Innovation is transforming key sectors of the global economy, from novel small molecules to polymers, new pharmaceutical compositions, cosmetics, food, etc. These advances are typically protected by intellectual property covering compounds, formulations production processes, delivery methods, etc. IP is touted as the cornerstone of a well-protected business, allowing a firm to reap the benefits of its hard work without fear that “fast followers” will enter the space with cheap knock offs. A strong IP portfolio is of top importance for start-ups seeking to demonstrate tangible value to investors and potential partners. For established players, strong IP is imperative to maintain profits margins after years of investment and risk, with a blockbuster product worth billions per year. Firms pursuing new acquisition targets prioritize strong IP protection when vetting merger and acquisition candidates in the pharma space. Conversely, an entire commercial frontier can be lost, such as the case for the famous Wistar patents on monoclonal antibodies. A weak IP portfolio that can be invalidated provides no real-value while leaving a firm vulnerable to being blindsided by an IP savvy competitor. Worse, a company that is focused on quantity over quality of IP filings will waste valuable resources creating weak patents that are easily invalidated or circumvented. Operating blindly, they will waste millions of dollars on R&D to create pharmaceutical compositions or small molecules that cannot be commercialized due to the existence of blocking compounds.
This article will provide an expert overview of effective IP small molecule searching and common problems to avoid. Over the last few years we’ve been asked to redo many searches that were carried out by other firms which failed to accurately identify critical prior art the client became aware of. This experience has yielded critical insight into the “Best Practice” when small molecule searching is carried out, and the important role played by the five following successful factors:
  • The technical background of the specialist implementing the search;
  • The importance of speaking directly to the specialist;
  • The implementation process;
  • Transparency to confirm what was actually covered;
  • Importance of having the specialist walk through the coverage and top findings
Specific to the chemical industry, it is important to go beyond broad technological understanding when conducting small molecule searching and analysis. For small molecule IP analysis, both prior art/invalidity and freedom-to-operate (FTO) searches should be considered as part of developing a robust patent portfolio. These two efforts are functionally different due to how the claims should be viewed. Prior art, which can be used for the construction of new IP does not have to consider broad claims such as Markush structures (more below). For prior art, searching can be performed using keywords based on commercial and IUPAC names, or better yet, target compounds can be identified using databases such as Chemical Abstract Services (STN) Registry. To facilitate finding highly relevant documents in a prior art search, the structure search should encompass not only the specific compound of interest, but also look for structurally similar compounds to create a ‘103’ obviousness argument. This is our first Best Practice recommendation: The technical background of the specialist. A specialist with a masters or PhD in organic/material chemistry from a U.S. Top Tier University would consider key structural elements of a compound and determine the “essential” functional groups as can be found in a structure-activity relationship (SAR). These can then be leveraged to target compounds with the same functionality, while varying other aspects of the molecule.

To convey these complex parameters in an efficient and effective manner, we cannot stress enough the importance of speaking directly to the specialist, our second Best Practice recommendation. The ability to directly communicate with the specialist allows for a clearly communicated goal, which will hone the search focus and allow the specialist to focus on key features without re-treading old ground. The specialist should be able to quickly customize the search parameter and include often missed sources such as chemical forms like salts, or stereoisomers, reactions conditions and other important parameters.
Our third Best Practice recommendation is the implementation process itself, which should clearly define the search type, coverage period and coverage. For chemical structure searching, prior art and FTO will require different approaches and very different coverage. For FTO coverage, Markush structures are the main challenge. Markush structures were allowed to be patented back in 1924, which allows for multiple independently variable (R) group. The use of R groups allows broad range of structures to be defined, turning many patents from claiming a single compound to claiming a class of compounds. Such varied coverage is only possible through STN's MARPAT database, which provides manual coverage of Markush structures. However, use of MARPAT requires a level of technical expertise and experience to create a comprehensive search strategy broad enough to capture the various ways your target compound could be described in a Markush claim, while not returning an excessive amount of findings that would make a search truly cost prohibitive.
To better illustrate the nuance of small molecule prior art searching, an example is provided below.
