After creating something of a frisson due to the apprehension that the Federal Circuit might be convinced to re-evaluate whether it was a necessary element for establishing obviousness for the skilled artisan to have had a reasonable expectation of success (see "U.S. Patent Office Challenges the Reasonable Expectation of Success Prong of Obviousness Law Precedent in Immunogen v. Vidal")*, cooler (or perhaps more conventionally doctrinal) heads prevailed in the Court's recent decision in Immunogen, Inc. v. Stewart (albeit by ignoring the argument while nevertheless affirming the District Court's obviousness determination).
The technology at issue (in U.S. Patent Application Publication No. US 2015/0132323 A1) was directed to methods for treating ovarian and peritoneal cancer patients using an antibody-drug conjugate ("ADC") called IMGN853 (mirvetuximab soravtansine). The molecule is a conjugate of "an antibody known as 'huMov19,' . . . a toxic maytansinoid payload known as 'DM4,' and . . . a charged chemical linker known as 'charged sulfo-SPDB linker.'" However, as set forth in the opinion, the drug had the deleterious side-effect that it was capable of causing ocular toxicity, including keratitis and blurred vision; this side effect was not recognized in the prior art. The methods recited in the rejected claims specify that the administered dose be calculated from the adjusted ideal body weight (or "AIBW"), which will vary from patient to patient and will also likely vary for the same patient during the course of the treatment; claim 1 is set forth as being representative (wherein the limitation in italics was at issue here):
1. A method for treating a human patient having an FOLR1-expressing ovarian cancer or cancer of the peritoneum comprising administering to the patient an immunoconjugate which binds to FOLR1 polypeptide,
wherein the immunoconjugate comprises an antibody or antigen-binding fragment thereof that comprises the variable light chain (VL) complementarity determining region (CDR)-1, VL CDR-2, VL CDR-3, variable heavy chain (VH) CDR-1, VH CDR-2, and VH CDR-3 of SEQ ID NOs: 6-9, 11, and 12, respectively, and a maytansinoid, and
wherein the immunoconjugate is administered at a dose of 6 milligrams (mg) per kilogram (kg) of adjusted ideal body weight (AIBW) of the patient.
The standard for determining the amount of ADC to be administered is different from the total body weight (or "TBW") standard used in the prior art. Using the TBW standard led to an unacceptable level of ocular toxicity which was not recognized in the art, and such ocular toxicity was significantly alleviated if this drug was dosed using the AIBW approach.
This is the second time Immunogen has come before the Federal Circuit to appeal rejections for indefiniteness and obviousness from the Patent Office for the '809 application. In the first case, Immunogen challenged the rejections by filing suit under 35 U.S.C. § 145 and the District Court held for the Office on summary judgment. The Federal Circuit (before a panel of Judges Newman, Stoll, and Clevenger) vacated and remanded; see "ImmunoGen, Inc. v. Hirshfeld"). With respect to obviousness, the Court's prior judgment was based on factual errors appreciated by the panel, finding that there were genuine issues of material fact in dispute mandating reconsideration by the District Court on remand.
Here, the Office once again prevailed at the District Court on Immunogen's § 145 action and once again Immunogen appealed to the Federal Circuit. Once again, the District Court found the claims to be invalid for indefiniteness under § 112(b) and obviousness under § 103 (as well as obviousness-type double patenting, which was not at issue in the appeal). The indefiniteness judgment was based on the specification "fail[ing] to define AIBW . . . anywhere in its claims" which was significant because the District Court also found that "there are various formulas for AIBW from which a person of ordinary skill in the art could have chosen." The District Court also held that method of treatment claims using this drug were obvious in view of Immunogen's earlier disclosure of IMGN853 administration using total body weight (TBW) dosing and AIBW dosing for other drugs. The specific bases for the District Court's obviousness determination set forth in the opinion was that "(i) the problem of ocular toxicity was known, (ii) skilled artisans understood that changing the dose was a possible solution for adverse side effects such as ocular toxicity, and (iii) the prior art disclosed AIBW dosing as a potential means to eliminate or ameliorate ocular toxicity."
