Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-14-01547/USCOURTS-ca13-14-01547-0/pdf.json

Parties Involved:
Illumina, Inc.
Appellee
Trustees of Columbia University in the City of New York
Appellant

Document Text:

NOTE: This disposition is nonprecedential. 

United States Court of Appeals 

for the Federal Circuit ______________________ 

TRUSTEES OF COLUMBIA UNIVERSITY IN THE 

CITY OF NEW YORK,

Appellant

v.

ILLUMINA, INC.,

Appellee

______________________ 

2014-1547

______________________ 

Appeal from the United States Patent and Trademark 

Office, Patent Trial and Appeal Board in No. IPR2012-

00006.

-----------------------------------------

TRUSTEES OF COLUMBIA UNIVERSITY IN 

THE CITY OF NEW YORK, 

Appellant

v. 

ILLUMINA, INC., 

Appellee

______________________ 

2014-1548

Case: 14-1547 Document: 61-2 Page: 1 Filed: 07/17/2015
2 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

______________________ 

Appeal from the United States Patent and Trademark 

Office, Patent Trial and Appeal Board in No. IPR2012-

00007.

-----------------------------------------

TRUSTEES OF COLUMBIA UNIVERSITY IN THE 

CITY OF NEW YORK, 

Appellant

v. 

ILLUMINA, INC., 

Appellee

______________________ 

2014-1550

______________________ 

Appeal from the United States Patent and Trademark 

Office, Patent Trial and Appeal Board in No. IPR2013-

00011.

______________________ 

Decided: July 17, 2015

______________________ 

PAUL REINHERZ WOLFSON, Wilmer Cutler Pickering 

Hale and Dorr LLP, Washington, DC, argued for 

appellant. Also represented by MATTHEW GUARNIERI; 

DONALD J. CURRY, ROBERT SETH SCHWARTZ, ANTHONY M.

ZUPCIC, Fitzpatrick, Cella, Harper & Scinto, New York, 

NY; JOHN P. WHITE, Cooper & Dunham, LLP, New York, 

NY.

Case: 14-1547 Document: 61-2 Page: 2 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 3

EDWARD R. REINES, Weil, Gotshal & Manges LLP, 

Redwood Shores, CA, argued for appellee. Also 

represented by DEREK C. WALTER, MICHELE GAUGER,

MARION MCLANE READ, Redwood Shores, CA; AUDREY 

LYNN MANESS, Houston, TX. 

______________________ 

Before PROST, Chief Judge, SCHALL and WALLACH,

Circuit Judges.

WALLACH, Circuit Judge. 

This opinion addresses companion appeals from the 

inter partes reviews of three patents before the Patent 

Trial and Appeal Board (“PTAB”) of the United States 

Patent and Trademark Office, with Illumina, Inc. 

(“Illumina”), as petitioner and the Trustees of Columbia 

University in the City of New York (“Columbia 

University”) as patent owner. The patents are generally 

directed to sequencing (i.e., determining the nucleotide 

sequence of) deoxyribonucleic acid (“DNA”), and include 

U.S. Patent Nos. 7,713,698 (the “’698 patent”) (Appeal No. 

2014-1547), 8,088,575 (the “’575 patent”) (Appeal No. 

2014-1548), and 7,790,869 (the “’869 patent”) (Appeal No. 

2014-1550). The PTAB found all challenged claims 

anticipated or obvious over the prior art. For the reasons 

set forth below, this court affirms. 

BACKGROUND

I. The Science of DNA as It Relates to These Appeals

DNA is a double-stranded molecule that encodes the 

genetic information of living organisms. Each strand 

consists of a series of chemical structures called 

nucleotides, the particular order of which determines the 

heritable characteristics of living organisms. DNA 

sequencing is useful in a variety of fields, especially 

medicine, where it can help researchers uncover the 

genetic bases of diseases and in turn design targeted 

therapies. 

