Oligonucleotide Therapeutics Patenting: Strategies for Success

A. Hot spots and footprints

It is not uncommon for a researcher to generate a panel of oligonucleotides against a desired target such that the panel tiles across the entire length of the transcript. That is, an oligonucleotide is tested for every part of the target transcript. Used in a relevant, cell-based in vitro screen, one can determine the regions of the target transcript that are most efficacious for modulating expression. From these screens, two potentially useful findings may be revealed. Relatively large sections of the transcript may be ripe for targeting. These larger sections are hot spots in the target transcript that may be claimed to offer broader protection beyond the exact target site of a single oligonucleotide, which may only be around 20 nucleotides in length. The screen may also identify critical footprints within the transcript. An oligonucleotide targeting one of these footprints robustly silences the target, but with a shift of even a few nucleotides to the left or right, silencing plummets. In either case, these screens reveal targets useful for modulating expression that would have been unpredictable but for the screen. As will be discussed later, telling a story of unpredictability in your patent application is an important component in characterizing an inventive and non-obvious invention. An exemplary patent claim under this category might include: 1.

An oligonucleotide compound that is between 15 and 50 bases in length comprising substantial complementary to sequence X.

Here, sequence X may be a region larger than the precise footprint of a single oligonucleotide (e.g., larger than 20 nucleotides) or the limited to the footprint itself.

Sequence-specific oligonucleotides:

One level down in claim breadth from the hot spots and footprints are the sequence-specific oligonucleotides. These would include, for example, the specific sequence of an ASO or the antisense and sense strands of an siRNA. While the hot spot and footprint claims afford variability to the oligonucleotide sequence, including level of complementarity to the target, the sequence-specific oligonucleotide claims are more restrictive in claim scope. The sequence-specific oligonucleotide claims may also generically recite the requirement for any chemical modification or a conjugate. They are nonetheless valuable claims of intermediate scope that will be easier to obtain and enforce. An exemplary patent claim under this category might include: 1.

A siRNA comprising an antisense strand of SEQ ID NO: X, or a chemical modified variant thereof, and a sense strand of SEQ ID NO: Y, or a chemical modified variant thereof.

B. The picture claim—chemical modifications and all

The narrowest of oligonucleotide composition claims are the picture claims, which require the specific sequence and chemical modification pattern of an oligonucleotide. These claims are the narrowest but also the easiest to obtain and enforce. While one invention story may be the identification of hot spot and footprint target regions, another potent story is the identification of a particular chemical modification pattern that offers better activity compared with other chemical modification patterns with the same underlying oligonucleotide sequence.

When possible, effort should be made to identify one or more potential clinical candidates having a preferred sequence and chemical modification pattern. Ideally, a separate clinical candidate patent application should be filed after the filing of the broader hot spot/sequence-based oligonucleotide application to extend patent term on the future product composition of matter. The timing of a clinical candidate application will depend on a prior art search, which will be discussed further below. The nature of the prior art may necessitate that the clinical candidate picture claims be included in the initial composition of matter application. Thus, identifying the final sequence and final or near-final chemical modification pattern in the initial discovery phase may be necessary.

C. Platform technology

While the composition of matter claims described above provide focused protection on a product, platform claims apply a concept or technology to the broad genus of oligonucleotides. With respect to oligonucleotides, platform technology may include: 1) novel chemical modifications to the nucleobase, sugar, or phosphodiester backbone; 2) broadly applicable chemical modification patterns; and 3) oligonucleotide conjugates that confer additional properties onto the oligonucleotide.

Novel nucleobase, sugar, or phosphodiester backbone modifications, in principle, can be applied to any oligonucleotide or a subset of oligonucleotides, such as ASOs or siRNAs. When claiming such novel modifications, care should be taken to broadly cover the genus of the chemical modification with any obvious variants or easy workarounds, while also covering the placement of the modification anywhere in the oligonucleotide. However, narrower embodiments requiring a specific type of oligonucleotide (e.g., siRNA) and specific positions to place the modification within said oligonucleotide should also be captured. These narrower embodiments are driven by the data available with the new modification. In addition to claims covering the novel modification as a composition, claims to the synthesis should also be drafted.

An exemplary U.S. patent, 11,820,985, ⁵ claims unique internucleotide linkages termed extended nucleic acid (exNA) that enhance stability, which is described in further detail in Yamada et al. ⁶

Unique chemical modification patterns differ conceptually from the novel modifications described above in that they utilize known modifications in a new and useful arrangement. Claims to these unique chemical modification patterns can be difficult to obtain, with patent examiners often raising an “obvious to try” argument while citing any one of numerous prior art references that describe each of the known modifications. Indeed, there are prior art references that describe screens of chemical modifications with the stated purpose of identifying a preferred, unique arrangement. See, e.g., U.S. Patent No. 9,796,974, ⁷ which describes and claims a broadly applicable dsRNA chemical modification pattern. Thus, to obtain such claims, and assuming your unique pattern is formally novel, criticality must be shown. This is best demonstrated by showing that your unique pattern provides the same enhancement to multiple different oligonucleotide sequences. The more sequences tested and the more divergent those sequences, the better. Moreover, testing similar patterns against the claimed pattern to show criticality in the exact placement of modifications is also helpful.