Creating Stronger Chemical Patents to Capture the Investment in Innovation: Best Practices
Figure 1. Chemical Structure of Elafibranor
Elafibranor, or formally known as 2-[2,6-dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methyl-propanoic acid, is an PPAR agonist that is currently being developed by Genfit for cardiometabolic diseases, such as nonalcoholic steatohepatitis (NASH). Elafibranor can be identified with CAS Registry number 923978-27-2. To ensure coverage of all salts and isomeric forms, a targeted structure search should be utilized to capture all 18 non-deuterated registry numbers associated with elafibranor. Which bring us to the fourth Best Practice recommendation: Transparency to confirm what was actually covered. A good search strategy should leverage several databases for a comprehensive search strategy. Beside searching CAS databases such as Registry, keywords (i.e. NASH OR (nonalcoholic OR non-alcoholic) steatohepatitis) and IPC/CPC classes (i.e. A61K 31/192) can serve as helpful sources but only as supplements. Searching should not be limited to English language art. Foreign art such as Japan, China, German and other countries, performed by a specialist native speaker is a rich source of prior art. It is important to note that chemical compound searches using robust database such as CAS carries a high cost, while there could be other methods or database (such as PatSnap, an OCR-based database or SciFinder, the academic version of CAS) that offers a lower price point, they are often unreliable, so beware of structure searching proposals that sounds too good to be true. For structure searching, the cost is focused on database access and specialist expertise, both of which are well worth the expense.
Figure 2. Core structure of Elafibranor
Extending on the discussed above, the structure search should encompass not only the specific compound of interest, but also look for structurally similar compounds for the target indication (NASH) to create a ‘103’ obviousness argument. Key structural features, as identified by our specialists in figure 4, include fibric acid, and the use of a phenyl ring, that may be attached via a thiazole moiety. Whereas the propenone group, which acts as a linker, can vary in other PPAR agonists used to treat NASH, such as seladelpar (figure 5).
Figure 3. Chemical Structure of seladelpar
PPAR agonists, such as elafibranor and seladelpar, have been known since at least the 2000s. And it is imperative to understand the prior art surrounding PPAR agonists for treatment of NASH for Gemfit to produce the best prior art. It is details like this that highlight our final Best Practice: the importance of having the specialist walk through the coverage and top findings. Having the specialist who performed the search discuss the findings in a clear and organized manner can be a great time saver that will facilitate your analysis, obviate the need to review “background” references, and provide additional insight into the top findings that could be missed. Many clients note that the discussion of top references by an expert searcher is a great time saver that allows them to focus on a subset of more relevant references and significantly reduces their time needed to review the findings. Additional questions regarding any reference can also be addressed and resolved in a timely manner.
Prior art is a powerful tool. It can provide a technical overview of the state-of-the art, and it can help guide the development of new chemical technology. A solid understanding of the prior is essential to guide the creation of new claims and effectively capture the benefits of innovation with strong patents. A comprehensive understanding of prior art, especially for small molecules, should be performed by knowledgeable experts to ensure the highest quality. Prior art missed by a poor quality search, like an iceberg beneath the water, will emerge and wreck havoc if not flagged and distinguished. The use of technical databases entails a relatively minor upfront expense and can provide a huge financial payoff. For small molecule searching, it is also important to understand the core structure and key features, guided by a technical specialist holding an advance degree in organic chemistry. The 5 Best Practice Steps outlined above will help produce the most efficient strategy and consistently ensure an accurate knowledge of the prior art to support filing strong patents. For further information contact:
Cassie Daddario, Ph.D. Chemical and Materials Group Leader, Global Prior Art Email: cdaddario@globalpriorart.com
Sung Hei Yau, Ph.D. Chemical and Materials Senior Analysis, Global Prior Art Email: sayu@globalpriorart.com
Bruce Rubinger Managing Director, Global Prior Art Email: rubinger@globalpriorart.com
Volume 51, Issue 1
BPLA-logo
2019 Ⓒ Boston Patent Law Association
hometwitter-squaredlinkedInmailfacebook
TOC
TOC
Message from the President Michael Bergman
Foreign Counsel Membership Invitation
Minutes of the Annual Meeting
Brief for Amici Curiae Boston Patent Law Association in USPTO v. Booking.com
2020 Diversity and Inclusion Roundtable
2019 Writing Competition Winner - Synopsis of "Hazards in Obviousness-Type Double Patenting"
calendarcalendar__2_
Creating Stronger Chemical Patents to Capture the Investment in Innovation: Best Practices
Message from the Editor-in-Chief
New Report on Underrepresented Groups in Patenting
Making Connections Event Summary
What makes Massachusetts small but mighty?
2019 Annual Meeting
The Case Law Club Kicks Off 2020 with Arthrex v. Smith & Nephew
Officers and Board of Governors
Job listings
Community Calendar
Legislative Meeting Summary
Spring IP Symposium
David Gooder Appointed USPTO Commissioner for Trademarks