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Ready, Set, Go: Crystalize Your Thinking

In Gilead Sciences, Inc. v. Apotex, Inc., No. 20-cv-189 (D. Del. May 26, 2021) Judge Noreika in the District Court of Delaware construed claim terms in Gilead’s patents, including in U.S. Pat. Nos. 8,754,065 (“the ’065 patent) and 9,296,769 (“the ‘769 patent”). The ‘065 and ’769 patents contain compound, composition, and method of making claims. Of interest to life science patent application drafters and prosecutors, evaluators of third party U.S. patents, AIA post-grant proceeding practitioners, and litigators is the court’s analysis of whether terms in the claims of those two patents are limited to salt forms and non-ionized/unassociated forms or whether a broader construction should apply.

The Court construed the claim terms “tenofovir alafenamide hemifumarate,” “tenofovir alafenamide monofumarate”, “fumaric acid, and “tenofovir alafenamide.”  Relevant claims of the patents are shown below.

Relevant ’065 Claims

Claim 1. Tenofovir alafenamide hemifumarate.

Claim 4. Tenofovir alafenamide hemifumarate, having an X-ray powder diffraction (XRPD) pattern that comprises 2theta values of 6.9± 0.2° and 8.6± 0.2°.

Claim 6. A composition comprising tenofovir alafenamide hemifumarate according to claim 1, wherein the ratio of fumaric acid to tenofovir alafenamide in said composition is 0.5±0.1.

Claim 27. A method for preparing tenofovir alafenamide hemifumarate comprising admixing a) aprotic organic solvent; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide hemifumarate.

Claim 30. A method for preparing tenofovir alafenamide hemifumarate, comprising the steps of: admixing a) a solvent comprising water, isopropyl alcohol, acetone, acetonitrile, toluene, ethyl acetate, isopropyl acetate, heptane, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide hemifumarate at a temperature from about 0ºC to about 70ºC.

Relevant ’769 Claims

Claim 1. A composition comprising tenofovir alafenamide hemifumarate, wherein the composition comprises less than about 5% by weight of tenofovir alafenamide monofumarate.

Claim 2. The composition of claim 1, wherein the composition comprises less than about 1% by weight of tenofovir alafenamide monofumarate.

Claim 3. The composition of claim 1, wherein the composition comprises less than about 0.5% by weight of tenofovir alafenamide monofumarate.

Claim 4. The composition of claim 1, wherein the ratio of fumaric acid to tenofovir alafenamide in said composition is 0.5±0.1.

Claim 5. The composition of claim 1, wherein the ratio of fumaric acid to tenofovir alafenamide in said composition is 0.5±0.01.

“Tenofovir Alafenamide Hemifumarate” and “Tenofovir Alafenamide Monofumarate” Include Not Only Salts, but Also Other Forms, such as Co-Crystals

Gilead proposed that “tenofovir alafenamide hemifumarate” (“TAF Hemi”) be construed as “a hemifumarate form of tenofovir alafenamide,” whereas Defendants proposed it be construed as “a hemifumarate salt of tenofovir alafenamide.” Similarly, Gilead proposed that “tenofovir alafenamide monofumarate” (“TAF Mono”) be construed as “a monofumarate form of tenofovir alafenamide,” whereas Defendants proposed it be construed as “a monofumarate salt of tenofovir alafenamide.”

The court adopted Gilead’s proposed constructions for both terms and construed the terms as encompassing various forms, not just salts. According to the court, the specification supported a broad construction of “hemifumarate form of tenofovir alafenamide” covering salts and co-crystals by consistently describing the invention as a “hemifumarate form of tenofovir alafenamide.” The word “salt” did not appear in the patents, except in titles of cited publications.  Additionally, an example in the specification disclosed a structural formula of TAF Hemi with a dot between the TAF and the fumaric acid, which Defendants’ expert recognized can depict both salts and co-crystals. Furthermore, there was extrinsic evidence of use of the term “hemifumarate” in the industry that did not “necessarily imply a salt as a matter of nomenclature.” Id. at *5.

Defendants’ prosecution history-based arguments were not successful. The provisional applications to which the ’065 and ‘769 patents claimed priority used the phrase “a co-crystal complex or a salt.” The district court was not persuaded that omitting the term “co-crystal” in the ‘065 and ‘769 patents showed the inventors no longer considered co-crystals to be part of their invention. The ‘065 and ‘769 patents use the general term “forms” rather than specifying either “a co-crystal complex or a salt.” Id. at *6. Nor was the court persuaded that the inventors adopted the patent examiner’s characterization of “tenofovir alafenamide hemifumarate” (TAF Hemi) as “a salt of a compound at a 2:1 stoichiometric ratio of compound to fumaric acid” by amending rejected dependent claims reciting “TAF Hemi with close to a 0.5 ratio of fumaric acid to tenofovir alafenamide.” Id. (emphasis added). The examiner’s characterization was not sufficient to show a “clear and unmistakable disavowal” or override “the patents’ clear lexicography.” Id.

