Ever since the Supreme Court's decision in Dickinson v. Zurko, federal courts (including the Federal Circuit) are compelled under the Administrative Procedures Act to review factual determinations by the U.S. Patent and Trademark Office under a substantial evidence standard. The consequences of this standard are illustrated (once again) in the Federal Circuit affirming the Office's determination in an inter partes review (IPR) proceeding invalidating the challenged claims, in Novartis Pharma AG v. Regeneron Pharmaceuticals, Inc.
Challenger Regeneron obtained institution of the IPR for all claims on U.S. Patent No. 9,220,631 owned by Novartis. The claims were directed to "a small volume syringe such as a syringe suitable for ophthalmic injections." Such syringes are useful for administering therapeutic agents (such as vascular endothelial growth factor (VEGF) antagonists) to the eye for treating ocular diseases. Suitable syringes must be sterile and in order to avoid damaging the therapeutic agent must be sealed to prevent sterilizing agents (such as hydrogen peroxide) from contaminating the drug. Tight seals have the disadvantage of increasing the pressure (force, termed according to the opinion the "break-loose force") required to administer the drug into the delicate ocular tissues. A solution known in the prior art, treating the syringe with silicone oil, had the drawback that it can cause medical complications should it get into the patient's eye.
The invention claimed in the '631 patent provided the following solution illustrated by claims 1 and 21:
1. A pre-filled, terminally sterilized syringe for intravitreal injection, the syringe comprising a glass body forming a barrel, a stopper and a plunger and
containing an ophthalmic solution which comprises a VEGF-antagonist, wherein:
(a) the syringe has a nominal maximum fill volume of between about 0.5 ml and about 1 ml,
(b) the syringe barrel comprises from about 1 μg to 100 μg silicone oil,
(c) the VEGF antagonist solution comprises no more than 2 particles >50 μm in diameter per ml and wherein the syringe has a stopper break-loose force of less than about 11N.
21. A blister pack comprising a pre-filled syringe according to claim 17, wherein the syringe has been sterili[z]ed using EtO or H2O2 with a Sterility Assurance Level of at least 10–6.
According to the Federal Circuit's opinion, Novartis did not "meaningfully dispute" Regeneron's assertions that that the prior art disclosed all the limitations recited in the challenged claims, in particular PCT Publication No. WO 2011/006877 ("Siggs") that disclosed "a pre-filled terminally sterilized syringe containing a VEGF-antagonist" and PCT Publication No. WO 2009/030976 ("Boulange") that disclosed "a stopper with the claimed silicone oil and break-loose force limitations." Rather, it was Novartis's contention that the worker of ordinary skill in the art would not have been motivated to combine these references having a reasonable expectation of success in doing so. Novartis also asserted that objective indicia of non-obviousness supported its claims in defense of Regeneron's challenge.
The Patent Trial and Appeal Board (Board) agreed with Regeneron in an extensive (128 page!) Final Written Decision that the challenged claims were obvious, supporting this determination by prior art references that include the Sigg and Boulange references. The Board found that Sigg provided a terminally sterilized pre-filled syringe and that Boulange taught silicone sterilization methods that would minimize the risk of contamination. Additionally, the Board found that the skilled worker would have had a reasonable expectation of success using the choice of stopper (Stopper C) taught by Boulange, which provided a tight enough seal to permit the syringe to be sterilized while having a break-loose force within the claimed 11N limit. Regarding Novartis's assertion of objective indicia of non-obviousness, the Board opined that "[t]he stronger evidence of obviousness cannot be overcome with the weaker evidence of long-felt need and failure of others."
The Federal Circuit affirmed, in an opinion by Judge Chen joined by Judges Prost and Reyna. From the thirteen (!) arguments raised by Novartis, the opinion states that it considered only Novartis's principal ones. The first of these was that the prior art teaches away from the combination of the Sigg and Boulange references. In assessing and rejecting this argument, the Court noted that "teaching away" raised a question of fact, citing In re Fulton, 391 F.3d 1195, 1199–200 (Fed. Cir. 2004), and that the Board's factual determinations were reviewed by the Federal Circuit for substantial evidence, citing PersonalWeb Techs., LLC v. Apple, Inc., 917 F.3d 1376, 1381 (Fed. Cir. 2019). The opinion summarized the Board's analysis as consisting of finding "a motivation to combine Sigg's sterilization process with Boulange's Stopper C because Boulange's baked-on siliconization process 'would help reduce the amount of "residual" or "free" silicone oil that can enter the protein formulation and cause negative effects'" and reviewed each in turn. Regarding Boulange's Stopper C teachings, the panel rejected Novartis's contention that because the break-loose force of this stopper increased from 4.7N to 8.4N over three months, the skilled worker would not have chosen it in favor of stoppers with more consistent break-loose force characteristics over time. The opinion notes that the challenged claims do not recite a limitation regarding consistent break-loose force and that the written description of the '631 patent disclosed that prior art stoppers having break-loose forces of up to 20N were "known in the prior art to be acceptable for intravitreal injections." The Board's conclusions in this regard were also supported by the testimony of Regeneron's expert, and Novartis "did not submit any evidence showing that a skilled artisan would have been dissuaded from using a syringe that has a roughly 4N increase in break-loose force over time." The Board's determination concerning the combination of Sigg with Stopper C as taught by Boulange was supported by substantial evidence according to the opinion.
