Significant Decision by the Israel Patent Office Regarding Patent Term Extensions

Recognition of a Biological Substance as a “New Substance” Despite the Absence of Differences in the Primary and Secondary Structure of the Protein Compared to a Previously Registered Substance.

1. A recent decision^[1] by the Israel Patent Office in the matter of IL Patent No. 199925^[2] in the name of Genzyme Corporation, addressed the question of whether the patent was eligible for a patent term extension (PTE) order, considering that the request for the extension was based on the registration of the medical preparation NEXVIAZYME®, having avalglucosidase alfa as its Active Pharmaceutical Ingredient (API), while another medical preparation, MYOZYME®, containing the API alglucosidase alfa, was already registered in the Israeli Drug Registry.
2. This question arose in light of Section 64D(3) of the Israeli Patent Law,^[3] which stipulates that a PTE order shall not be granted unless the registration of the medical preparation in the drug registry is the first registration that allows the substance to be used in Israel for medical purposes.
3. The central question is concerned with when it is appropriate to recognize a substance (in this case, avalglucosidase alfa) as different from a pre-existing substance. This issue has been discussed in a series of decisions concerning biological products, which will be mentioned later. These decisions did not emerge in a vacuum; they were preceded by case law development concerning small molecules, with two landmark decisions in the matters of Novartis^[4] and Lundbeck^[5]. The bottom line from these decisions was the emphasis on the structure of the substance.^[6] In a mixture, where each of the substances is separate and the bonds between the substances are intermolecular, no difference will be seen between the mixture as a “substance” and its separate constituent components. In contrast, when it comes to a compound consisting of components linked by intramolecular bonds, the compound will be regarded as a new substance.
4. The ILPTO’s decisions concerning proteins, evolved in a slightly different direction, with the Israel Patent Office deviating somewhat from the above-mentioned test focusing on intramolecular bonds. On one hand, the question addressed was whether a protein variant was indeed a new substance due to a structural change relative to an earlier version of the protein lacking the variation, and on the other hand, it was determined that not every structural change will be sufficient to justify grant of a PTE – the more substantial the structural change, the more likely that it will be considered as a new substance. Conversely, when a structural change is considered to be “small”, it must be determined whether there are differences in activity between the substances which result from the structural difference.
5. Against this backdrop, it was established that changes in DNA structure and thus the primary structure of the protein is significant ^[7]. On the other hand, changes due to post-translational processing, especially different glycosylation (up until the recent Genzyme decision), were previously not recognized as significant enough to justify the recognition of a substance as a new one.

For example, in the matter of Bayer,^[8] a request for PTE was denied based on the finding that the amino acid sequence of the API in Kovaltry® (a recombinant Factor VIII clotting factor) was identical to that of a previously registered Factor VIII product named Kogenate®, despite the fact that Kovaltry® differed in the glycosylation of the API and had different pharmacokinetic activity from the previous product.

Similarly, in the matter of Ferring,[9] a request for PTE based on registration of the API Follitropin delta was denied because its protein sequence was identical to that of previously registered substances (Follitropin alpha or Follitropin beta) and there were only “small” differences in the glycosylation profile of the protein compared to the previous substances.

6. Following these decisions, the recent decision in the Genzyme matter was issued. The outcome of the decision is significantly different from the outcome of other decisions concerning glycoproteins as it recognizes that there are cases where a different glycosylation pattern results in a new substance despite supposed identity at the amino acid level with a previous substance. Although there was no dispute that the difference in avalglucosidase alfa is not a change in the primary or secondary structure of the protein, it was successfully argued that the change in the API is a result of glyco-engineering, which created a structure of artificial glycans which was covalently attached to the protein, to create a new molecule. Such a glycan structure does not exist in nature and cannot be produced in a biological system. Additionally, it was argued that avalglucosidase alfa exhibits different activity, reflected in improved clinical efficacy compared to alglucosidase alfa.
7. The Genzyme decision held that even though there are no differences in the primary and secondary structure of the protein moiety of alglucosidase alfa and avalglucosidase alfa, the structural modification of the protein due to the covalently attached artificial glycans involves an intramolecular bond, intentionally created. This is in contrast to the Ferring case, where the Registrar determined that the difference in the glycosylation pattern of the protein (due to a different host cell production system), was not sufficient to recognize Follitropin delta as a new substance. In other words, the different structure of avalglucosidase alfa is not the result of the glycosylation added to the protein in the course of the recombinant protein production process, but rather an enzymatic “addition” to the protein, designed to increase the binding of the protein to its cognate receptor. In fact, this determination alone was sufficient to recognize the API as a “different substance,” but the decision also established that the patent owner met the burden of proving that the structural change also led to a significant functional change.