Case: 14-1547 Document: 61-2 Page: 3 Filed: 07/17/2015
4 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

Each nucleotide within the DNA molecule consists of 

three distinct parts, including a sugar, a base, and one or 

more phosphate groups:

Appellant’s Br. 4.1 

Four bases exist in naturally-occurring DNA, 

including adenine (“A”), guanine (“G”), cytosine (“C”), or 

thymine (“T”). A and G are known as “purines,” while C 

and T are known as “pyrimidines.” The sugar component 

of each nucleotide is comprised of five carbon atoms, 

conventionally numbered 1’ (“one prime”) through 5’ (“five 

prime”) and represented by the vertices of the pentagonal 

sugar structure, as illustrated. Nucleotides not 

incorporated into a DNA strand contain a hydroxyl group 

(oxygen bonded to hydrogen, or “OH”) at the 3’ position 

(“3’-OH group”). When nucleotides join together to form 

DNA, a single oxygen atom (“O”) links the phosphate 

group with the sugar at the 3’-OH position: 

1 All references to the briefs and Joint Appendix 

(“J.A.”) are to Appeal No. 2014-1547 unless otherwise 

indicated.

 

Case: 14-1547 Document: 61-2 Page: 4 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 5

Appellant’s Br. 4. 

In living organisms, DNA exists as a double-stranded 

helical structure held together by hydrogen bonds 

between “complementary” base pairs. A and T are 

complementary, and thus pair with each other, and G and 

C are complementary, and thus pair with each other. 

During DNA replication (such as during sequencing), the 

two strands are separated and a short chain of 

nucleotides known as a “primer” binds to a portion of the 

single-stranded DNA where copying will begin. 

Polymerase, an enzyme, causes the primer to be extended 

in a manner complementary to the chain being copied 

(i.e., matching A to T, and G to C). Important to the 

present matter, the phosphate group of each new 

nucleotide added to the lengthening DNA strand bonds to 

the 3’-OH group of the last nucleotide already in the 

strand. 

In the 1970s, British biochemist Frederick Sanger and 

Alan Coulson invented a sequencing method that relies on 

modified nucleotides called dideoxynucleotides 

(“ddNTPs”), which have a hydrogen atom (“H”) rather 

Case: 14-1547 Document: 61-2 Page: 5 Filed: 07/17/2015
6 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

than OH at the 3’ position. See Frederick Sanger et al., 

DNA Sequencing with Chain-Termination Inhibitors, 74 

Proc. Nat’l Acad. Scis. 5463 (1977). In the original version 

of Sanger sequencing, the DNA template molecule is 

mixed with polymerase, a primer, isolated nucleotides 

(“dNTPs”), and a small amount of ddNTPs. When a 

ddNTP is randomly incorporated into the nucleotide 

chain, elongation of the new strand cannot continue 

because there is no 3’-OH group to which the next 

nucleotide would otherwise bond. This chain termination 

cannot be reversed, and the result is an array of 

fragments of different lengths, each containing a single 

ddNTP. 

Each ddNTP, and therefore each fragment, contains a 

radioactive label (or, in subsequently developed versions 

of Sanger sequencing, a fluorescent label) that can be 

detected. After the fragments are sorted by size using a 

process called electrophoresis, the length information can 

be combined with the label information to determine the 

sequence of the DNA. One challenge of Sanger 

sequencing is ensuring the fluorescent labels remain 

attached to the base. It was discovered that increased 

stability can be achieved if the label is attached to a 

carbon atom at the 7’ position of a purine base (A or G) 

rather than to a nitrogen atom, which normally occupies 

the 7’ position. Purines in which the nitrogen atom at the 

7’ position has been replaced by a carbon atom are known 

as “deazapurines.” 

Due to the electrophoresis step, Sanger sequencing 

was too slow to efficiently sequence entire genomes, which 

may contain billions of nucleotides. A new type of process 

called sequencing by synthesis (“SBS”) avoided the need 

for electrophoresis by placing removable, label-bearing 

“caps” at the 3’-OH group, which would block synthesis 

long enough to detect the label (and thereby identify the 

nucleotide) but would then be removed to allow synthesis 

to continue. Unfortunately, this type of SBS worked 

Case: 14-1547 Document: 61-2 Page: 6 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 7

poorly because the “caps” were located near the “active 

site” of the polymerase and thereby interfered with its 

operation. 

According to Columbia University, Dr. Jingyue Ju and 

his colleagues avoided the problem caused by the bulky 

caps by placing an unlabeled removable cap on the 3’-OH 

group and attaching the label instead to a cleavable linker 

attached to the deazapurine base: 

Appellant’s Br. 10. Dr. Ju’s method is the subject of the 

three patents at issue in this suit, each of which is titled 

“Massive Parallel Method for Decoding DNA and RNA.” 

