Polymorph Patents

Companies interested in researching, developing, and commercializing pharmaceutical compounds should be aware of not only strategies for patenting the compound itself, but strategies for patenting polymorphs of the compound.

A polymorph is a 3D crystalline structure of a chemical compound. These variations in crystal structure are unpredictable and result in differing physiochemical properties, such as melting point, solubility, dissolution rates, bioavailability, and stability. Therefore, patenting polymorphs can potentially add value to an IP portfolio.

Original Compound Patent

An initial application directed to a pharmaceutical compound would likely constitute as prior art to any subsequently filed polymorph patent under 35 U.S.C. § 102(a)(1) and should be drafted with the prior art effect in mind. Therefore, although the specification should include a synthetic method for making the compound, it should not include working examples reciting specific recrystallization conditions, generic disclosures of suitable recrystallization solvents or conditions, or general discussions concerning physical forms of the compound (e.g., hydrates or solvates, crystalline or amorphous).

However, it should be noted that, in some rare situations, it is possible for a polymorph patent to be entitled to the priority date of a provisional application that is directed to a pharmaceutical compound even if the compound patent does not explicitly disclose the polymorph. In Amgen Inc. v. Sandoz Inc., 66 F.4th 952 (Fed. Cir. 2023), the Federal Circuit, without reaching the issue of inherency, held that such a provisional application actually disclosed the crystalline form of the compound. The court’s decision rested on the fact that the patentee provided the results of over a dozen experiments following the procedure in an example of the provisional application, all of which resulted in the specific crystalline form of the compound, whereas the defendant did not produce the results of any experiment showing that the crystalline form was not produced.

For the remainder of this article, it is assumed that the polymorph patent does not claim priority to the compound patent. However, the ability to claim a polymorph based on an inherent disclosure should not be discounted.

First Polymorph Patent(s)

Let’s say a polymorph screen is conducted during formulation development. The compound is determined to be highly polymorphic, but only a single polymorph, anhydrous Form A, having the best formulation characteristics, (e.g., flowability and hygroscopicity) is fully characterized and selected for drug development. A patent application directed to this polymorph is then drafted.

Content of Application
The specification should include detailed information concerning several recrystallization conditions and solvent mixtures that yield Form A, provide an X-ray powder diffraction (XRPD) spectrum showing all of its peaks (including strong peaks, intermediate peaks, and minor peaks), as well as the differential scanning calorimetry (DSC) and infrared (IR) spectra. XRPD peak tables should also be provided, as well as express teachings that define Form A by its major peaks or, alternatively, by the major peaks together with the intermediate and minor peaks. The patent application can also disclose the administration of Form A to humans in an oral dosage form, but it may be silent as to the precise dosage conditions, such as frequency of administration or whether the drug is administered with or without food.

Applicants should be cautious if claiming polymorphs by large numbers of XRPD peaks. In Glaxo v. Novopharm II, 110 F.3d 1562 (Fed. Cir 1997), the patentee attempted to enforce a polymorph claim reciting a 29-peak IR spectrum. The Federal Circuit held that the patentee must establish that the XRPD of the alleged infringing material contains each of these 29 peaks to establish infringement. As some of these peaks are low intensity that may not be identifiable in the XRPD of a given batch, claiming polymorphs by large numbers of XRPD peaks can create difficulties when trying to establish infringement. See Merck Sharp & Dohme Corp. v. Amneal Pharmaceuticals LLC, 881 F.3d 1376 (2018) (to establish infringement, a one-to-one correspondence is not required).

Applicants should also be cautious of claiming a polymorph by a few major XRPD peaks. As the claims could inadvertently read on multiple polymorphs that share the same low resolution XRPD pattern but differ in other physical properties, it could leave such a claim open to a 35 U.S.C. § 112 attack for lack of written description or enablement. See AbbVie Deutschland v. Janssen Biotech, 759 F.3d 1285 (Fed. Cir. 2014).

