By Andrew Williams —

One of the first IPR petitions ever filed, IPR2012-0006, was related to biotechnology — specifically DNA sequencing.  Illumina, Inc. filed that petition, and two others, IPR2012-00007 and IPR2013-00011, against patents owned by The Trustees of Columbia University in the City of New York ("Columbia").  The PTAB issued its Final Written Decisions in early 2014, canceling all of the challenged claims, which we reported at the time (see "IPR Update — The First Biotech IPR Decisions").  The Federal Circuit just recently concluded its review of these cases, affirming the decision of the Board.  The clear take away message from this decision is that anyone wanting to challenge a PTAB decision is likely going to face an uphill battle.  Even though the Court did write an opinion in this case, albeit non-precedential, the expectation is that the majority of IPR reviews appealed to the Federal Circuit will end in Rule 36 affirmances.  It is possible that the extreme deference that the Court appears to be showing the Patent Office could be a direct result of the deluge of cases that are anticipated for the next couple of years (if not longer).  Perhaps by signaling the uphill nature of these appeals, the Court may be attempting to discourage a perfunctory appeal in every case. Or, they may be setting the stage to make the Rule 36 judgements easier to issue.  Of course, there is another possible explanation.  It is conceivable that the first few petitions filed were really strong and/or were filed against low-hanging fruit.  As stronger patents get challenged, the PTAB may find themselves faced with closer cases, which may result in an increase in reversals or remands issued by the Federal Circuit.  Only time will tell.

In our previous review of the PTAB decisions, we provided a detailed explanation of the technology in this case.  Briefly, nucleotide analogues for use in sequencing by synthesis were at issue, which is a technique of sequencing by which every added nucleotide is determined using a label, such as a fluorescently detectable label.  Basically, this technology involves incorporating a labeled nucleotide analogue into a primer strand using DNA polymerase, in a manner comparable to that used when a DNA strand is synthesized.  Normally, when a DNA strand is synthesized, the 5' position of the sugar in a new incoming nucleotide is linked to the 3'-OH group of the sugar of a preexisting nucleotide in the strand under synthesis.  The difference in this sequencing technique, though, is that the newly incorporated nucleotide analogues have cleavable chemical groups capping the 3'-OH to prevent the incorporation of any successive nucleotides before the identity of the nucleotide analogue is determined. This nucleotide is identified with a detectable label attached to the nucleotide, with a unique label used for each base (A, C, G, or T).  In order to sequence an entire region of DNA, the 3'-OH cap is cleaved and the process repeated step-wise until the entire sequence is deduced.

Columbia scientists purported to invent particular nucleotide analogues utilized by this technique.  Specifically, the analogues have the detectable label attached to the base instead of the 3'-OH group, they have a cleavable chemical group capping the 3'-OH group, and at least some of the claims require the use of a deaza-substituted base, such as 7-deazapurine (a deazabase is one in which a natural nitrogen atom in the base ring is substituted with a carbon atom).  The opinion included an example of such a nucleotide analogue from Colombia's briefing:

Representative claims of the patents-at-issue, with the emphasis as added by the Federal Circuit noted, include:  Patent No. 7,713,698, claims 1 and 11:

1.  A method of determining the identity of a nucleotide analogue incorporated into a nucleic acid primer extension strand, comprising:
    a) contacting a nucleic acid template attached to a solid surface with a nucleic acid primer which hybridizes to the template;
    b) simultaneously contacting the product of step a) with a polymerase and four nucleotide analogues which are either (i) aA, aC, aG, and aT, or (ii) aA, aC, aG, and aU, so as to incorporate one of the nucleotide analogues onto the nucleic acid primer and form a nucleic acid primer extension strand, wherein each nucleotide analogue within (i) or (ii) comprises a base labeled with a unique label and contains a removable chemical moiety capping the 3'-OH group of the sugar of the nucleotide analogue, and wherein at least one of the four nucleotide analogues within (i) or (ii) is deaza-substituted; and
    c) detecting the unique label of the incorporated nucleotide analogue, so as to thereby determine the identity of the nucleotide analogue incorporated into the nucleic acid primer extension strand.