II. Procedural Background

In March 2012, Columbia University sued Illumina 

for infringement of five DNA sequencing patents, 

including the three at issue in these appeals. Illumina 

petitioned for inter partes review of the ’698, ’869, 

and ’575 patents in September and October 2012. The 

PTAB found most of the challenged claims of the three 

patents obvious over one or more of the following prior art 

references: (1) Roger Tsien et al., WO 91/06678 (May 16, 

1991) (“Tsien”); (2) James Prober et al., A System for 

Rapid DNA Sequencing with Fluorescent ChainTerminating Dideoxynucleotides, 238 Science 336 (1987) 

(“Prober”); (3) Rabani et al., WO 96/27025 (Sept. 6, 1996) 

Case: 14-1547 Document: 61-2 Page: 7 Filed: 07/17/2015
8 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

(“Rabani”) (J.A. 3095–3154); (4) U.S. Patent No. 4,804,748

(issued Feb. 14, 1989) (“Seela”) (J.A. 3155–58); (5) U.S. 

Patent No. 5,547,839 (issued Aug. 20, 1996) (“Dower”); (6) 

U.S. Patent No. 7,270,951 B1 (issued Sept. 18, 2007) 

(“Stemple”); (7) Takeshi Anazawa et al., WO 98/33939 

(Aug. 6, 1998) (“Anazawa”). In addition, the PTAB found 

a number of claims anticipated by Tsien, Stemple, or 

Dower. Columbia University timely appealed. This court 

has jurisdiction under 28 U.S.C. § 1295(a)(4)(A) (2012) 

and 35 U.S.C. § 141(c) (2012).

DISCUSSION

I. Standards of Review and the Legal Standard for 

Obviousness

This court reviews the PTAB’s factual findings for 

substantial evidence and its legal conclusions de novo. 

Rambus Inc. v. Rea, 731 F.3d 1248, 1251–52 (Fed. Cir. 

2013). “A finding is supported by substantial evidence if a 

reasonable mind might accept the evidence to support the 

finding.” K/S Himpp v. Hear-Wear Techs., LLC, 751 F.3d 

1362, 1364 (Fed. Cir. 2014). “Substantial evidence is 

more than a mere scintilla. It means such relevant 

evidence as a reasonable mind might accept as adequate 

to support a conclusion.” In re Gartside, 203 F.3d 1305, 

1312 (Fed. Cir. 2000) (internal quotation marks and 

citation omitted).

A patent is invalid for obviousness “if the differences 

between the subject matter sought to be patented and the 

prior art are such that the subject matter as a whole 

would have been obvious at the time the invention was 

made to a person having ordinary skill in the art 

[(“PHOSITA”)] to which said subject matter pertains.” 35 

U.S.C. § 103(a) (2006).2 Whether an invention would 

2 Section 103 has since been amended. See Leahy 

Smith America Invents Act, Pub. L. No. 112-29, § 3(c), 125 

 

Case: 14-1547 Document: 61-2 Page: 8 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 9

have been obvious at the time it was made is a question of 

law, which this court reviews de novo, based on 

underlying facts. Gartside, 203 F.3d at 1316. Underlying 

factual inquiries include: (1) “the scope and content of the 

prior art”; (2) “differences between the prior art and the 

claims at issue”; (3) “the level of ordinary skill in the 

pertinent art”; and (4) “secondary considerations [such] as 

commercial success, long felt but unsolved needs, [and] 

failure of others.” Graham v. John Deere Co., 383 U.S. 1, 

17 (1966).

II. Certain Challenged Claims Were Obvious at the Time 

of Invention

A. The PTAB’s Failure to Resolve the Dispute Regarding 

the PHOSITA’s Qualifications Was Not Error

Columbia University asserts the PTAB erred in 

“fail[ing] to resolve the parties’ dispute regarding the 

qualifications of the [PHOSITA].” Appellant’s Br. 36. It 

argues its expert, Dr. Trainor, possessed the 

qualifications of a PHOSITA while Illumina’s expert, Dr. 