Novartis also argued that Stopper C was "markedly inferior" to another stopper (B1) disclosed in the Boulange reference. The panel rejected this argument on the basis that "[i]n assessing whether prior art teaches away, that 'better alternatives exist in the prior art does not mean that an inferior combination is inapt for obviousness purposes,'" the opinion citing Bayer Pharma AG v. Watson Lab'ys, Inc., 874 F.3d 1316, 1327 (Fed. Cir. 2017) (quoting In re Mouttet, 686 F.3d 1322, 1334 (Fed. Cir. 2012)). Once again, the Board relied on Regeneron's expert, who testified that "a skilled artisan would have been motivated to use Stopper C because it was comprised of rubber and coated with silicone oil—a common stopper design in the prior art," as well as the break-loose force of Stopper C being within the claimed 11N and the 20N limits disclosed in the '631 specification.
The last argument from Novartis regarding "teaching away" was that Stopper C's "friction forces . . . were relatively high, something which does not appear to be acceptable for a medical device." However, the data from the Boulange reference regarding such friction forces were obtained using versions of Stopper C that were not siliconized, whereas the embodiments of Stopper C relied upon by Regeneron in making its obviousness assertions in the IPR were siliconized. It is this embodiment of Stopper C that the skilled worker would consider using, according to the Board (and this opinion), and for these embodiment the Court held that the Board's obviousness determination was supported by substantial evidence.
Novartis's second argument was that the Board erred in finding that the skilled worker would have had a reasonable expectation of success in combining the Sigg and Boulange references to achieve the claimed invention, a question also reviewed under the substantial evidence standard under, inter alia, Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1366 (Fed. Cir. 2016). The basis for the Board's decision in this regard was that "Boulange's Stopper C was sealed tightly enough to be terminally sterilized using Sigg's vaporized hydrogen peroxide sterilization process," which Novartis argued was error because "Boulange's syringes were not sufficiently gas-tight to be able to use Sigg's sterilization process." The Court considered Novartis's argument to be flawed as being "premised on an incorrect view of the [meaning] of the claim term 'terminally sterilized.'" This is because the Board's meaning of the term was that it required "only minimizing the contact between the drug product and the sterilizing agent" (emphasis in opinion) and Novartis had not challenged that construction on appeal. Thus, statements in the Sigg reference that few products had the "required tightness . . . to avoid ingress of sterilizing gasses [into the prefilled drug containing syringe]' (emphasis added) did not deprive the Board of substantial evidence regarding the skilled worker's reasonable expectation of success. Yet again, the Board relied on Regeneron's expert testimony that "it was standard to design prefilled syringes to be gas-tight to protect the drug from degrading over its shelf life and to prevent sterilizing gas from entering the syringe," which was consistent with the Boulange reference, which disclosed that "lower break-loose forces are achievable in the invention 'without having to add lubricant and while preserving the tightness of the contact region between said two parts'" (emphasis in opinion). In addition, the opinion notes that there was no evidence asserted that "any special tightness or specific stopper material, coating, or dimensions[] would have been required to achieve terminal sterilization."
A final Novartis argument addressed by the Court in the opinion was the Board's determination that the Sigg reference disclosed the limitation in claim 21 of a sterility assurance level of at least 10–6 being achieved using vaporized hydrogen peroxide. The panel found the Board's conclusion in this regard to be supported by substantial evidence based on statements in the Sigg reference that "sterility for a health care product as achieving a sterility assurance level of 10–6" combined with a description of vaporized hydrogen peroxide as being a "sterilization treatment." The Board combined these teachings from the prior art with expert testimony from Regeneron to conclude that "a skilled artisan would have known a sterility assurance level of 10–6 was based on regulatory requirements for health care products, and therefore pre-filled syringes are required to meet that sterility assurance level," which, according to the opinion, was supported by substantial evidence. Although (for this issue) the Court implicitly acknowledged Novartis's identification of an inconsistency in some of Regeneron's evidence, the Federal Circuit held that under the substantial evidence standard "one inconsistent piece of evidence does not undermine [the Board's] finding."
In a footnote, the opinion addressed two other arguments made by Novartis. First, the Court held that the Board's reliance on certain non-prior art was not error because its determinations were supported by substantial evidence even if that art were ignored. Second, regarding Novartis's arguments concerning the objective indicia of non-obviousness, the opinion notes that the parties had "extensively redacted this portion of the public version of the Board's decision" but the Court had found substantial evidence supporting the Board regardless (perhaps evincing an acknowledgement from the Court that the public deserved to be told the outcome even if the parties' redactions prevented the Court from setting forth the bases for its decision in the opinion.
Novartis Pharma AG v. Regeneron Pharmaceuticals, Inc. (Fed. Cir. 2024)
Nonprecedential disposition
Panel: Circuit Judges Prost, Reyna, and Chen
[View source.]
