declaration of J.B. Etter dated 10 February 2018
Pfizer and Hexal each filed an appeal against the opposition division's decision.
The patent is directed to new polymorphic forms of rucaparib salts.
The invention is based on the finding that crystalline rucaparib camsylate is particularly suitable for the preparation of solid dosage forms due to its physical stability and low hygroscopicity. The patent identified three crystalline forms of rucaparib camsylate, which were designated as Forms A, B and C. Form A could be prepared by the methods disclosed in paragraphs [0146], [0147] or [0165]. This form appeared to be non-hygroscopic and highly stable (paragraphs [0073] and [0158]). Form C could be prepared from Form A (paragraph [0160]). With regard to Form B, the patent showed its PXRD pattern in Figure 15.
It was common ground between the parties that document D1 was the closest prior art. The document, D1 discloses a list of about 60 pharmaceutically acceptable salts of rucaparib that can be used in therapy. The list includes camsylate, although the preferred salts are phosphate and gluconate.
The parties agreed that D1 was the closest prior art but disagreed on whether inventive step should be assessed starting from the whole list in paragraph [0043] or the specific disclosure of the camsylate salt in that one paragraph.
The board agrees with Pfizer that the starting point should be the whole list rather than the specific option of the camsylate salt.
In paragraph [0043] of D1, the camsylate salt of rucaparib is not singled out. D1 neither illustrates the camsylate salt of rucaparib nor presents it as a standalone embodiment. Paragraph [0043] is merely a notional disclosure in which camsylate is one among a long list of possible options, but not among the preferred ones. The isolation of one of the non-preferred options from paragraph [0043] would distort the teaching of D1, putting an inappropriate weight on that option.
Starting from the list of pharmaceutically acceptable salts in paragraph [0043] of D1, the subject-matter of claim 1 differs in the selection of camsylate as the rucaparib salt and the additional requirements that the salt be crystalline and show three specific PXRD peaks.
As to the technical effect brought about by these differences, the board stated that claim 1 defines a rucaparib salt that contains Forms A and/or B, and that, additionally, it may contain Form C.
The patent shows in paragraphs [0073] and [0158] (that Form A of rucaparib camsylate is non-hygroscopic and highly stable even under conditions of high temperature and humidity. These properties were confirmed in declarations D30 and D33, the content of which was not disputed by the both parties.
According to D30 (paragraph [0004]), rucaparib camsylate can be prepared as R- or S-camsylate and both stereoisomers have an equivalent crystalline Form A. Therefore, the physico-chemical properties of the R- and S-camsylate salts should be identical. D30 confirmed that rucaparib S-camsylate Form A is highly stable and soluble. Similar statements can be found in D33.
On the relationship between Form A and the other two polymorphs of rucaparib camsylate identified in the patent, D30 states that Form A is thermodynamically the most stable of the three forms and that it is preferentially formed during crystallisation. Therefore, Form A can be easily crystallised to provide highly crystalline material in a controlled manner and a very pure form, preventing the formation of Form C. Form A is also highly soluble and dissolves rapidly (D30).
Form C is an anhydrous polymorph which converts to Form A in solvent-mediated systems (D30). Therefore, the presence of Form C can easily be avoided but, if present, Form C would not impair the anhydrous properties of crystalline rucaparib camsylate for solid oral formulations.
As to Form B, D30 states that Form A and Form B repeatedly and reversibly convert into each other by heating within the range 128 to 140°C (D30). In other words, Form B exists only at high temperatures incompatible with storage or therapeutic conditions; at temperatures lower than 128°C, Form B converts into Form A.
The low number of crystalline polymorphs of rucaparib camsylate, and the relationship between these polymorphs and the physical properties of Forms A and C, the only existing forms in use, make crystalline rucaparib camsylate particularly suitable for the formulation of a solid dosage form.
Hexal AG argued that because claim 1 encompasses salt mixtures that could contain only low amounts of Form A, the advantageous properties shown for Form A would not arise across the whole breadth of claim 1. Therefore, a technical effect could not be considered for the formulation of the objective technical problem.
Board said, Form B does not exist at in-use temperatures. The only possible components in the salt of claim 1 when present in a solid formulation are Forms A and C. Form C, also confers advantageous properties on the formulation since it is anhydrous. Furthermore, the only polymorph to which Form C can evolve is Form A. The evolution of Form C to the most advantageous Form A can only improve the properties of the formulation even further. Therefore, the crystalline rucaparib camsylate according to claim 1 is particularly suitable for the formulation of oral dosage forms of rucaparib.
Hexal AG also argued that the advantageous effects of Form A had only been shown for the S-camsylate. Nevertheless, as stated in D30, the S- and R-camsylates have equivalent Forms A and are expected to have the same physical properties.
Consequently, the board agreed with the objective technical problem proposed by the appellant-patent proprietor, i.e. the provision of a solid form of rucaparib having a suitable combination of properties for development into a solid dosage form.
The board is satisfied that the subject-matter of claim 1 solves this problem, as explained above in the context of the technical effect achieved by the difference from the closest prior art.
On the issue of obviousness, the board concluded, D1 does not deal with the formulation of solid forms of rucaparib. It contains no teaching on whether any of the salts in the long list of paragraph [0043] might possibly be suitable for preparing an oral solid formulation. The skilled person would have needed to study each of the salts for assessing: first, whether they are solid; second, how many solid forms they may adopt; and third, whether there are forms with properties suitable for a solid formulation.
Therefore the Board said, the salt of claim 1 involves an inventive step and claim 1 meets the requirements of Article 56 EPC.
Independent claims 9, 10 and 13 are directed to a pharmaceutical composition comprising the salt of claim 1, a use of the salt of claim 1, or a process for the preparation of the salt of claim 1, respectively. As the salt of claim 1 is novel and inventive, the subject-matter of claims 9, 10 and 13 is also considered to be novel and inventive. As a consequence, the board agreed with the conclusion reached by the opposition division that the main request in these appeal proceedings is allowable.
Decision here
