The Adipate Salt That Makes a Cancer Drug Hold Its Shape Crystal Forms of a KRAS G12C Inhibitor

This application covers solid forms of a cancer drug candidate, and above all its adipate salt. The title names only the free base, a long chemical name for a quinazoline that blocks the cancer-driving KRAS G12C mutation, but claim 1 is to the mono adipate salt itself, and the claims go on to cover its crystal forms, four other salts, and methods of treating cancer. It was filed by Genentech, Inc., names Antonio Giovanni DiPasquale as the sole inventor, and is a divisional of Australian application 2023215488.

The Problem

A drug molecule is rarely made or sold as the bare molecule. Chemists pair it with an acid to form a salt, and then the salt can pack into different crystal arrangements, each with its own stability, solubility and handling behaviour. The background is blunt about this: it is not possible to predict whether a given molecule will crystallise in one form or several, and the differences between forms can unpredictably affect processing, stability, bioavailability, formulation and storage.

The compound here, called Compound 1 in the specification, is the free base of a KRAS G12C inhibitor. Its chemical name in the specification matches that given for divarasib (also coded GDC-6036) on its public record. The specification itself never uses the name divarasib. The stated need is for stable, well-defined forms that can be isolated and made at scale.

The screening results show why that is not trivial. Compound 1 was tried with 21 acids in four solvent systems. Many combinations gave gels or amorphous material instead of crystals. The amorphous adipate was no better: when the freeze-dried amorphous mono adipate was stored at 25 degrees C and 97 per cent relative humidity, or at 40 degrees C and 75 per cent relative humidity, all the samples had deliquesced after seven days, meaning they absorbed enough water to dissolve.

What This Invention Does

Claim 1 is a compound, drawn as a structure labelled (A). It is the free base shown together with a six-carbon diacid, which the description identifies as adipic acid, making Compound A the mono adipate salt. Claim 2 then covers a crystal form of Compound A defined by its X-ray powder diffraction pattern, with characteristic peaks at 9.6474, 11.0365, 15.4059, 16.4193 and 18.7038 (plus or minus 0.1 degrees 2-theta). The description calls this Form A and says it is an anhydrate that can be obtained from acetone, THF or ethyl acetate. Claims 12 to 17 cover a second adipate form, defined by peaks at 9.7745, 11.0487, 15.2452, 18.6477 and 18.7908, which the description calls Form D, a hemihydrate.

The same pattern repeats for four other salts. Compound B is a fumarate, Compound C an ethylenesulphonate, Compound D a besylate and Compound E a mesylate. Each gets crystal form claims defined by XRPD peaks, with some also defined by thermal analysis. A sixth salt, an acetate called Compound F, appears in the description but is not the subject of any claim in the set. The remaining claims cover a pharmaceutical composition, oral formulation, and methods: treating a cancer with a KRAS G12C mutation after first determining that the patient has it, treating lung cancer including non-small cell lung cancer, treating colorectal cancer, inhibiting tumour cell proliferation and inhibiting metastasis, plus use and “for use” claims. The claims run to 53.

The case for the adipate rests on the polymorph screen. Form A and a third form, Form B, were both found from adipate screening, and in slurry competition experiments mixtures of A and B converted to Form A in toluene and in isopropanol, including at minus 20 degrees C. Form A’s DSC trace shows two endotherms at 68.8 and 169.1 degrees C. Variable humidity XRPD showed only small changes between 44 and 46 per cent relative humidity that persisted up to 80 per cent, and the sample reverted at 30 per cent, which the description reads as a channel-like hydrate system that can hold a range of water contents without changing structure. The specification’s summary says the adipate salt is far more stable than the other salt forms found and is useful for crystallisation and purification in large scale synthesis. Form B, by comparison, had an adipic acid to free base ratio measured at 1.65, not a clean one to one.

Key Features

• A salt claimed as a compound. Claim 1 protects the adipate salt itself, not only a crystal form of it, which is the broadest position this family can hold on that salt.
• Crystal forms defined by diffraction peaks. Form A is defined by five XRPD peaks, and further claims widen that to at least five or ten peaks from a stated table, or to a pattern substantially as shown in a figure.
• A hemihydrate as a second adipate form. Form D, claimed from claim 12, is a hemihydrate with a single DSC endotherm at about 173.4 degrees C.
• Four alternative salts. The fumarate, ethylenesulphonate, besylate and mesylate are claimed as crystal forms, so a competitor cannot simply swap the acid.
• Treatment claims tied to the mutation. One method requires determining that the patient’s cancer carries a KRAS G12C mutation before dosing, and further claims name lung, colorectal and pancreatic cancer.
• Single crystal structures. The description reports single crystal X-ray work on Forms A, C and D, including a Form C adipate anion with one carboxylate group disordered over two sites, roughly 50/50.

Who Is Behind It

The applicant is Genentech, the South San Francisco biotechnology company founded in 1976 and fully owned by Roche since March 2009, according to its Wikipedia entry. The sole named inventor is Antonio Giovanni DiPasquale. The Australian agent of record is Griffith Hack.

On the drug, Genentech announced on 1 July 2026 that the Phase III Krascendo 1 trial of divarasib in previously treated, advanced or metastatic KRAS G12C non-small cell lung cancer met its primary endpoint of progression-free survival against sotorasib or adagrasib, with a statistically significant overall survival result at an interim analysis, according to its press release. The release gives 338 randomised adults and no effect sizes. That is a public development, not a statement in this specification, which pre-dates and does not mention any clinical results.

On priority, the specification states that it claims the benefit of U.S. Provisional Patent Application No. 63/307526, filed 7 February 2022, and that it is a divisional of Australian Patent Application No. 2023215488. The page headers throughout the specification carry the international publication number WO 2023/150706 and PCT/US2023/061976, which identify the international application behind the family.

Why It Matters

Most of the commercial value in an approved drug does not sit in the molecule that was first made. It sits in the form that can be manufactured to a consistent specification, stored on a shelf and dosed predictably. Patents on salts and polymorphs are how companies protect that form. A divisional with this claim set lets Genentech pursue the salt and several crystal forms separately from whatever the parent application covers.

The specification is candid about its own limits. It contains no pharmacokinetic or efficacy data, only solid-state characterisation, screening tables and crystal structures. The argument that the adipate is the right form to develop is made through its resistance to conversion, its behaviour under humidity and its use in purification. What the form does in a patient is left to other documents.

Related Concepts

• Polymorphism (materials science) – the ability of one compound to crystallise in more than one arrangement, which is the subject of every crystal form claim here.
• Powder diffraction – the technique that produces the peak lists used to define each claimed crystal form.
• Adipic acid – the six carbon diacid that forms the claimed salt with the drug.
• Non-small-cell lung carcinoma – the main cancer type named in the treatment claims.
• Deliquescence – the dissolving in absorbed moisture that the amorphous adipate showed under humid storage.
• Amorphous solid – the non-crystalline form the specification judges unsuitable for development.

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AU 2026202275 was published in the Australian Official Journal of Patents on 9 April 2026 and is open for public inspection. Patent applications represent inventions that are sought to be protected and do not necessarily reflect commercially available products.