Detection of paternal cell-free fetal DNA (cffDNA) in maternal blood (the technology at issue in Ariosa v. Sequenom) was in a different incarnation the subject of an interference between professors at two universities; the decision of the U.S. Patent and Trademark Office Patent Trial and Appeal Board in favor of Dennis Lo and the Chinese University of Hong Kong was reversed on July 3, 2017 and remanded for further proceedings, in Board of Trustees of the Leland Stanford Junior University v. Chinese University of Hong Kong.
This embodiment of the technology was directed to detecting aneuploidies, or an abnormal number of chromosomes in a cell; noted examples include Downs Syndrome (trisomy 21) and Turner's syndrome (XO). While the opinion recognizes Dr. Lo as the discoverer of cffDNA in 1996, Stanford's professor (Dr. Stephen Quake) developed a new method for detecting small changes in the number of chromosomes characteristic of aneuploidy, employing a technology the Court terms "digital analysis," which did not distinguish between paternal and maternal sources of DNA. There were four steps to Dr. Quake's claimed method as set forth in the opinion:
(1) obtaining a maternal tissue sample, preferably blood; (2) distributing single DNA molecules from this sample to a number of discrete reaction samples; (3) "[d]etecting the presence of the target in the DNA in a large number of reaction samples"; and (4) performing "[q]uantitative analysis of the detection of the maternal and fetal target sequences."
The opinion also sets forth disclosure from Dr. Quale's specification relating to the use of "second generation massively parallel sequencing [(MPS)] methods and PCR amplification of chromosome DNA as being useful in the practice of the invention.
Dr. Lo's invention, according to the opinion, was claimed in U.S. Patent Application Nos. 12/178,181; 13/070,275; 13/070,240; 12/614,350; 13/070,251; and 13/417,119. The claims of these applications were directed to "random sequencing" of cffDNA followed by sequence alignment to a reference human genome sequence to detect DNA sequence fragments specific for each chromosome, using MPS methods as in Dr. Quake's patents and application. Aneuploidies for each chromosome where they exist are detected by finding a greater frequency of aligned fragments for particular chromosomes than others.
At issue in the interference were Stanford U.S. Patent Nos. 7,888,017 and 8,008,018 and U.S. Application No. 12/393,833. Dr. Lo and CUHK application in interference was U.S. Application No. 13/070,275. Three interferences were declared, identified as lack of written description. Quake v. Lo, No. 105,920 (P.T.A.B. Apr. 7, 2014); Lo v. Quake, No. 105,923 (P.T.A.B. Apr. 7, 2014); and Lo v. Quake, No. 105,924 (P.T.A.B. Apr. 7, 2014); In a footnote, the Federal Circuit opinion notes that the Board's opinion in all three interferences "contained largely the same findings" and to the opinion cited the '920 interference throughout as being applicant to all three interferences. Dr. Quakes was accorded the benefit of his earliest provisional filing, February 2, 2007; Dr. Lo's priority date as disclosed in the Declaration of Interference was July 3, 2007. Thus, Dr. Lo and CUHK were designated as the Junior Party and would have the burden of establishing an earlier date of invention should the interference reach the priority phase.
Both parties requested the PTO declare the interferences, which were all declared in 2013, and during each of the proceedings, CUHK filed preliminary motions that Stanford's '018 patent and '833 application were invalid for failure to satisfy the written description requirement of 35 U.S.C. § 112(a) (this posing a threshold question in the interference wherein Junior Party Lo would prevail if its motion was persuasive to the Board). At least part of the basis for this allegation was that Dr. Quake changed the claims pending in the application that matured into the '018 patent to more closely parallel Dr. Lo's claims; indeed, Junior Party Lo contended that Senior Party Quake had copied the pending claims of CUHK's '181 application. These motions were supported by expert testimony, as were Stanford's rebuttals to these motions. The Board was persuaded by CUHK's motions and granted them, thus ending the interference and invalidating Stanford's patents. In these decisions, the Board (according to the panel opinion) "repeatedly credited the testimony of [CUHK's expert] Dr. Gabriel, including in finding that (1) the specification of the '018 patent is directed to the use of 'digital analysis' of predetermined targeted sequences in a sample, and (2) the language relied upon by Quake could have related to either random or targeted sequencing but that, because 'the main focus of the Quake '018 patent [was] on diagnosing aneuploidy with digital PCR, those of skill in the art would have understood the discussion of massively parallel sequencing to refer to sequencing targeted, predetermined portions of the DNA in a sample, not sequencing of random DNA'" (and was not persuaded by Stanford's attacks on that testimony). In summary, the Board stated that:
Though the Quake inventors may have possessed parts of such a method, including massively parallel sequencing, randomly fragmenting DNA, and aligning sequences to genomic sequences, the facts do not indicate that those of ordinary skill in the art would have understood the inventors had put these pieces together into a complete method of sequencing random DNA fragments and identifying the sequenced fragments to determine aneuploidy.