Therefore, applicants should pursue claims of varying scope to (1) a polymorph characterized by the XRPD pattern, (2) a polymorph characterized by the major peaks, (3) a polymorph characterized by the major and moderate peaks, and (4) a polymorph defined by melting point, DSC, and/or IR spectra, either independently or together with the XRPD information. Errors in the d-spacing values should be expressly recited in the claims so the courts do not impute an error value broader or narrower than intended.

Timing of Filing the Application
The timing of filing a polymorph application is an important consideration. If the polymorph application is filed before the prior art date of the compound patent, it would not provide significant additional patent term beyond the term of the compound patent. If, on the other hand, the polymorph application is filed too long after the prior art date of the compound patent, third parties may begin to research and file patent applications covering any polymorphs they identify.

If the compound exhibits a high degree of polymorphism and the compound patent is silent as to physical forms and recrystallization conditions, the filing of the polymorph application can be delayed past the prior art date of the compound patent to maximize effective patent term.

On the other hand, if the prior art includes a process to produce a crystalline form, then characterizing the crystalline form resulting from that process would likely be held obvious. See Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals, Inc., 98 F.4th 1056 (Fed. Cir. 2024) (the court held that the polymorph claim was obvious because the methods for characterizing the crystalline form were well known and readily available to a person of ordinary skill in the art and were nothing more than routine optimization).

Balancing the risks, if a compound exhibits a high degree of polymorphism or if the compound was not previously known to exist in a highly polymorphic state, a first polymorph application can be filed before the clinical results of the compound are widely reported in scientific literature.

Polymorph Strategy for Europe
In EPO Board of Appeals decision T 777/08, the claims were directed to a particular polymorph of crystalline atorvastatin hydrate and the closest prior art was the amorphous form of atorvastatin. The Board held that, in the absence of any technical prejudice or unexpected property, a new crystalline form of a known compound does not involve an inventive step. This case has been distinguished in two subsequent cases. See T 0643/12 (a polymorph of the mesylate salt of lenvatinib exhibited inventive step when the mesylate salt was not in the prior art); T 1422/12 (crystalline form of tigecycline exhibited inventive step in light of unexpected improvement in stability with respect to an epimerization reaction); T 1418/22 (crystalline form of acalabrutinib exhibited inventive step in light of the “technical difficulty” of crystallizing this polymorph, and the crystalline form exhibited unexpected non-hygroscopicity). However, the general rule in Europe is, contrary to the law in the United States, that a prejudice in the field or unexpectedly superior properties are necessary to obtain a patent on a polymorph in the EPO.

In light of the divergent legal standards for polymorph patents between the United States and Europe, filing polymorph patents in Europe should proceed only in situations where there are potential unexpected or superior properties or some teaching away in the art.

Best Practices

1. In a patent application directed to a new chemical compound, specific disclosure concerning precise recrystallization conditions or physical forms of the compound (salts, hydrates, polymorphs) should be avoided.
2. A polymorph screen should be conducted early in the product development process, and patent applications should be filed directed to the polymorph to be used in the drug product as well as any potentially bioequivalent alternatives.
3. Applicants should bear in mind potential hurdles to filing a polymorph application, including prior public use and prior art disclosures of a process to produce the crystalline form.
4. If the compound of interest exhibits a high degree of polymorphism or if the compound of interest was not previously known to exist in a polymorphic state, filing patent applications after the prior art date of the compound patent can be considered on a case-by-case basis.
5. The pharmaceutical drug product should be evaluated on a regular basis for new polymorphic forms of the API.
6. Polymorphic forms should be claimed in multiple ways—by XRPD peaks listings of various lengths, XRPD spectra as well as other physical properties such as melting point or IR spectra.
7. When claiming polymorphic forms in terms of XRPD peak listings, the language “characterized by” should be used in defining the recited peaks.
8. Interconversions of various polymorphic forms should be considered. Efforts should be made to identify and claim the lowest energy form without purity limitations in the absence of prior art constraints. However, make sure to include a description of purity levels in the specification to have broader levels of written description support if necessary.

This article appeared in the 2025 Life Sciences IP Tool Kit.