Weinstock, did not. According to Columbia University, a 

PHOSITA would be skilled in “both biology and synthetic 

nucleotide chemistry” and hold “a graduate degree in 

chemistry or chemical biology or a related discipline.” Id.

(internal quotation marks and citation omitted). 

Columbia University asserts that because Dr. Weinstock 

had not worked in the area of nucleotide synthesis, he 

was unqualified to opine on matters of synthetic 

nucleotide chemistry. 

Stat. 284, 287–88 (2011) (“AIA”). However, because the 

applications that led to the ’698, ’869, and ’575 patents 

were filed before March 16, 2013, the pre-AIA § 103(a) 

applies. See AIA, 125 Stat. at 293. 

 

Case: 14-1547 Document: 61-2 Page: 9 Filed: 07/17/2015
10 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

This court has explained that the failure to make 

explicit findings regarding the level of skill in the art does 

not necessarily constitute reversible error: 

While it is always preferable for the factfinder 

below to specify the level of skill it has found to 

apply to the invention at issue, the absence of 

specific findings on the level of skill in the art does 

not give rise to reversible error “where the prior 

art itself reflects an appropriate level and a need 

for testimony is not shown.” 

Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 

2001) (quoting Litton Indus. Prods., Inc. v. Solid State 

Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985)). However, 

where the fact finder has failed to make a finding or has 

made an incorrect finding with respect to the level of 

ordinary skill in the art in a manner that impacts the 

ultimate conclusion of obviousness, the failure or incorrect 

finding could constitute reversible error. Custom 

Accessories, Inc. v. Jeffrey–Allan Indus., Inc., 807 F.2d 

955, 963 (Fed. Cir. 1986). 

Here, Illumina’s expert Dr. Weinstock asserted the 

PHOSITA need only have been skilled in molecular 

biology or associated sciences, but made no mention of 

chemistry. Columbia University proposes the level of 

ordinary skill should have additionally included skill in 

chemistry. See Appellant’s Br. 36. That is, Columbia 

University argues the PTAB should have explicitly stated 

a PHOSITA would have possessed a higher level of skill 

than that advocated by Illumina. In general, the higher 

the PHOSITA’s skill level, the more likely the PHOSITA 

would find an invention obvious. Kinetic Concepts, Inc. v. 

Smith & Nephew, Inc., 688 F.3d 1342, 1366 (Fed. Cir. 

2012) (“[I]t is generally easier to establish obviousness 

under a higher level of ordinary skill in the art.”). 

Because the PTAB found the claims would have been 

obvious to a PHOSITA not necessarily possessing the 

Case: 14-1547 Document: 61-2 Page: 10 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 11

additional skill Columbia University proposed, the claims 

would have also been obvious to a PHOSITA with a 

higher level of knowledge and ability. 

With respect to Columbia University’s argument that 

Dr. Weinstock was “unqualified to opine on matters of 

synthetic nucleotide chemistry,” Appellant’s Br. 36, the 

PTAB found Dr. Weinstock had “experience in DNA 

sequencing” and was “qualif[ied] to testify on the issues 

discussed in his declaration,” J.A. 3. The PTAB was 

entitled to weigh the credibility of the witnesses in light of 

their qualifications and evaluate their assertions 

accordingly. See Inwood Labs., Inc. v. Ives Labs., Inc., 456 

U.S. 844, 856 (1982) (“Determining the weight and 

credibility of the evidence is the special province of the 

trier of fact.”); Anchor Sav. Bank, FSB v. United States, 

597 F.3d 1356, 1367 (Fed. Cir. 2010).

B. Prior Art Disclosure of Base Labeling, Cleavable 

Linkers, and Deazapurine

All of the claims at issue in case number 14-1547 

involve modified nucleotides that contain: (1) a labeled 

base; (2) a removable 3’-OH cap; and (3) a deazasubstituted base. Columbia University first asserts it 

would not have been obvious at the time of invention to 

use “a reversible chain-terminating nucleotide with a 

label attached to the base, rather than to the cap on the 

3’-OH group of the sugar.” Appellant’s Br. 37. Second, it 

asserts using “a cleavable linker (as required by claim 15

[of the ’698 patent]) would not have been obvious.” Id. at 

41. The PTAB made factual findings related to these 

arguments, which address the state of the art prior to 

October 2000, i.e., the date U.S. Patent Application No. 