The Federal Circuit affirmed, in an opinion by Judge Lourie, joined by Judges Dyk and Prost. Regarding obviousness, the panel addressed Immunogen's argument that the District Court erred in its motivation to combine analysis. According to Immunogen, the ocular toxicity motivating use of AIBW was not recognized in the art. The Federal Circuit made the distinction that, while the solution to an unappreciated problem may be non-obvious "it does not follow that a claimed solution to an unknown problem is necessarily non-obvious" (emphasis in opinion). According to the Court, what matters (under KSR Int'l Co. v. Teleflex Inc) is "the objective reach of the claim," i.e., "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed," citing KSR, Janssen Pharms., Inc. v. Teva Pharms. USA, Inc., 97 F.4th 915, 929 (Fed. Cir. 2024), and Alcon Rsch., Ltd. v. Apotex Inc., 687 F.3d 1362, 1368 (Fed. Cir. 2012). Accordingly, the opinion rejected Immunogen's argument because specific problems not recognized in the prior art do not mandate a finding of non-obviousness under KSR in the Court's view. The opinion credits the District Court's determination that ocular toxicity was a "well-known adverse event in administration of immunoconjugates" comprising the maytansinoid component of IMGN853 (despite such effects not being seen in experimental animals). Lack of knowledge does not prevent the skilled worker from being motivated to monitor for the unknown side effects according to the panel (which seems to smack at least a little of hindsight and special pleading).
The panel similarly rejected Immunogen's contentions that the specific use of AIBW in place of TBW would not have been obvious. The District Court held that the skilled worker would have been motivated to try to solve the unrecognized ocular toxicity problem by using alternative methods for determining an effective dose known in the art (as was AIBW, known for avoiding ocular toxicity in drugs such as antibiotics, radioimmunoconjugates, and other anticancer drugs). These facts formed the bases for the District Court in finding motivation for using AIBW as a dosing metric and the Federal Circuit found no clear error in this determination. This decision was based on the panel's apprehension that, while not having been used to determining dosing for an ADC in the prior art, it "would have been within the range of knowledge of a person of ordinary skill in the art when confronted with dosing-induced toxicities, and particularly when confronted with dosing-induced ocular toxicity" (despite ocular toxicity for IMGN853 not being appreciated in the prior art). The District Court (and the Federal Circuit) supplemented the art with Immunogen's own U.S. Patent Application Publication No. 2012/0282282 (ImmunoGen's own publication) that disclosed both IMGN853 and ocular toxicity.
Turning to the question of the specific dose (6 mg/kg) set forth in the claims, a seemingly important factor (for both the District Court and the Federal Circuit) was that "patients who weigh exactly their ideal body weight receive an identical dose of IMGN853 when dosed based on either AIBW or TBW." There was specific disclosure in the art for administering "about" 6 mgkg (5 mg/kg or 6 mg/kg) of IMGN853. In addition to these facts, the panel was concerned that in finding the claimed method non-obvious the Court could be "prevent[ing] doctors from practicing what is already disclosed in the prior art for patients at their ideal body weight" (which would occur even if the doctor did not know the amount to be administered using AIBW dosing). This outcome should be sufficient to support the District Court's obviousness conclusion according to the opinion, citing PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1196 (Fed. Cir. 2014), quoting In re Oelrich, 666 F.2d 578, 581 (CCPA 1981).
Finally, turning to the question of reasonable expectation of success that the Patent and Trademark Office had argued should not be a consideration in this and similar cases, Immunogen's argument was focused on the lack of such reasonable expectation for the 6 mg/kg dose. The absence of any limitation in the claims relating to avoiding ocular toxicity formed the basis for the panel to reject this argument; specifically what the District Court was required to do (and did under these circumstances according to the Court) was to determine whether "a person of ordinary skill in the art would have had a reasonable expectation that dosing a human at 6 mg/kg AIBW would have been effective in treating ovarian and peritoneal cancers," citing Teva Pharms. USA, Inc. v. Corcept Therapeutics, Inc., 18 F.4th 1377, 1381 (Fed. Cir. 2021). The Court again relied on this dosage being the same using AIBW as was found using TBW to provide the requisite reasonable expectation of success to support the District Court's obviousness holding.
For Immunogen, the outcome was the same as in the earlier appeal, but for the rest of us some comfort can be taken that the Court did not take the USPTO's suggestion that it fundamentally rewrite how obviousness is properly determined.
* In its briefing, the Office took the position that claims to methods for administering drugs (particularly ones subject to independent patent protection) that rely, as do Immunogen's, on dosing regimens are (almost per se) obvious. This position included an attack on Immunogen's argument that the claims were non-obvious because the unpredictability of these claims would preclude the skilled worker from having the requisite reasonable expectation of success. The Office decried this argument, asserting that "ImmunoGen should not be able to use 'unpredictability' as talisman for getting a patent. Otherwise, drug companies may be able to get patent protection on any follow-on pharmaceutical development no matter how obvious to try - because the result of pharmaceutical experiments are nearly always somewhat unpredictable."
Immunogen, Inc. v. Stewart (Fed. Cir. 2025)
Panel: Circuit Judges Lourie, Dyk, and Prost
Opinion by Circuit Judge Lourie
[View source.]
