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Risk of Patent Infringement Unprotected by the Hatch-Waxman Safe Harbor in Cell-Based Therapeutic Product Development

The advent of cell-based therapeutics, such as chimeric antigen receptor T-cells (“CAR-T cells”), as well as their development and manufacture, brings with it a level of complexity not previously seen in biologics and pharmaceuticals.  These products, as well as their development and manufacture, involve a large number of technologies, which are potentially covered by third party patents.  For instance, the development and manufacture of these products requires the use of multiple technologies, such as vectors to introduce functional elements, such as the CAR itself, into the cell, as well as gene editing to modify the cellular genome.  The result is that the scope of the freedom to operate analysis is greatly expanded.  Thus, assessing freedom to operate requires evaluation of the operation of the Hatch-Waxman Act’s safe harbor from patent infringement for use of a patented invention ‘‘solely for uses reasonably related to the development and submission of information to the [FDA]” set forth in 35 U.S.C. § 271(a) in the context of the expanded universe of potentially patented technologies in the development and manufacture of these products.  Indeed, the nature of these products and their development and manufacture raises issues and increased risks of infringement not normally seen and that arise at earlier times in development than in the contexts of small-molecule pharmaceuticals and even other types of biologics.  

Courts generally hold that the Hatch-Waxman safe harbor is not applicable to the use of research tools in drug development.  The seminal case on this issue is Proveris Scientific Corp. v. Innovasystems, Inc., 536 F.3d 1256 (Fed. Cir. 2008), in which the Federal Circuit held that the safe harbor does not apply to the manufacture and sale of optical spray machines used in the characterization of aerosol sprays in drug delivery devices that were only used in development of data for submission to the FDA because the spray machines themselves were not subject to FDA premarket approval.  Last year, a district court applied this reasoning in the context of complex biologics in Regenxbio Inc. v. Sarepta Therapeutics, Inc., No. 202-1226, 2022 U.S. Dist. LEXIS 1945 (D. Del. Jan. 4, 2022), to hold that use of patented cultured host cells to manufacture an adeno-associated virus gene therapy product in clinical development was not covered by the safe harbor because it was the gene therapy product that required FDA approval for marketing, not the cells used to make it. A minority of district courts have distinguished Proveris as involving making of research tool and sale of it by a third party to a party using it in drug development rather than the actual use of the research tool in drug development to find the latter within the harbor.  See Teva Pharms. USA, Inc. v. Sandoz Inc., No. 09-10112, 2013 U.S. Dist. LEXIS 99121 (S.D.N.Y. July 16, 2013). However, in rejecting this reasoning, cases such as Regenxbio reason that the Federal Circuit in Proveris did not make any distinction between accused infringers who used the patented product in drug development and those who sold the patented product to third parties that used it in development of drug, but rather focused on whether the patented and accused products were subject to FDA premarket approval and that the statute makes clear that the safe harbor applies to those who infringe by use as well as sale.   

The reasoning in Regenxbio in the context of cells used to make a recombinant viral gene therapy product appears equally applicable to vectors and gene editing technology used to make CAR-T cells during product development.  While CAR-T cell products are regulated as a gene therapy products under FDA’s existing framework for biological products and thus are themselves subject to FDA approval, the vectors and gene editing technologies used in development of such products are not separately subject to FDA approval. Thus, there is a very significant risk that the safe harbor would not apply to infringement of third party patents by the use of patented research tool technologies such as vectors and gene editing technologies in the development of CAR-T therapeutics.

Beyond the complicated and fact-specific analysis that surrounds application of the safe harbor to research tools used in development, it is beyond peradventure that it does not apply to the use of patent technology in commercial manufacture, such as the manufacture of commercial batches or batches stockpiles for commercial use prior to marketing approval.  Manufacture of commercial batches or batches stockpiled for commercial use not protected.  This is because the safe harbor applies to uses of patented inventions that are reasonably related to the development and submission of an application to the FDA for approval.  The manufacture of CAR-T cells and certain other cell-based therapeutics requires repeated use of patented technologies, such as vectors and gene editing tools, that are typically only used during development in the context of biologics and small molecule therapeutics.  For instance, the use of such technologies would be necessary to manufacture different batches of allogenic CAR-T cells, where manufacture of each batch requires genetic modification of and the use of vectors to introduce genetic elements into T-cells derived from a donor for use in multiple patients.  Likewise, preparation of autologous T-cells for an approved therapy, requires genetic modification of and the use of vectors to introduce genetic elements into the patient’s own T-cells.  Such commercial uses would undoubtedly fall outside the Hatch-Waxman safe harbor.    


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