09/684,670 was filed, to which each of the three patentsin-suit claims priority. 

Although Columbia University concedes that 

“[d]uring the 1990s [there was] some interest in baselabeled nucleotide analogues,” J.A. 5, it argues the most 

Case: 14-1547 Document: 61-2 Page: 11 Filed: 07/17/2015
12 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

relevant reference, Tsien, contains a “marked preference” 

for labeling the 3’-OH caps as opposed to the base, 

Appellant’s Br. 37–38. Illumina responds that “a labeled 

base and 3’-OH cap were preferred by the late 1990s.” 

Appellee’s Br. 5 (capitalization omitted). 

The PTAB addressed this factual issue, concluding 

“Columbia’s characterization of the prior art as having 

‘some interest in base-labeled nucleotide analogues’ 

understates the interest level shown in the prior art.” 

J.A. 5. This finding was supported by substantial 

evidence, as is apparent from an examination of the prior 

art references considered by the PTAB. Tsien, for 

example, which bears an international publication date of 

1991, noted the label could be attached to the base, and 

cautioned its nomenclature should not be read to “imply 

that this is the sole place where labeling can occur.” J.A. 

3011. Tsien described base labeling in some detail:

While the above-described approaches to labeling 

focus on incorporating the label into the 

3’-hydroxyl blocking group, there are a number of 

alternatives—particularly the formation of a 

3’-blocked dNTP analogue containing a label such 

as a fluorescent group coupled to a remote position 

such as the base. . . . 

One method involves the use of a fluorescent tag

attached to the base moiety. The tag may be 

chemically cleaved (either separately from or 

simultaneously with the deblocking step) . . . . 

This method is included because a number of base 

moiety derivatized dNTP analogues have been 

reported to exhibit enzymatic competence. . . . 

In another type of remote labeling the fluorescent 

moiety or other innocuous label can be attached to 

the dNTP through a spacer or tether. The tether 

can be cleavable if desired . . . . There are several 

cleavable tethers that permit removing the 

Case: 14-1547 Document: 61-2 Page: 12 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 13

fluorescent group before the next successive 

nucleotide is added . . . . Long tethers may be 

used . . . . Typical tethers are from about 2 to 

about 20 . . . atoms in length. 

J.A. 3028–30 (emphases added). Tsien thus discloses a 

reversible chain-terminating nucleotide and a label 

attached to the base via a cleavable tether.

Columbia University argues that although Tsien 

describes both (1) cleavable tethers and (2) cleavable 

labels attached to the base, it does not explicitly disclose 

the combination of these two elements (i.e., a label 

attached to the base via a cleavable tether). See J.A. 3029 

(Tsien) (describing a “fluorescent tag attached to the base 

moiety” and noting “[t]he tag may be chemically cleaved”). 

Although Tsien does not expressly disclose a cleavable 

tether attached to the base, the excerpted portions above, 

which describe both base labeling and the use of cleavable 

tethers, are derived from two adjacent paragraphs of 

Tsien, supporting the PTAB’s finding that “[a PHOSITA] 

reading Tsien would have recognized that its teaching of a 

cleavable tether to release the label would have been 

useful when the label is attached to the base.” J.A. 15; see 

also J.A. 3029 (“Long tethers may be used so that the 

large fluorescent groups are spaced sufficiently far away 

from the base and triphosphate moieties . . . .”). 

The PTAB also cited Dower and Stemple as reflecting 

“recognition within the prior art that such nucleotides 

[i.e., those that are base-labeled and contain removable 

3’-OH moieties] were useful and effective in SBS 

methods.” J.A. 6. Dower states: 

One important functional property of the 

monomers is that the label be removable. . . . The 

label position may be anywhere on the molecule

compatible with appropriate polymerization. . . . 

Nucleotide analogs used as chain-terminating 

reagents will typically have both a labeling moiety 

Case: 14-1547 Document: 61-2 Page: 13 Filed: 07/17/2015
14 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

and a blocking agent while remaining compatible 

with the elongation enzymology. As the blocking 

agent will usually be on the 3’ hydroxyl position of 

the sugar on a nucleotide, it would be most 

convenient to incorporate the label and the 

blocking agent at the same site providing for a 

single reaction for simultaneous removal of the 

label and blocking agent. However, it is also 

possible to put a label on another portion of the 

nucleotide analog than the 3’ hydroxyl position of 

the sugar, thereby requiring a two-step reaction 

cycle for removing the blocking and labeling 

groups. . . . 

