Antibody-drug conjugate (ADC) is a promising class of most cancers therapies with accelerating U.S. Meals and Drug Administration (FDA) approval and quickly rising market dimension as mentioned in earlier articles on this collection. This text discusses patent methods for ADC innovations.
Introduction
ADCs present plentiful alternatives for brand spanking new most cancers therapies, innovation, and collaboration throughout completely different industries as a result of they mix three distinct applied sciences: (1) an antibody, (2) a poisonous payload, and (3) a linker that joins them. Whereas ADCs are based mostly on the seemingly easy concept of utilizing the concentrating on capacity of antibodies to ship extra toxically potent medicine to particular most cancers cells, ADCs are difficult molecules that pose important technical, regulatory, and mental property challenges.
Certainly, improvement of an efficient and secure ADC remedy requires important analysis and innovation to make sure that the appropriate parts are mixed in the appropriate method to keep away from unwanted side effects, inefficiency, tumor resistance, and pharmacokinetic profiles that make the drug supply unpractical. In some circumstances, overcoming these challenges requires improvement of latest generations of ADC modalities by utilizing novel payloads, modified antibody backbones, and new drug linker-release mechanisms, as reviewed in Tsuchikama, Okay. et al., Nature Rev. Clin. Oncol., 21, 203–223; 2024.
Though the event of an efficient ADC requires intense analysis to seek out the appropriate mixture, Patent Workplaces or Courts could discover ADCs to be an “apparent” mixture in circumstances the place the parts of the ADC have been beforehand used for a similar function because the ADC. Obviousness could current a significant impediment for patent safety of ADC improvements if the patent claims will not be sufficiently supported by proof and patent prosecution methods.
Methods For Addressing Obviousness Challenges To ADC
The Authorized Normal for Obviousness
The present framework for analyzing obviousness was established by the Supreme Courtroom determination in KSR Worldwide Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). In accordance with KSR, when a claimed invention is rejected for obviousness as a result of the invention seems to be a mixture of identified components, the Examiner should, “establish a motive that might have prompted an individual of atypical talent within the related area to mix the weather in the way in which the claimed new invention does.” See KSR, 550 U.S. at 401. The Federal Circuit additional defined in post-KSR choices that the mere plausibility of prior artwork mixtures is inadequate to ascertain a prima facie case of obviousness. See PersonalWeb Tech v. Apple, 848 F.3d 987, 994 (Fed. Cir. 2017) stating that:
[The] reasoning appears to say not more than {that a} expert artisan, as soon as introduced with the 2 references, would have understood that they could possibly be mixed. And that isn’t sufficient: it doesn’t indicate a motivation to pick these two references and mix them to reach on the claimed invention.
A prima facie case of obviousness could also be rebutted by submitting goal proof that the claimed invention offered surprising outcomes. The post-KSR determination in Bristol-Myers Squibb Co. v. Teva Prescription drugs USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) decided that “notably probative” proof of surprising outcomes “set up[es] that there’s a distinction between the outcomes obtained and people of the closest prior artwork, and that the distinction wouldn’t have been anticipated by considered one of atypical talent within the artwork on the time of the invention.”
Thus, an ADC shouldn’t be held apparent merely as a result of the completely different parts of the ADC have been beforehand identified. Fairly, the ADC may be held apparent if enough steering or motivation to mix the particular parts the identical means as within the claimed ADC has been established. Even when there may be motivation to mix identified parts right into a particularly claimed ADC, the ADC should be patentable if the ADC gives surprising outcomes. Subsequently, patenting ADCs with identified parts will usually hinge on discovering causes a talented artisan would not mix the particular ADC parts or exhibiting that the actual ADC yielded surprising outcomes in comparison with the parts, as additional mentioned and illustrated under.
Demonstrating a scarcity of motivation to make the claimed mixture
1) ADC remedy claims could also be nonobvious as a result of they recite options that the antibody portion of the ADC did not carry out by itself.
