By Andrew Williams --
Earlier this month, on March 6, 2014, the Patent Trial and Appeal Board ("Board") issued three related inter partes review opinions, marking the first set of opinions related to either the Biotech or Pharmaceutical industry. The cases were IPR2012-00006, IPR2012-00007, and IPR2013-00011, and the parties were Illumina, Inc. (Petitioner) and The Trustees of Columbia University in the City of New York ("Columbia") (Patent Owner). The technology at issue related to nucleotide analogues for use in sequencing by synthesis, a technique of sequencing by which every added nucleotide is determined using a label, such as a fluorescently detectable label. As should not be surprising at this point, the Board cancelled all of the reviewed claims as either being anticipated or rendered obvious by the prior art. The Board also either denied Columbia's motion to amend the claims, or dismissed them as moot. The claim amendments were found to either be of the same scope as those that were the subject of the review, or were separately unpatentable. Here also, there was no surprise, as the Board has yet to grant a motion to amend claims. Finally, the Board dismissed motions from both parties to exclude evidence as being moot.
The Technology
The technology at issue in this IPR generally related to sequencing by synthesis. Simply put, 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. In essence, the strand is terminated with the addition of the new nucleotide. This nucleotide is identified with a detectable label attached to the nucleotide, such as a fluorescent tag. Each base (A, C, G, or T) has a unique label, thereby allowing its identification. 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 did not invent sequencing by synthesis, and indeed, the method was fairly well established when the applications in question were filed. Instead, Columbia asserted that the novelty of the three reviewed patents was the particular nucleotide analogues utilized. Specifically, the analogues have the detectable label attached to the base (as opposed to 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).
Representative claims of the patents-at-issue 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 Cited Art
The following references were cited in one or more the final written decisions of these three IPRs. Even though each review had its individual nuances pertinent to the particular patent involved, we will address the various rejections below as a group.
Tsien
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). For the claims requiring no more than these limitations, the Board found Tsien to be an anticipatory reference. Columbia argued that this was impermissible, because there was no express statement in Tsien to use a cleavable linker to attach the fluorescent label to the base. However, the Board found that one of ordinary skill would have envisaged such a configuration based on a reading of the Tsien disclosure. The Board explained that "specific examples are not necessary to establish anticipation when there is a small genus disclosed and each member can be at once envisaged." IPR2012-00007 Final Written Decision, pg. 10.
Tsien and Prober I
Even though Tsien disclosed unique labels and a removable 3'-OH capping group, it lacked an explicit disclosure of a deaza-substituted base. However, it did explicitly reference the Prober I reference. Prober I (James M. Prober et al., A System for Rapid DNA Sequencing with Fluorescent Chain-Terminating Dideoxynucleotides, 238 Science 336-41 (1987) disclosed a nucleotide comprising a deazapurine base to which a label has been attached. The Board found it significant that Tsien referenced Prober I, and did not otherwise "disparage[] these alternative nucleotide analogues." Moreover, Columbia was unable to identify why one of ordinary skill in the art would conclude that the deazapurine base was unsuitable for the sequencing by synthesis method. In other words, the Board made it the patent holder's burden to provide evidence against the obviousness of the claims when the primary reference itself specifically mentions the combined reference, even if the combination is not specifically called out.
Stemple
U.S. Patent No. 7,270,951 ("Stemple") purportedly describes DNA sequencing by synthesis. Specifically, it described "chain terminating nucleotides that include a blocking group at the 3'-OH of the ribose . . . and a fluorescent label attached to the nucleotide base." The Board found that at least one claim as anticipated by Stemple, which Columbia did not contest. Instead, Columbia attempted to cancel that claim, a request which was ultimately denied.