There are several suitable labeled, terminator 

structures as follows: . . . (b) The fluorophore is 

placed in a position other than the 3’OH of the 

nucleoside,[3] and a different group placed on the 

3’OH of the dNTPs to function as the chain 

terminator. The fluorphore and the 3’ blocking 

group are removed [in a single step or separate 

steps]. 

Dower col. 15 l. 52–col. 16 l. 6; col. 25 ll. 23–37 (emphases 

added). Figure 1B of Stemple illustrates a fluorochrome 

attached to the base via a photolabile (i.e., cleavable by 

light) linker: 

3 “A ‘nucleoside,’ unlike a nucleotide, contains only 

a sugar and a base. Nucleotides can be equivalently 

referred to as nucleosides with added phosphate groups 

(hence, ‘deoxyribonucleoside triphosphate’).” Appellant’s 

Br. 3 n.1.

 

Case: 14-1547 Document: 61-2 Page: 14 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 15

Stemple, fig.1B. Stemple explains: “Panel B depicts an 

alternative configuration in which the fluorochrome is 

attached to the base of the nucleotide by way of a 

photolabile linker. The 3’-OH is blocked by a separate 

photolabile group . . . .” Id. col. 10 ll. 44–47. This 

arrangement is described by Stemple as a “preferred 

embodiment.” Id. col. 3 l. 31. These disclosures constitute 

substantial evidence supporting the PTAB’s findings that 

the prior art disclosed “nucleotides with a label on the 

nucleotide base with a removable 3’-OH group,” J.A. 6, 

and “a cleavable tether to release the label” from the base 

moiety, J.A. 15.4 

C. Motivation to Combine

As discussed above, the prior art discloses labels 

attached to the base, cleavable tethers, and reversibly 

capped 3’-OH groups. There does not appear to be any 

dispute that the prior art discloses deazapurines. See, 

e.g., Natalya Ramzaeva et al., 7-Deazaguanine DNA, 80 

4 The PTAB found neither Stemple nor its 

predecessor PCT application was anticipatory because 

neither disclosed a deaza-substituted base. See J.A. 76–

77. 

 

Case: 14-1547 Document: 61-2 Page: 15 Filed: 07/17/2015
16 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

Helvetica Chimica Acta 1809 (1997) (J.A. 5257–59); F. 

Seela et al., Duplex Stability of Oligonucleotides 

Containing 7-Substituted 7-Deaza and 8-Aza7-Deazapurine Nucleosides, 16 Nucleosides & Nucleotides 

963 (1997) (J.A. 5271–72). Columbia University argues, 

however, that “the [PTAB] erred in concluding that a 

skilled artisan would have combined the prior art to 

achieve Dr. Ju’s invention.” Appellant’s Br. 34 (emphasis 

added) (capitalization omitted). 

The obviousness of an invention is not established 

“merely by demonstrating that each of its elements was, 

independently, known in the prior art.” KSR Int’l Co. v. 

Teleflex Inc., 550 U.S. 398, 418 (2007). In addition, the 

court must determine “whether there was an apparent 

reason to combine the known elements in the fashion 

claimed by the patent at issue.” Id.; see also Star 

Scientific, Inc. v. R.J. Reynolds Tobacco Co., 655 F.3d 

1364, 1374–75 (Fed. Cir. 2011) (“[E]ven when all claim 

limitations are found in prior art references, the factfinder must not only determine what the prior art 

teaches, but whether prior art teaches away from the 

claimed invention and whether there is a motivation to 

combine teachings from separate references.”). “[T]he 

analysis need not seek out precise teachings directed to 

the specific subject matter of the challenged claim, for a 

court can take account of the inferences and creative steps 

that a person of ordinary skill in the art would employ.” 

KSR, 550 U.S. at 418. 

Columbia University asserts that if “Tsien disclosed 

such nucleotides in 1991,” then it is difficult to explain the 

“decade-long SBS research efforts that followed.”5 Reply 

5 Although this argument might appropriately have 

been raised in support of the secondary consideration of 

long-felt need, Columbia University did not assert longfelt need.