Stanford appealed this decision to the District Court under 35 U.S.C. § 146 in the Northern District of California (Judge Susan Illston of Sequenom fame). However, based on its decision in Biogen MA, Inc. v. Japanese Found. for Cancer Research, 785 F.3d 648 (Fed. Cir. 2015), that the provisions of the Leahy-Smith America Invents Act precluding appeals to the district courts should apply, the parties jointly asked the District Court to transfer the appeal to the Federal Circuit, and this opinion followed.
The Federal Circuit reversed, in an opinion by Judge O'Malley, joined by Judges Reyna and Chen. The panel rejected Stanford's invitation to "rethink" its Biogen decision regarding whether appeals from interferences could no longer be brought before the district courts under § 146. On that question the opinion states that Biogen is the law in this circuit and we, as a panel, will not revisit it. Similarly, the panel refused to consider the evidence adduced during the brief discovery period before the California District Court and the Biogen decision, because the District Court did not have subject matter jurisdiction under the panel's appreciation of the law after Biogen ("the activities in the district court are a nullity when the district court lacks subject matter jurisdiction to consider a matter," citing Ruhrgas AG v. Marathon Oil Co., 526 U.S. 574, 577 (1999)) and CUHK cannot waive lack of subject matter jurisdiction. Having made this decision, the Federal Circuit's review was limited to the "four corners" of the record before the PTAB, and the panel agreed with CUHK that it would "treat the district court proceedings as if they never occurred."
Turning to the merits (which the Court reviewed for substantial evidence as the question of written description is one of fact; In re Gartside, 203 F.3d 1305, 1314 (Fed. Cir. 2000)), the panel held that the PTAB had erred in invalidating Stanford's patents. The basis for this determination was found in CUHK's expert's testimony and some of the references upon which her conclusions had been based. The deficiency arose based on the lack of correspondence between what was expressly disclosed in Stanford's patents and applications and what the references relied upon by CUHK's expert disclosed (and upon which she based her conclusion on the adequacy of disclosure question). According to the opinion:
All of the published references on which the Board relies focus on the Roche 454 platform, not the Illumina platform actually referenced in the specification. The Board did not cite evidence to connect targeted sequencing on the Roche 454 platform to targeted sequencing on the Illumina system, nor has the Board explained what it found persuasive about the Roche 454 platform references.
The evidence put forward by Stanford was that its disclosure related to a so-called "second generation" (Illumina) sequencing apparatus and that CUHK's expert relied on references directed to a "first generation" (Roche 454) machine. In addition (and perhaps providing the panel's best support for its opinion), "Dr. Gabriel and the Board failed to cite to the Roche 454 references with specificity, leaving us with no reviewable record to conclude that the disclosed methods or platform would have been applicable to Illumina on Quake's priority date." It is one thing to give deference to the PTAB and apply the substantial evidence standard; it is apparently another thing not to provide a reviewing court (or at least the Federal Circuit) with sufficient evidence for the substantiality thereof to be assessed.
The panel was also unimpressed with the distinctions raised by CUHK's expert regarding targeted versus random MPS:
The Board's finding that the '018 specification's language does not preclude targeted MPS ignores the fact that the same description might be able to disclose both random and targeted sequencing. Put another way, even if the '018 specification could indicate targeted sequencing, it could also disclose random sequencing, or it could disclose both random and targeted sequencing. The Board frames its finding in terms of an erroneous premise: the Board's task was to determine whether the '018 patent's written description discloses random MPS sequencing, as recited by the later-added claims, not whether the description does not preclude targeted MPS sequencing.
In addition, this was another instance where the Federal Circuit believed the PTAB had not properly explained its reasoning: "The Board's error on this issue is compounded by its failure to explain the meaning of key sentences and phrases in the specification's discussion of the sequencing process, and its failure to compare these statements to the claim limitations."
On remand, the panel directed the PTAB to "examine whether a person of ordinary skill in the art would have known, as of the priority date, that the '018 specification's reference to Illumina products meant random MPS sequencing as recited in the claims," based on the understanding in the art at the priority date, and should "examine whether a person of ordinary skill would have understood that the '018 patent's specification disclosed random MPS sequencing, as opposed to whether the specification did not preclude targeted MPS sequencing." Of course, should the Board find that the evidence does not support invalidating any or all of Stanford's patents or application, the interference should proceed to address other motions and ultimately put CUHK to its priority proofs regarding who was the first inventor of the claimed technology.
Board of Trustees of the Leland Stanford Junior University v. Chinese University of Hong Kong (Fed. Cir. 2017)
Panel: Circuit Judges O'Malley, Reyna, and Chen
Opinion by Circuit Judge O'Malley