Oligonucleotide conjugates, wherein the oligonucleotide is linked to a functional moiety, is another area to protect platform technology. The functional moiety may confer any number of useful properties onto the oligonucleotide, with tissue-specific or cell-specific targeting being a common property. For example, a trivalent N-acetylgalactosamine (GalNAc) conjugate for preferential liver targeting ⁸ is one of the most well characterized siRNA conjugates, being found in several approved products, such as Leqvio® (inclisiran), GIVLAARI™ (givosiran), and Oxlumo™ (lumasiran). Patent filings have focused on other classes of functional moieties as well, such as hydrophobic conjugates for delivery to non-liver tissues. See, e.g., U.S. Patent No. 10,633,653, ⁹ which is further described in Biscans et al. ¹⁰ and Osborn et al. ¹¹ Other functional moieties include, but are not limited to, antibodies, peptides, and small molecules (such as drugs or detectable markers).

Beyond the functional moiety itself, areas oligonucleotide conjugate IP protection may include the linker, where a novel linker is employed, and novel methods of conjugation.

Another platform technology not discussed in detail here is a broadly applicable formulation, which may include a unique combination and concentration of excipients that confer a useful property on an oligonucleotide. For example, U.S. Patent Publication 2024/0287526 ¹² claims an siRNA formulation containing divalent cations for use in the central nervous system. The claims allow for an siRNA of any sequence targeting any gene. Other formulation IP may focus on the use of lipid nanoparticles (LNPs), which encapsulate the oligonucleotide for delivery and are often formulated with a cocktail of four separate lipids that come together to form the LNP.

D. Product formulations

Patents covering formulations that are broadly applicable to any oligonucleotide are powerful tools to create exclusivity in a field. However, claims to the specific formulation of a specific oligonucleotide product are useful for extending patent term on a product and potentially keeping a generic manufacturer at bay. Commonly, the product formulation excipients are well known excipients, such as sodium chloride, a buffer (e.g., tris- or phosphate-based buffers), a cryoprotectant, and a preservative. The product formulation may also employ an LNP for encapsulating the oligonucleotide, using a known LNP formulation. In either case, the difficulty in obtaining claims here is similar to the unique chemical modification pattern claims described above. Thus, the solution to getting these claims allowed is similar—having expansive comparative data showing that the specific formulation was critical for formulating the specific oligonucleotide.

E. Methods of treatment and combination therapy

Another area to potentially extend patent term on a product is to cover the specific treatment protocol from the clinical trials. Ideally, claims issuing from such an application will track the language found on the product label. The claims are generally drafted narrowly with respect to the product, that is, the product picture claim or sub genus one level above the picture claim in terms of breadth. If the application is the first instance of describing the product in the treatment of the particular disease, then claims should be drafted broadly capture the disease without additional limitations. Based on the content of the clinical trial protocol, dependent claims should be layered on that cover the dosing schedule (e.g., administration every 2 weeks), a dose range and separate specific doses, an administration route (e.g., subcutaneous), and a specific patient population. For example: 1.

A method of treating cancer, comprising administering to a subject in need thereof an ASO comprising complementarity to SEQ ID NO: X [the mRNA target of the ASO product], thereby treating the cancer in the subject.

The exemplary claims encompass a genus of ASOs targeting the product target site and any form of cancer. The claims narrow down to the dosing schedule, the dose, the administration route, and the specific patient population. Often the final approved treatment protocol will not be known until long after the clinical trial application has been filed. Thus, it is important to have adequate support in the application for all tested parameters (e.g., dose, dose schedule, etc.). Getting claims allowed that mirror the product label can be like hitting a moving target but having detailed support for the possible outcomes makes this task easier.

In-line with the method of treatment claims described above, combination therapies are another avenue of protection. The ease with which one may obtain broad combination therapy claims will depend, in part, on the nature of the prior art, which will be discussed more below. However, one can help their cause tremendously if synergistic effect can be shown between the oligonucleotide and the combination compound. A mere additive effect may not be enough when both the oligonucleotide and the combination compound are in the prior art.