Stemple and Anazawa
Even though Stemple described sequencing by synthesis, it did not disclose a deazabase. Anazawa (WO 98/33939) was an application published Japanese that taught a deazapurine base coupled to a detectable label. Stemple did reference Anazawa as describing a particular base to which a fluorochrome-photolabile linker conjugate can attach. However, the Board also found that even absent this disclosure, it would have been obvious for one of skill in the art to use Anazawa's deazapurine labeled nucleotide
Dower
U.S. Patent No. 5,547,839 ("Dower") purportedly describes methods for sequencing DNA. The Board found that Dower was anticipatory of the claims not requiring the deazapurine base. With regard to those other claims, Illumina had contended that Prober I was incorporated by reference. It had pointed out that Dower describes Prober I as teaching deazapurine bases, even though such teaching only had an irreversible 3'-OH blocking group. However, the Board disagreed, because it did not believe that Dower had any teaching of using Prober I to modify Dower's nucleotides with a reversible 3'-OH capping group. "Illumina has not pointed to anything convincing in Dower that teaches replacing Dower's dideoxy terminated nucleotide with a removable 3'-OH cap or vice-versa." IPR2013-00011 Final Written Decision, pg. 16. Therefore, Dower combined with Prober I was not found to render obvious the claims that recited deazapurine bases.
Secondary Considerations
As the Board explained, secondary considerations must always be considered as part of the evidence, not just when the decision maker has doubts after reviewing the art. These considerations can often be the most probative and cogent evidence, and helps the court avert the hindsight trap. In this case, Columbia alleged that its inventions were not obvious because they provided "unexpectedly improved properties," commercial success for Illumina in its sequencing by synthesis products, evidence of attempted licensing, and praise and skepticism. As for the first two factors, Columbia alleged that its inventions had unexpected properties over pyrosequencing, and that Illumina experienced commercial success practicing the inventions in comparision to pyrosequencing. The Board rejected these arguments, because pyrosequencing was not the closest art – "[t]o establish unexpected results, the claimed subject matter must be compared with the closest prior art." IPR2012-00006 Final Written Decision, pg. 33. The Board pointed out that Tsien was the closest art, and therefore must be the one that is used for comparison. As such, these secondary considerations were not sufficiently demonstrated by Columbia. The Board also considered the fact that Illumina had attempted to license Columbia's technology, because licensing can be evidence that a licensor recognizes the merits of the invention. Nevertheless, even though Illumina did inquire about licensing, there was no evidence it did so because it believed that the patents had independent merit. Instead, the invention that had merit was that disclosed in Tsien. The Board found that it was possible Illumina was simply trying to license these patents because they potentially covered its own product, and there was insufficient evidence to establish that this was not the case. Finally, the Board considered the praise and skepticism surrounding the inventions, but found this information to be of insufficient weight and relevance to be persuasive.
In total, the Board cancelled all reviewed claims of these three patents that were the subject of these three IPRs. It will be interesting to observe whether the trend toward cancellation of all claims continues when other biotech or pharmaceutical-related patents are reviewed. We will continue to monitor these cases and provide periodic updates.
Count me confused regarding:
The Board also considered the fact that Illumina had attempted to license Columbia's technology, because licensing can be evidence that a licensor recognizes the merits of the invention. Nevertheless, even though Illumina did inquire about licensing, there was no evidence it did so because it believed that the patents had independent merit. Instead, the invention that had merit was that disclosed in Tsien. The Board found that it was possible Illumina was simply trying to license these patents because they potentially covered its own product, and there was insufficient evidence to establish that this was not the case.
Was Tsien somehow involved (at all) in the licensing fact pattern? Is the indication that the potential infringer thought that it was potentially infringing enough to remove a secondary consideration?
Posted by: Skeptical | March 25, 2014 at 07:38 AM
Dear Skeptical,
Unfortunately, that is about the extent of the analysis provided in the three written decision (all three IPRs made the same observation). The Board did say that there was evidence from an Illumina witness (Dr. Barnes), and Illumina’s marketing literature, that suggested that what Illumina thought had merit was the invention of removable 3’-OH capping groups and base labels. This is what was taught by Tsien. If I understand the Board correctly, they appear to make the distinction between “merit” patents and “blocking” patents (“There is insufficient evidence that Illimina’s licensing strategy was driven by recognition of the merits of the claimed invention, rather than knowledge of a patent potentially covering their own product”). However, as you suggest, if the “blocking” patent was so much a hindrance that Illumina considered taking a license, maybe it had more merit than the Board indicated. Thanks for your comment.
Andrew
Posted by: Andrew Williams | March 25, 2014 at 08:53 AM
Andrew,
You are welcome.
Let me be more blunt: this appears to be an intentional conflation of the licensing secondary factor. There is a clear road map being drawn to potential infringers.
