Making Just Enough Acid, and Only Where the Light Falls A Cascade Reaction for Building DNA Chips

This application covers a way of building DNA microarrays one base at a time using light. Instead of washing the chip in acid to strip the protecting group off each growing strand, the method coats it in a light sensitive solution that manufactures a weak acid, in the worked example acetic acid, only where the light reaches, and regenerates its own starting reagent as it goes. The applicant is Vibrant Holdings, LLC, the patent holding entity of the Californian laboratory group trading as Vibrant America and Vibrant Wellness.

The Problem

The background section is short and unusually specific about where array synthesis goes wrong. Microarrays are used everywhere in biological research, the specification says, because they give unprecedented information on nucleic acids in applications from gene expression to genotyping. The difficulty is in the making, and it comes down to two failure modes that pull in opposite directions.

Every cycle of building a strand ends with the removal of a protecting group, usually DMT, from the last base added, so the next base has somewhere to attach. Acid does that job. Use a strong photoacid and you get depurination, where adenine and guanine bases are lopped off the backbone. Use a weaker one and deprotection is incomplete, so a fraction of the strands at that spot silently stop growing and the feature ends up holding a mixture of truncated products instead of one defined sequence.

Neither is a small problem, because the cycle repeats many times at every location, and yield losses multiply rather than add. The specification puts it plainly: even a small decrease in reaction efficiency can have a dramatic effect on total yield.

What This Invention Does

Claim 1 is a method in four steps. Provide a support carrying a protected nucleic acid at a first feature. Contact it with a photoresist solution containing a photoacid generator. Expose it to light, so the generator produces a weak acid through a cascade reaction and that acid deprotects the nucleic acid at that feature. Then bind a new protected nucleic acid to the deprotected one.

The cascade is the part worth slowing down on. In the worked example the solution is propylene glycol methyl ether acetate carrying poly(methyl methacrylate), 4-tert-butylphenyl acetate and isopropylthioxanthone, a photosensitiser borrowed from ultraviolet curing chemistry. Under light at around 365 nm the thioxanthone catalyses a reaction between the butylphenyl acetate and acetate from the solvent, producing acetic anhydride and 4-tert-butyl phenol. Those two intermediates then react with each other, handing back the original butylphenyl acetate and releasing a molecule of acetic acid. The reagent is not consumed. It cycles, releasing weak acid steadily for as long as the light is on, which is how the method gets enough acid for complete deprotection without ever putting a strong acid on the chip.

The rest of the process is photolithography as a semiconductor fab would recognise it: spin coat the wafer, expose selected regions through a photomask for around 500 milliseconds per field, allow a post exposure delay of three to six minutes, strip the resist, couple the chosen nucleotide, cap the unreacted sites, repeat. A second scheme takes a different route to the same goal, synthesising the light removable NPPOC protecting group in place from a chloroformate reagent baked onto the wafer, rather than buying monomers that already carry it.

Key Features

• Weak acid generated on demand. The photoacid generator makes acetic acid in place under light, giving complete deprotection without the depurination that follows strong acid exposure.
• A reagent that rebuilds itself. The intermediates formed in the cascade recombine to regenerate the starting butylphenyl acetate, so one loading of reagent keeps producing acid throughout the exposure.
• Standard photoresist processing. The chemistry is delivered as a spin coated resist and patterned through a photomask, so synthesis runs on ordinary semiconductor equipment.
• A menu of cascade pairs. Beyond the acetate system the specification lists carbonate, phosphate, sulfonate, triflate and benzoate pairings yielding carbonic, phosphoric, sulfonic or benzoic acid instead.
• Protecting groups built on the chip. The alternative scheme forms NPPOC groups in situ, which changes the cost base of the consumables.
• Scale written into the claims. Dependent claims contemplate supports with at least 10, 100, 1,000 or 10,000 features, the cycle repeating until each holds a polynucleotide of intended length and sequence.

Who Is Behind It

Vibrant Holdings, LLC holds intellectual property for the Vibrant group, a Californian clinical laboratory business in the San Francisco Bay Area operating a CLIA certified and CAP accredited laboratory. Its testing runs on an in house silicon chip microarray platform, diced and assembled using semiconductor techniques, used for multiplexed antibody and nucleic acid panels covering food sensitivity, autoimmunity and tick borne disease. The holding company has no separate website, so the links here point to the operating brands. Being both the maker and the user of its arrays explains why a diagnostics company is patenting resist chemistry at all.

Seven inventors are named: John J. Rajasekaran, Vasanth Jayaraman, Anirudh Venugopal, Kang Bei, Tianhao Wang, Karthik Krishna and Hari Krishnan Krishnamurthy. Rajasekaran, the first named inventor, is the chief executive of the Vibrant laboratory business, and the same grouping recurs across the company’s array and assay filings.

The priority chain is compact by divisional standards. This is a divisional of Australian application 2019266303, the national phase entry of PCT/US2019/031555 filed on 9 May 2019, which claims priority from United States provisional application 62/668,964 filed on 9 May 2018.

Why It Matters

Light directed oligonucleotide synthesis has been commercial since the 1990s, and every version of it lives or dies on stepwise yield. The choice between photolabile protecting groups and photogenerated acid is an old one, and the acid route has always carried the depurination penalty. A cascade that produces a weak acid continuously, from a reagent that reforms itself, is a genuinely different answer to a well worn problem.

The commercial logic sits underneath. A laboratory that manufactures its own chips buys yield twice: once in usable features per wafer, and again in the confidence that a signal at a spot reflects the intended probe rather than a truncated one. On a panel carrying thousands of distinct sequences, a percentage point of coupling efficiency per cycle compounds into the difference between a saleable product and scrap.

The filing shape is worth noting too. Claim 1 is a method of synthesis rather than a claim to an array or a chemical, which is what you choose when the thing worth controlling is a manufacturing process a competitor would run behind closed doors. Keeping the Australian family alive through a divisional in 2026, on a 2018 priority, suggests the process is still in use.

Related Concepts

• Photoacid – the class of light activated acid source the method reworks into a cascade.
• Phosphoramidite – the monomer chemistry that supplies the incoming protected nucleotides.
• Wafer – the semiconductor substrate the arrays are built on.
• Genotyping – one of the array applications the background section names.
• Acetic acid – the weak acid produced by the worked example of the cascade.
• Divisional application – the filing mechanism carrying this 2018 priority into 2026.

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AU 2026202114 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.