Patent claims protecting a selected ADC remedy could also be discovered nonobvious attributable to a scarcity of motivation to mix identified components into the claimed ADC if the antibody and/or conjugate did not deal with a selected affected person inhabitants individually. For instance, U.S. Patent 7,575,748 survived an Inter Partes Evaluate (IPR) problem based mostly on obviousness as a result of the claimed ADC could possibly be used to deal with a selected indication that the antibody portion of the ADC couldn’t deal with by itself as highlighted within the quoted declare language under. See Phigenix, Inc. v. Genentech, Inc. and Immunogen, Inc., IPR2014-00842. The allowed claims in U.S. 7,575,748 recited:
A way for the remedy of a tumor in a mammal, comprising the steps of
(i) figuring out stated tumor as being characterised by overexpression of an ErbB2 receptor and as being a tumor that doesn’t reply, or responds poorly, to remedy with an anti-ErbB antibody, and
(ii) intravenously administering to the mammal a therapeutically efficient quantity of a conjugate of a humanized antibody huMab 4D5-8 covalently linked by way of a thioether linking group with a maytansinoid DM1….
U.S. Patent 7,575,748 illustrated that methodology claims protecting an ADC shaped by identified parts may be discovered allowable based mostly on properties of the ADC.
2) Establishing {that a} part of the ADC was discouraged
U.S. Patent 8,337,856 is directed to ADC composition claims, and upon problem the claims have been held legitimate despite the fact that they recited identified antibodies and conjugates. See Phigenix, Inc. v. Immunogen, Inc., Case IPR-2014-00676, Remaining Written Selections dated October 27, 2015 (Paper 39). Unbiased declare 1 of the ‘856 patent recites:
1. An immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, whereby the antibody is huMAb4D5-8.
huMAB4D5-8 was commercialized within the prior artwork product, Herceptin®, and used for treating breast most cancers together with different cytotoxic brokers. As well as, maytansinoid had already been used as a conjugate to completely different antibodies. The patent challenger, due to this fact, argued that it might be apparent to make use of Herceptin® with maytansinoid.
Nevertheless, the Patent Proprietor efficiently introduced proof suggesting to a talented artisan that “Herceptin-maytansinoid immunoconjugates would have been anticipated to exhibit unacceptable ranges of antigen-dependent toxicity in regular human liver tissue in sufferers.” See pages 16–22 of IPR-2014-00676 (Paper 39). The Board discovered this argument persuasive as a result of the patent challenger had not defined that an atypical artisan would have been motivated to make the claimed ADC, given the reported liver toxicities of maytansinoid immunoconjugates.
Given these circumstances, methods for overcoming obviousness rejections could possibly be discovered by figuring out if:
- There are identified issues of toxicity related to the poisonous payload part of the ADC or different causes to not use the poisonous payload as claimed, and
- The antibody portion of the ADC has beforehand been reported to be ineffective by itself towards the claimed indication.
As will likely be mentioned additional under, the claims of U.S. Patent 8,337,856 have been additionally discovered legitimate due to surprising outcomes, which is one other central technique for acquiring patent protection of ADCs.
Surprising Outcomes achieved by the ADC
1) Instance of ADC claims discovered legitimate based mostly on surprising outcomes
The claims of U.S. Patent 8,337,856 have been discovered legitimate based mostly on surprising outcomes despite the fact that the parts of the claimed ADC have been identified. See Immunogen, Inc., IPR-2014-00676 (Paper 39). Specifically, the Board held that the Herceptin-maytansinoid immunoconjugate claims have been non-obvious as a result of the Patent Proprietor offered substantial proof of unexpectedly superior outcomes in comparison with the “closest prior artwork” composition. See pages 23-25, Immunogen, Inc., IPR-2014-00676 (Paper 39). The “closest prior artwork” was the antibody by itself, and the outcomes demonstrated that the ADC overcame some limitations of the “bare” antibody.
2) Instance of proof of surprising outcomes not enough to ascertain nonobviousness
Demonstrating surprising outcomes may be difficult, as proven in Hospira v. Genentech, IPR2017-00731 (Paper 120, at web page 23 (PTAB October 3, 2018)), the place the claims of U.S. Patent No. 7,846,441 have been discovered unpatentable. The claims of U.S. Patent No. 7,846,441 are represented by declare 1:
1. A way for the remedy of a human affected person with a malignant progressing tumor or most cancers characterised by overexpression of ErbB2 receptor, comprising administering a mixture of an intact antibody which binds to epitope 4D5 inside the ErbB2 extracellular area sequence and a taxoid, within the absence of an anthracycline spinoff, to the human affected person in an quantity efficient to increase the time to illness development in stated human affected person, with out enhance in total extreme opposed occasions.