I do not want to suggest that any prior art by Tsien is not fair game in an obviousness investigation. But this is plain bootstrapping here. If on the other hand, the record indicates that licensing was also sought from Tsien, it might (just might) makes me less...
Posted by: Skeptical | March 25, 2014 at 10:15 AM
Andrew,
What we're seeing here in these IPRs is the unfortunate consequence of what happened in the Fresenius case where a post-grant ruling by the USPTO can trump a federal court ruling because the standard of review for validity is different for IPRs before the PTAB (preponderance of the evidence) versus infringement actions in federal district courts (clear and convincing evidence). There's also the additional problem that the USPTO/PTAB uses a different standard for claim construction (BRI) versus the federal district courts ("ordinary and customary meaning"). As Judge Newman correctly noted in her vociferous dissenting opinion in Fresenius, what we have here in these IPRs potentially creates a serious violation of "separation of powers" if accused infringers can, in essence, "relitigate" before the PTAB adverse validity determinations in federal district courts, and may even implicate "separation of powers" issues because of the disparate standards for review and claim construction.
Posted by: EG | March 25, 2014 at 10:33 AM
Andrew:
Does the patentee not have the ability to amend claims as of right? In other words, if the patentee has asserted against her claims a 102 rejection, and then wants to limit the scope of the claim to overcome the rejection, doesn't she have the right to do so (even if the Board decides that the claim is then obvious)?
Posted by: moondog | March 25, 2014 at 11:25 AM
"secondary considerations must always be considered as part of the evidence, not just when the decision maker has doubts after reviewing the art. These considerations can often be the most probative and cogent evidence, and helps the court avert the hindsight trap."
There are, of course, just as many opportunities for mistakes made when looking at these "secondary factors" as there are when making the prima facie case. Primarily, there is no evidence of any nexus between the licensing of a presumed-valid patent and the obviousness of such a patent when challenged in court, i.e., many heavily-licensed patents are proven obvious. So why is post-grant licensing even a consideration at all when determining obviousness? You'll have to ask the "judicial activists" who created the law.
Posted by: The Sweet Taste of Your Tears | March 25, 2014 at 06:46 PM
Regarding the "trend" towards cancellation of all claims in these proceedings, I'm not sure why this is surpring. In most every patent, the independent claim(s) are where all the action is. The dependent claims almost always rise and fall with the independent claims because the dependent claims typically recite obvious variants of the alleged invention, e.g., variants that are not expected to yield any unexpected results based on the additional limitations relative to the independent claims.
Posted by: The Sweet Taste of Your Tears | March 25, 2014 at 06:52 PM
Three questions for you, The Sweet Taste of Your Tears,
1) Are you the person that posts under the pseudonym Malcolm Mooney, MM, or any of the other seemingly near countless related sockpuppets?
2) Why do you stay in a field that you so evidently despise?
3) Do you think that you are fooling anyone at all?
And while I ask these questions, that I will receive a direct and honest answer from you, I remain...
Posted by: Skeptical | March 26, 2014 at 05:39 AM
Hey Skeptical,
Once more, TSTOYT is "guilty" of being MM until proven otherwise.
Posted by: EG | March 26, 2014 at 09:58 AM
Dear Moondog,
Sorry for the delay in responding to your question. Unfortunately, in an IPR proceeding, the patent holder only has one opportunity to file a motion to amend the patent in one of two ways (A) cancel any challenged claim, or (B) propose a reasonable number of substitute claims. See 35 U.S.C section 316(d). As of the date of the Illumina decision, the Board had not granted any such motion (and I am not aware of any such motions being granted in the interim). Thanks for the question.
Andrew
Posted by: Andrew Williams | March 26, 2014 at 07:35 PM
" Unfortunately, in an IPR proceeding, the patent holder only has one opportunity to file a motion to amend the patent in one of two ways (A) cancel any challenged claim, or (B) propose a reasonable number of substitute claims. See 35 U.S.C section 316(d). As of the date of the Illumina decision, the Board had not granted any such motion (and I am not aware of any such motions being granted in the interim)."
Andrew,
How can the PTAB possibly grant no motions under 35 USC 316 to this point? In other words, what Chief Judge Rader said was true: IPRs are simply "patent killers." If that's the case, we potentially have here a gross violation of due process, as well as the APA.
Posted by: EG | March 27, 2014 at 08:06 AM