^{[1] Patent Registrar decision in re a PTE application for patent 199925 (objection to examiner decision) Genzyme Corporation (Nevo, 26 March 2024).}           

^{[2] National phase application of PCT/US2008/051429; International publication No. WO/2008/089403.}

^{[3] This provision corresponds to Article 3(d) of Regulation (EC) No 469/2009 Of The European Parliament And Of The Council and to 35 U.S.C. § 156(A)(5)(a).}

^{[4] Patent Registrar: Decision regarding a PTE application for patent 97219, Novartis AG (Nevo, 26 Dec 2005); District Court: Miscellaneous Appeal (Tel Aviv-Yafo) 1063-06 Novartis AG v. Registrar of Patents, Designs and Trademarks (Nevo, 26 Feb 2007); Supreme Court: Civil Leave to Appeal 2890/07 Novartis AG v. Registrar of Patents, Designs and Trademarks (Dinim, 8 Jun 2009).}

^{[5] Patent Registrar: Decision in re opposition to PTE application for patent 90465 Unipharm Ltd. v. H. Lundbeck A/S (Nevo, 3 Feb 2009). District Court: Miscellaneous Appeal (District Jerusalem) 223/09 H. Lundbeck A/S v. Unipharm Ltd. (Nevo 25 May 2009); Supreme Court: Civil Leave to Appeal 5267/09 H. Lundbeck AS v. Unipharm Ltd. (Nevo, 15 Mar 2010).}

^{[6] In the Novartis case, a request for a patent term extension order was based on the registration of the drug Co-Diovan, which is a tablet containing two active components, where different products containing each of the components had already been registered in the drug registry previously. In the Lundbeck case, the distinction between a racemic mixture containing both R and S enantiomers and a substance containing only the S enantiomer (Escitalopram) was addressed.}

^{[7] See the decision regarding PTE application for patent 168754, Genentech, Inc., for the product Ocrevus® (different CDRs of antibodies directed to the same epitope is a significant change) (Nevo, 16 Apr 2019) .}

^{[8] Patent Registrar decision in re a PTE application for patent 124123 (objection to examiner decision under section 161 of the law) Bayer Healthcare LLC (Nevo, 16 Apr 2018).}

^{[9] Patent Registrar decision in re PTE application for patent 208538 (objection to examiner decision) Ferring International Center SA (Nevo, 20 Jul 2020); In the decision regarding Ferring, the Registrar noted that there may be cases where differences in glycosylation and sialylation profiles could constitute sufficient structural differences to result in different activity of the protein compared to its predecessors, and that each case should be examined individually. In the circumstances of the Ferring case, the Registrar determined that the structural differences between Follitropin delta and previous substances stem from post-translational modification resulting from the cells in which the protein was expressed and the growth conditions (the host cell of follitropin delta was human, while the follitropin alpha and beta were produced in CHO cells). The Registrar further determined that the evidence presented indicated that the structural differences between Follitropin delta and previous substances do not translate into differences in the pharmacodynamics or clinical efficacy of the substance, and that if there are differences in the safety and efficacy of the products, these cannot be attributed to differences in the structure of the substances. On this decision, an appeal was filed to the district court (Civil Miscellaneous Appeal District-Tel Aviv 32305-11-20 Ferring International Center SA v. The Registrar of Patents, Designs and Trademarks (Nevo, 4 Mar 2021) which remanded the hearing to the ILPO, after it partially granted a motion to introduce additional evidence. However, Ferring withdrew the objection before a final decision was made, and the original decision remained in effect.}