 

Case: 14-1547 Document: 61-2 Page: 16 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 17

Br. 29; see also Appellant’s Br. 61. However, Illumina 

points out that Dr. Ju’s invention “was not reduced to 

practice until six years later using important changes not 

disclosed in the patents at issue.” Appellee’s Br. 53; see 

also J.A. 4130–31. Although the record does not provide a 

conclusive explanation for either of these long lags, some 

testimony suggests large capital investments may provide 

a partial answer. See J.A. 3581. With these principles 

and considerations in mind, the language of the claims of 

each patent at issue will be considered. 

Claims 1 and 11 are the only independent claims of 

the ’698 patent reviewed by the PTAB, and recite:

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 deazasubstituted; and 

c) detecting the unique label of the incorporated 

nucleotide analogue, so as to thereby determine 

the identity of the nucleotide analogue 

Case: 14-1547 Document: 61-2 Page: 17 Filed: 07/17/2015
18 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

incorporated into the nucleic acid primer 

extension strand.

’698 patent col. 35 ll. 2–23 (emphases added). 

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 deazasubstituted, 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.

Id. col. 36 ll. 24–31 (emphases added). 

The only challenged independent claim of the ’869 

patent is claim 12, which recites:

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.

’869 patent col. 33 ll. 40–50 (emphases added). In 

addition, claim 15 of the ’869 patent recites: “15. The 

nucleotide of claim 12, wherein the base is a 

deazapurine.” Id. col. 33 ll. 10–11 (emphasis added).

Case: 14-1547 Document: 61-2 Page: 18 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 19

The only challenged independent claim of the ’575 

patent is claim 1, which recites:

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.

’575 patent col. 33 ll. 30–45 (emphases added). In 

addition, claim 6 of the ’575 patent recites: “6. The method 

of claim 1, wherein said base of at least one of said 

nucleotide analogues is a deazapurine.” Id. col. 34 ll. 42–

43 (emphasis added).

Inter partes review of independent claims 1 and 11 of 

the ’698 patent was instituted on grounds of anticipation 

by Dower, and obviousness over Tsien, Prober, and Seela. 

Inter partes review of claim 12 of the ’869 patent was 

instituted on grounds of anticipation by Tsien and 

Case: 14-1547 Document: 61-2 Page: 19 Filed: 07/17/2015
20 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

Stemple, and claim 15 on grounds of obviousness over 

Tsien, Prober, Stemple, and Anazawa. Inter partes 

review of claim 1 of the ’575 patent was instituted on 

grounds of anticipation by Dower and Tsien, and of claim 

6 on grounds of obviousness over Tsien, Prober, and Seela. 

The PTAB evaluated the content of the prior art, 

finding Tsien disclosed an SBS method that used “a 

fluorescent tag attached to the base moiety,” and a 

removable 3’-OH blocking group. J.A. 10–11. The PTAB 

noted “Tsien does not disclose a deaza-substituted base, 

but references Prober I, which does.” J.A. 12. 

Columbia University argues Tsien’s citation to Prober 

does not render obvious its invention because “Tsien does 

not cite Prober for labeling purines,” but only for labeling 

pyrimidines. Appellant’s Br. 43. However, Tsien 

explicitly invites the PHOSITA to consider Prober in a 

paragraph discussing both purines and pyrimidines. 

Although Tsien asserts “[t]he C-8 position of the purine 

structure presents an ideal position for the attachment of 

a label,” J.A. 3030, it also states: 

While the above-described approaches to labeling 

focus on incorporating the label into the 

3’-hydroxyl blocking group, there are a number of 

alternatives—particularly the formation of a 

3’-blocked dNTP analogue containing a label such 

as a fluorescent group coupled to a remote 

position such as the base. This dNTP can be 

incorporated and the fluorescence measured and 

removed according to the methods described 

below. . . . One method involves the use of a 

fluorescent tag attached to the base moiety. The 

tag may be chemically cleaved. . . . This method is 

included because a number of base moiety 

derivatized dNTP analogues have been reported 

to exhibit enzymatic competence. . . . Prober et al. 