The ADC lined by this patent incorporates an antibody that binds to epitope 4D5 inside the ErbB2 extracellular area sequence and a taxoid. A earlier publication asserted towards this patent disclosed the identical antibody conjugated with a taxoid examined in a mouse mannequin. The Patent Proprietor argued that the claimed methodology yielded surprising ends in people as in comparison with the earlier mouse research. Nevertheless, the Board held {that a} mouse research is a “dependable predictor of success in people,” and the outcomes from the mouse research in prior artwork predict that the ADC would even be efficient in people. See Hospira v. Genentech, IPR2017-00731 (Paper 120, at web page 26 (P.T.A.B. Oct. 3, 2018).
As well as, the Board in Hospira v. Genentech discovered the Patent Proprietor’s statements to the FDA to be proof of obviousness of the claims. The Patent Proprietor had requested FDA approval of a mixture of an antibody binding ErbB2 (trastuzumab) and a taxoid (paclitaxel) as a result of a talented artisan would anticipate that this mixture was efficient based mostly on the identical prior artwork as asserted towards U.S. Patent 7,846,441. Therefore, the Board thought of the Patent Proprietor’s statements on the FDA as proof that the outcomes obtained with the claimed ADC have been anticipated. See Hospira v. Genentech, IPR2017-00731 (Paper 120, at pages 27-28 (P.T.A.B. Oct. 3, 2018).
The argument for nonobviousness based mostly on surprising ends in Hospira v. Genentech failed as a result of the closest prior artwork was a mixture of the identical parts because the claimed ADC. Accordingly, in circumstances the place the closest prior artwork to a claimed ADC solely discloses one of many parts of the ADC, the supply of useful outcomes obtained with the ADC will assist acquiring allowance of the claims or surviving a problem based mostly on obviousness.
Foremost Takeaways
Primarily based on the above overview, we offer the next concerns for figuring out methods for acquiring patent protection of ADCs in circumstances the place the parts of the ADC are identified:
1) Is use of one of many ADC parts discouraged for the claimed methodology (e.g., would it not be too dangerous)?
2) Might the chosen payload intrude with the properties of the antibody or vice versa (e.g., trigger aggregation, decrease solubility, or adjustments to vital post-translational modifications of the antibody)?
3) Have the parts of the ADC been used for treating the identical indications or is there a scarcity of steering for utilizing a number of of the ADC parts as claimed (i.e., lack of motivation)?
4) Is goal proof of surprising outcomes from the ADC obtainable (comparable to improved efficacy or tolerability as in comparison with particular person parts)?
Lastly, it needs to be famous that the linker chemistry can also be an vital a part of the ADC and patentability of the ADC. The ADC linker was not central to the above mentioned circumstances as a result of it was not recited by the unbiased claims. Nevertheless, the Board did analyze dependent claims reciting particular non-cleavable linkers IPR-2014-00676, which might additional distinguish U.S. Patent 8,337,856 from prior artwork. Accordingly, linker chemistry could confer patentability to an ADC.
Certainly, the linker chemistry presents fertile grounds for innovation and improvement of latest generations of ADCs. See Tsuchikama, Okay. et al., Nature Rev. Clin. Oncol., 21, 203–223; 2024. The linker chemistry can, for instance, be used to manage the quantity of poisonous payload (i.e., the drug-antibody ratio), and when and the place the payload is launched to enhance the efficacy and tolerability of the ADC. Though the linker chemistry by itself is probably not new, there could also be a scarcity of motivation to make use of a selected linker technique in an ADC as a result of the linker interferes with the antibody construction, adjustments post-translational modification of the antibody, causes aggregation, or gives too excessive or too low payload-antibody ratio. Thus, a cautious consideration of the linker and its results on the perform of the ADC is also crucial for acquiring patent safety of the ADC.
In the end, profitable methods of patenting ADCs will rely upon the outcomes obtained with the ADC, and what outcomes could be anticipated based mostly on frequent information of the antibodies, poisonous payloads, and linker chemistry that make up the ADC.
For extra sources on Antibody Drug Conjugates (ADCs) and the way they may change the well being care & life sciences and know-how industries, click on right here to learn the opposite articles in our collection.
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