11.  A plurality of nucleic acid templates immobilized on a solid surface, wherein a nucleic acid primer is hybridized to such nucleic acid templates each such nucleic acid primer comprising a labeled incorporated nucleotide analogue, at least one of which is deaza-substituted, wherein each labeled nucleotide analogue comprises a base labeled with a unique label and contains a removable chemical moiety capping the 3'-OH group of the sugar of the nucleotide analogue.

Patent No. 7,790,869, claims 12 and 15:

12.  A nucleotide having a base that is attached to a detectable label through a cleavable linker, wherein the nucleotide has a deoxyribose comprising a cleavable chemical group capping the 3' OH group, wherein the cleavable linker is cleaved by a means selected from the group consisting of one or more of a physical means, a chemical means, a physical chemical means, heat, and light, and wherein the cleavable chemical group capping the 3' OH group is cleaved by a means selected from the group consisting of one or more of a physical means, a chemical means, a physical chemical means, heat, and light.

15.  The nucleotide of claim 12, wherein the base is a deazapurine.

And Patent No. 8,088,575, claims 1 and 6:

1.  A method of determining the identity of a nucleotide analogue incorporated into a nucleic acid primer extension strand, comprising: a) contacting a nucleic acid template attached to a solid surface with a nucleic acid primer which hybridizes to the template; b) simultaneously contacting the product of step a) with a polymerase and four nucleotide analogues which are either (i) aA, aC, aG, and aT, or (ii) aA, aC, aG, and aU, so as to incorporate one of the nucleotide analogues onto the nucleic acid primer and form a nucleic acid primer extension strand, wherein each nucleotide analogue within (i) or (ii) comprises a base labeled with a unique label and contains a small removable chemical moiety capping the 3'-OH group of the sugar of the nucleotide analogue, wherein said small cleavable chemical group does not interfere with the recognition of the nucleotide analogue by polymerase as a substrate; and c) detecting the unique label of the incorporated nucleotide analogue, so as to thereby determine the identity of the nucleotide analogue incorporated into the nucleic acid primer extension strand.

6.  The method of claim 1, wherein said base of at least one of said nucleotide analogues is a deazapurine.

The PTAB's Failure to Resolve PHOSITA's Qualifications

The first allegation by Columbia addressed by the Federal Circuit was whether the PTAB erred because it did not resolve what the qualifications would be of a person having ordinary skill in the art.  Columbia's expert asserted that a PHOSITA would have been skilled in "both biology and synthetic nucleotide chemistry," while Illumina's expert's definition did not include any mention of chemistry.  The challenge was that Illumina's expert did not possess the qualifications of a PHOSITA, and therefore was unqualified to opine.

The Court explained that failure to make explicit finding regarding the level of skill in the art is not necessarily reversible error.  Moreover, it is normally easier to establish obviousness with a higher level of skill.  Thus, because the PTAB found the claim obvious regardless of whether a PHOSITA was skilled in chemistry, it follows that someone with that additional skill would have found the claims at least as obvious (if not more so).  And, because the PTAB found Illumina's expert's qualifications sufficient, its credibility determination was not reversible error.

Prior Art Disclosures

The Court next considered whether the prior art contained all of the limitations of challenged claims: (1) a labeled base, (2) a removable 3'-OH cap, and (3) a deaza-substituted base.  The cited art was detailed in our previous post, as mentioned above.  The primary reference, WO 91/06678 ("Tsien"), purportedly described the DNS sequencing by synthesis method, and therefore was a starting point for many of the rejections of the relevant claims.  Tsien disclosed unique labels attached to a base, and a removable 3'-OH chemical moiety (capping group).  Columbia argued that even though a cleavable label attached to a base might have been disclosed, it did not teach such a label with a cleavable tether.  The Board, however, found that because Tsien disclosed these two concepts in adjacent paragraphs, one skilled in the art would have recognized the utility of such a tether.  The Board also cited two additional references, Dower and Stemple, as disclosing base-labeled nucleotides that contain 3'-OH moieties.  The Federal Circuit found there was substantial evidence for the finding that the prior art disclosed "nucleotides with a label on the nucleotide base with a removable 3'-OH group," and "a cleavable tether to release the label" from the base.