A. The prior art

The first and arguably most critical step for assessing the patentability of your invention is to perform a prior art search. This should be done before drafting claims to your oligonucleotide compositions. The results of the search will not only influence the first application but each subsequent application in the entire portfolio. Over the past 20 years, the human genome has been fully mapped and many therapeutically relevant genes have been characterized. Therefore, when it comes to patenting oligonucleotides targeting a particular gene, you’re probably not the first person to the party. Many researchers employ a strategy of testing a large panel of oligonucleotides to identify their lead sequences. Those panels of oligonucleotides, whether in a mega table in a patent application or buried in the supplement of a research publication, are prior art that will influence the scope of the claims for your own compounds. So as an initial matter, one should perform a sequence search on a set of their preferred sequences to identify the most-relevant prior art. In the ideal scenario, one will not identify any relevant hits for their preferred hot spots. In this case, a broader hot spot/footprint type claim can be drafted. However, if a prior art reference is identified that describes an oligonucleotide against the same target site, a narrower claim must be drafted based on the differences between the prior art and your compound. For example, the prior art may teach an ASO against your target, while you have developed an siRNA. Alternatively, both the prior art oligonucleotide and your oligonucleotide may be of the same class (e.g., siRNA), but you employ a distinct chemical modification pattern. It is for this reason that identifying the top potential clinical candidates as early in development as possible is important. Whatever the differences are, having comparative data to show criticality in your design choices will be important to strengthen your claims against a rejection of being an obvious alternative.

Once the initial composition of matter patent application has been filed, an 18-month clock has started before your application will publish and thus become prior art against your follow-on filings, such as a specific product formulation application, a clinical trial application, or a combination therapy application. For this reason, it is generally advisable to keep the first application limited to the composition and generic methods of treatment, ensuring novelty for more specific concepts should those follow-on applications not get filed before the publication of the first application. It is nonetheless advisable to file whatever follow-on applications can be filed before the 18-month publication date to ensure one does not have to negatively characterize their composition of matter filing on the record. These negative characterizations can limit the scope of your granted composition claims.

B. Adequate disclosure

35 U.S.C. § 112 requires, among other things, that the application “shall contain a written description of the invention… …in such full, clear, concise, and exact terms as to enable any person skilled in the art… …to make and use the same” (35 U.S.C. § 112(a)). In practice, meeting the “112” bar for oligonucleotides has traditionally been easier compared with biological drugs, such as antibodies. This follows from well-established base pair complementarity rules. If you provide the sequence of a target transcript, no matter how large that sequence is, one of skill in the art can immediately envisage every possible oligonucleotide with complementarity to the target. This contrasts with protein-based drugs, where the interaction rules between proteins are less predictable. Nonetheless, respect must be paid to this requirement, with potential pitfalls specific to oligonucleotide claims.

An oligonucleotide must have a certain level of complementarity to the target to elicit the desired activity, but it need not have perfect complementarity. It is desirable to expand claim breadth by not requiring perfect complementarity, but the increased scope creates a higher “112” bar because the level of variability in the oligonucleotide possibilities increases. When claiming less than perfect complementarity to the target, consider your definition of the term in the application and how much complementarity is required. A functional definition requiring a certain mechanism of action, such as RNaseH-mediated cleavage of the target transcript for an ASOs, is one strategy. A structural definition paired with the functional definition is more useful, such as requiring perfect complementarity in the seed region of an antisense strand or in the DNA domain of an ASO (see Friedrich et al. ¹³ for a detailed summary of siRNA structural requirements).

Another area of breadth for oligonucleotide claims are with respect to the use of chemical modifications. The toolbox of nucleotide modifications is large, allowing for a vast number of oligonucleotide possibilities. It is desirable to obtain claim breadth to the use of any chemical modification for your oligonucleotide, when the prior art permits. To better support such claims, multiple different chemical modifications patterns should be employed to adequately describe the genus of modifications to your preferred oligonucleotide sequence. However, when there is a first filing on the oligonucleotide genus and a later filing on a picture claim to the specific product, care should be taken to not negatively characterize the genus application when prosecuting the product application.

Much discussion has been made as to the effect of the Amgen v. Sanofi supreme court decision in 2023 on the state of claiming antibodies. ¹⁴ Less discussed is the impact this case has on claiming oligonucleotides and in particular the standard for enabling one of skill to make and use the claimed oligonucleotides. The decision of the court emphasized the unpredictability of antibody sequences for specific targets. The courts have often noted that the number of possible antibody amino acid sequences that bind to a particular target is in the billions or greater. This is not an issue for oligonucleotides. As noted above, base pair complementarity rules are well established as well as the structure-function relationship between the structure of an oligonucleotide (primarily the sequence) and the function (cleavage of a target transcript). Thus, as of yet, there does not appear to be an increase in written description or enablement rejections on oligonucleotide-based claims.