The district court also construed the term “tenofovir alafenamide monofumarate” as not limited to salts based on the consistent contrast in the specifications between the “monofumarate form” from the “hemifumarate form of tenofovir alafenamide.” The court thus saw no reason to treat the “monofumarate” term differently than the “hemifumarate” term. Id.  And that conclusion is reinforced by the fact that both monofumate and hemifumarate can assemble in the solid state without exclusive classification as a salt.

“Fumaric Acid” Includes Ionized and/or Associated Forms

Gilead proposed a construction of “fumaric acid” as “including its ionized and/or associated forms.” Defendants proposed a construction limited to “the compound having the chemical name trans-1,2-ethylenedicarboxylic acid” and having the same chemical structure as that provided by Gilead.

No explicit definition was provided in the specification, but the court analyzed the disclosure and concluded that one of ordinary skill in the art “would understand that ‘fumaric acid’ in the patents describes both non-ionized/unassociated fumaric acid and ionized/associated fumaric acid.” Id. at *7. The specification included both disclosure of fumaric acid as a starting material, which is non-ionized and unassociated, and as a component of tenofovir alafenamide hemifumarate, where it is ionized or otherwise associated (without formal proton transfer) with the tenofovir alafenamide component.

“Tenofovir Alafenamide” Includes Ionized and/or Associated Forms

Gilead proposed a construction of “tenofovir alafenamide” as “including its ionized and/or associated forms.” Defendants proposed a construction limited to “the compound having the chemical name 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosph-inyl]methoxy]propyl]adenine” and having the same chemical structure as that provided by Gilead.

The patents included an explicit definition of this disputed term, stating “[t]he name for 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]pr opyl]adenine is tenofovir alafenamide.” However, the patents also defined tenofovir alafenamide as “L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester.” Id. at *8.

The court did not adopt a chemical name “because the parties agree on the chemical structure and principally argue what forms are encompassed.” Id.  Based on the specifications, and similarly to “fumaric acid,” the court construed “tenofovir alafenamide” to include both non-ionized/unassociated and ionized/associated forms. In particular, similarly to “fumaric acid,” the specifications disclose “tenofovir alafenamide” as a starting material and as a component of a composition comprising “tenofovir alafenamide hemifumarate,” a known prodrug of tenofovir.

Takeaways

Although the court adopted Patent Owner’s proposed constructions in this case, some of the dispute may have been avoided if the drafter had included explicit definitions for claim terms in the specification, unless of course those definitions were too narrow. For example, the Patent Owner could have defined “fumaric acid” expressly as encompassing both non-ionized/unassociated fumaric acid and ionized/associated fumaric acid.

Consistent use of the claim terms “tenofovir alafenamide hemifumarate” and “tenofovir alafenamide monofumarate” throughout the specifications bolstered Patent Owner’s case in the eyes of the judge and was sufficient to find a “clear lexicography.”

It is fundamental that, as the lexicographer of the application, the drafter of the patent application explain specifically what is included and excluded from the definition of each term relevant to the claims. Patent drafters should try to ensure that each claim term is defined, but not too narrowly, and that each claim term is used consistently throughout the claims and the specification. Deviation in terms may impact claim construction. See, e.g., Aqua-Aerobic Systems, Inc. v. Aerators Inc., 211 F.3d 1241 (Fed. Cir. 2000); Ortho-McNeil v. Caraco, 476 F.3d 1321(Fed. Cir. 2007). 

© 2021 Finnegan, Henderson, Farabow, Garrett & Dunner, LLPNational Law Review, Volume XI, Number 182
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Jill K. MacAlpine Patent Attorney Finnegan Washington DC
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Jill MacAlpine, Ph.D., leader of the firm’s patent office practice, focuses on strategic counseling, prosecution, and patent litigation, primarily in the chemical and pharmaceutical areas. With over 15 years of experience in intellectual property law, she spends a significant portion of her time involved in pre-litigation analyses, due diligence investigations, opinion preparation, and strategic client counseling, including patent portfolio management, Orange Book listings of patents covering FDA-approved drugs, and patent term extensions.

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Melissa Santos, Ph.D., focuses on patent prosecution, patent litigation, and client counseling in the areas of chemicals, pharmaceuticals, and materials science. She has technical experience with polymer chemistry, fabrication and characterization of materials, and protein and genetic engineering. 

Melissa worked on patent prosecution and various aspects of patent litigation during her time as a summer associate at Finnegan. She previously served as a legal intern in the patents group at a global pharmaceutical company, conducting inventorship interviews with scientists and...

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Thomas L. Irving Intellectual Property Finnegan, Henderson, Farabow, Garrett & Dunner Washington, DC
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Tom Irving has some 45 years of experience in intellectual property law. His U.S. pharma practice includes America Invents Act (AIA) post-grant proceedings, due diligence, counseling, patent prosecution, reissue, and reexamination. In addition to advising on procuring strong U.S. patents, Tom counsels clients on a wide range of mainly pharmaceutical matters, including pre-litigation, Orange Book listings of patents covering FDA-approved drugs, infringement issues, enforceability, supplemental examination, and validity analysis. He has served as lead counsel in numerous patent interferences...

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