When are Recombinant Proteins Structurally Different Than Their Natural Counterparts?

September 29, 2020

The answer to this question was central to the remand for a new trial on a judgement as a matter of law (JMOL) decision from the District Court overturning the jury verdict of anticipation in the Federal Circuit’s September 28, 2020 decision in Biogen MA Inc. v EMD Serono, Inv. Pfizer Inc. See http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/19-1133.OPINION.9-28-2020_1659873.pdf.

Biogen asserted their U.S. 7,588,755 against EMD Serono and Pfizer for patent infringement by the product Rebif, a recombinant interferon-β product used for treating Multiple Sclerosis. Bayer and Novartis were also initially part of the suit but the actions were severed from the issues in the appeal (fn 1).

Claim 1 of the patent is:

1. A method for immunomodulation or treating a viral condition[ ], a viral disease, cancers or tumors comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising:

a recombinant polypeptide produced by a non-human host transformed by a recombinant DNA molecule comprising a DNA sequence selected from the group consisting of:

(a) DNA sequences which are capable of hybridizing to any of the DNA inserts of G-pBR322(Pst)/HFIF1, G-pBR322(Pst)/HFIF3 (DSM 1791), G-pBR322(Pst)/HFIF6 (DSM 1792), and GpBR322(Pst)/HFIF7 (DSM 1793) under hybridizing conditions of 0.75 M NaCl at 68° C. and washing conditions of 0.3 M NaCl at 68° C., and which code for a polypeptide displaying antiviral activity, and

(b) DNA sequences which are degenerate as a result of the genetic code to the DNA sequences defined in (a);

said DNA sequence being operatively linked to an expression control sequence in the recombinant DNA molecule.

During the trial in District Court, the jury invalidated the patent based on anticipation “by two references teaching the use of native IFN-ß to treat viral diseases.” The Court granted Biogen’s JMOL in favor of Biogen. The Federal Circuit noted some inconsistencies in how the claims had been interpreted, particularly as to the nature of the recombinant e IFNβ and particularly the features of how that recombinant material was obtained (see the product-by-process limitation “produced by a non-human host transformed by a recombinant DNA molecule comprising a DNA sequence,” the limitation “therapeutically effective amount” and the disparity between the jury instructions and the argument put forth as to the structure of the protein.

The District Court on one hand:

. . . the claims require the polypeptide to have “antiviral activity” and be administered in a “therapeutically effective amount.” Summary Judgment Opinion at 28, Jan. 9, 2018, ECF No. 892. The district court concluded that those requirements necessitate that the polypeptide “be folded into its appropriate three-dimensional structure,” and that Bayer was therefore not entitled to summary judgment of anticipation by merely showing that the amino acid sequence of recombinant IFN-β and the amino acid sequence of native IFN-β were identical. Id.

but then on the other hand, in the instructions to the jury:

the district court told the jury that “[t]he term ‘polypeptide’ means ‘a linear array of amino acids connected one to the other by peptide bonds between the α-amino and carboxy groups of adjacent amino acids,’” and that the jury “must accept my definition of these words in the claims as correct.” Final Jury Instructions at 17, Feb. 21, 2018, ECF No. 968.

Of further note is that Biogen did not object to this instruction to the jury nor did they raise the issue that the protein should be inferred to have a three-dimensional structure.

The district court explained that because the claims required administration of a “therapeutically effective amount” of a recombinant polypeptide that “displays antiviral activity,” the product resulting from the claimed recombinant process is defined by the folded three-dimensional structure of the protein.

The district court held that the jury lacked substantial evidence that the native IFN-ß protein as disclosed in Kingham and Sundmacher was structurally or functionally identical to the claimed three-dimensional recombinant IFN-ß protein. Id

the attached carbohydrategroups in native IFN-ß protein were glycosolated, the attached carbohydrate groups in recombinant IFN-ß were not glycosolated, and that this change affected the three-dimensional structure of the protein.

The district court opined that the structural differences alone preclude anticipation.

The Federal Circuit found a few items lacking in the District Court’s reasoning:

. . . the district court: (1) declined to apply a product-by-process analysis to the claimed recombinant IFN-ß source limitation; and (2) in its alternative ground analysis, required identity of three-dimensional structures not specifically recited in the claims rather than the claimed and lexicographically defined “polypeptide.” Both of these determinations led to an erroneous conclusion on anticipation.

The Federal Circuit particularly called out the lack of analysis as to the source of the IFNβ and how it was obtained, specifically required in the claims:

Because a proper anticipation analysis of the claims in the ’755 patent turns not on the source of the claimed polypeptide but on a comparison of the claimed recombinant polypeptide and the prior art native polypeptide, the district court erred in concluding that the mere absence of recombinantly produced IFN-ß in the prior art was sufficient to grant JMOL of no anticipation.

The Federal Circuit further considered whether the limitation of “therapeutically effective amount” inferred a three dimensional structure to enable that type of activity despite a much broader definition in the specification:

Biogen explicitly defined “polypeptide” in the ’755 patent:

Polypeptide—A linear array of amino acids connected one to the other by peptide bonds between the α-amino and carboxy groups of adjacent amino acids.

’755 patent, col. 8, ll. 62–64. The “polypeptide” structure is thus defined by reference to its “linear” array, without regard to its folded protein structure. The district court charged the jury with this definition, adding that the jury “must accept my definition of these words in the claims as correct.”

Biogen argues that the district court was correct in requiring identity not just of the polypeptide, but also of the folded proteins, because the claims require the administration of “a therapeutically effective amount of a composition” and that the DNA sequences in the claims must “code for a polypeptide displaying antiviral activity.” Biogen asserts that only three-dimensional proteins can be therapeutically effective and have antiviral activity, and therefore that the “product” to be analyzed for novelty is the folded three-dimensional protein, not just the amino acid sequence.

Biogen is incorrect. First, Biogen’s argument fails to give effect to Biogen’s explicit definition of “polypeptide” in the specification. We must respect this lexicographic choice.

The claims, in calling for antiviral activity, do not recite any specific folded three dimensional structure that gives rise to that activity. While it is indisputable that an amino acid sequence alone cannot give rise to antiviral activity, it is also indisputable that every linear sequence of proteins will fold into some three-dimensional configuration. The claimed antiviral activity can arise from the administration of any three-dimensional protein with a linear amino acid sequence identical to the claimed recombinant “polypeptide.”

Finally, and importantly, Biogen did not ask for a jury instruction on anticipation that required comparing the three-dimensional protein structures of prior art IFN-β and the claimed recombinant IFN-β. Neither Biogen nor the district court can reframe the anticipation inquiry on JMOL to focus on the unclaimed three-dimensional protein structure, where the jury was instructed, without objection, to decide anticipation based on the linear amino acid sequence.

These last point that the specification definition controls and Biogen apparent waiver of a contrary jury instruction may be the ultimate demise of the patent.