Motivation to Combine

Columbia also argued that the PTAB erred in concluding that a person of skill in the art would have combined the above-referenced teachings with a 7-deazapurine nucleotide.  Tsien did reference another article, Prober.  And, Prober did disclose the labeling of purines.  However, Columbia asserted that Tsien only cited Prober for the proposition that purines could be labeled.  As such, the argument went, there was no motivation to combine.

The PTAB had found an express teaching of incorporating a 3'-blocked dNTP having a fluorescent label in the Prober reference.  Moreover, the Federal Circuit pointed out, the motivation to combine can be found even in the absence of an explicit mention of the one reference in the other.  This case was even stronger because Tsien pointed directly to Prober, even if not the specific section of Prober.  The Court found that the PTAB's finding was supported by substantial evidence.

Reasonable Expectation of Success

Columbia also argued that the chemistry for creating the claimed nucleotide analogues was complex, and that therefore there would not be a reasonable expectation of success.  However, even Columbia's expert admitted that the synthetic process would have been easily understood by one skilled in the art.  Therefore, the Federal Circuit found substantial evidence supporting the PTAB's finding regarding the expectation.

Secondary Considerations

The Court next considered the Board's analysis of the secondary considerations of non-obviousness.

• Simultaneous Invention weighs modestly in favor of obviousness

Not quite a consideration of non-obviousness, the near simultaneous invention by two other companies, Solexa (a predecessor of Illumina) and Amersham counseled that the invention was obvious.  Columbia argued that these "inventions" were not prior art, but the Court pointed out that they do not need to be for this consideration.  In fact, if they were, they would have been considered under §§ 102 and 103.

• Copying does not favor nonobviousness

Columbia asserted that Manteia, a company whose intellectual property was acquired by Solexa, copied the invention.  However, the Board did not make a specific factual finding regarding whether the invention was copied.  Nevertheless, the Court did find that simultaneous invention can weigh in favor of obviousness, but only does so modestly in this case.

• Attempted Licensing weights modestly in favor of nonobviousness.

Columbia also points to Illumina's attempts to license the technology.  However, the Court found that none of the correspondence specifically mentioned the patents at issue.  Therefore, at best, this was only modest evidence of nonobviousness.

• Commercial Success does not favor nonobviousness

Columbia alleged that Illumina had significant sales of technology covered by the patents at issue.  However, Illumina pointed out, and the Court agreed, that all of the features proclaimed by Columbia to be responsible for the success of the products could be found in the prior art Tsien reference.  Moreover, the fact that Columbia was relying on Illumina's sales complicated the matter, because the Court could not separate out potential simultaneous invention or copying.

• Unexpected Results do not favor nonobviousness

Finally, Columbia asserted that the claimed nucleotides were "unexpectedly" better than pyrosequencing.  The PTAB dismissed this argument because pyrosequencing was not the closet prior art, and therefore was not probative to the determination of nonobviousness.  The Federal Circuit agreed.

Anticipation

The Board has also found that certain claims were anticipated by Tsien, and other references independently.  Columbia argued that these references were non-enabling, and did not disclose all of the elements.  Tsien was described as teaching a genus, but not the specific claimed species.  However, the Court pointed out that when a genus is small enough, such that all members can be envisaged, a genus anticipates every species within the genus.  Also, the Court noted that the patents at issue also do not disclose the chemistry required to practice the invention, which suggests that the chemistry required was not novel or nonobvious.  Finally, the Court held that the PTAB did not abuse its discretion in denying Columbia's motion to amend.

Trustees of Columbia University v. Illumina, Inc. (Fed Cir. 2015)
Panel: Chief Judge Prost and Circuit Judges Schall and Wallach
Opinion by Circuit Judge Wallach