(1987) show enzymatic incorporation of fluorescent 

Case: 14-1547 Document: 61-2 Page: 20 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 21

ddNTPs by reverse transcriptase and 

SequenaseTM. 

J.A. 3028–29 (emphases added). Tsien thus invites use of 

the “method[] described [in Prober]” in combination with a 

“3’-blocked dNTP analogue” and a fluorescent label 

“coupled to a remote position such as the base.” Id. 

Prober’s method includes the use of a fluorescent dye 

“attached . . . to the 7 position in the 7-deazapurines” and 

explains “the 7-deazapurines were used to facilitate stable 

linker attachment at that site.” J.A. 3063. 

A PHOSITA may find reason to combine references to 

achieve a claimed invention even absent an explicit 

mention in one reference of the other. See KSR, 550 U.S. 

at 417 (“[I]f a technique has been used to improve one 

device, and a person of ordinary skill in the art would 

recognize that it would improve similar devices in the 

same way, using the technique is obvious unless its actual 

application is beyond his or her skill.”). Here, the express 

invitation to incorporate a 3’-blocked dNTP having a 

fluorescent base label using the method disclosed in 

Prober provides a motivation to combine Tsien with the 

7-deazapurine of Prober. 

Seela, issued in 1989, also helps to provide a 

motivation by teaching, according to the PTAB, that 

deazapurine nucleotides “can advantageously be used . . . 

in polymerase-based sequencing methods,” such as SBS. 

J.A. 80. In addition, Dr. Weinstock testified that a 

PHOSITA would be motivated to use the 7-deazapurines 

of Prober “to improve similar Tsien systems and 

methods.” J.A. 3181. When asked whether “[t]he use of 

ddNTP that . . . had fluorescent labels attached to the 

7-deazapurine position . . . was common by the year 2000 

[for Sanger sequencing],” Columbia University’s witness, 

Dr. Trainer, conceded that it was. J.A. 4250. Taken 

together, the testimony and references provide 

substantial evidence to support the PTAB’s finding that a 

Case: 14-1547 Document: 61-2 Page: 21 Filed: 07/17/2015
22 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

PHOSITA would combine the two references to achieve 

the claimed invention. 

Columbia University argues the PTAB “never 

identified any affirmative motivation that would have led 

a skilled artisan to abandon the ‘ideal,’ natural C-8 

position taught by Tsien.” Appellant’s Br. (-1550) 44. 

However, Tsien itself specifically references Prober as 

“show[ing] enzymatic incorporation of fluorescent 

ddNTP’s by reverse transcriptase and SequenaseTM,” J.A. 

3029, and Prober discloses attaching a fluorescent label 

via a linker only at the 7-deaza position, J.A. 4335 

(Question: “[Attaching a label to the 7-deaza position is] 

the only way that you [Trainer] disclose in this particular 

article [i.e., Prober]?” Answer: “Yes.”); see also J.A. 3063. 

Although Tsien described the C-8 position as “ideal,” J.A. 

3030, this court has previously explained that “just 

because better alternatives exist in the prior art does not 

mean that an inferior combination is inapt for 

obviousness purposes,” In re Mouttet, 686 F.3d 1322, 1334 

(Fed. Cir. 2012); see also In re Mills, 470 F.2d 649, 651 

(CCPA 1972) (“We find no merit in appellants’ contention 

that the disclosure of propylene is so submerged in 

Cooper, and the teaching of the use of ethylene so 

predominant, that Cooper cannot be said to place foams 

composed of the claimed ingredients in the possession of 

the public. All the disclosures in a reference must be 

evaluated . . . .”). 

Columbia University further argues there was no 

motivation for a PHOSITA to use deazapurines with SBS 

because “the need for ‘stable’ linkers was unique to 

Sanger sequencing, with its harsh conditions” associated 

with electrophoresis. Appellant’s Br. (-1550) 44. 

However, although Prober was concerned only with 

Sanger sequencing, Tsien’s explicit reference to Prober 

combined with the wide use of deazapurines with prior art

sequencing techniques, see J.A. 4335 (use of deazapurines 

was part of a “preferred embodiment” in Prober that was 

Case: 14-1547 Document: 61-2 Page: 22 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 23

“commercialized by Applied Bio-Systems”), 3401 

(deazapurines were “wide[ly] availab[le]” and “widely 

used”), provides substantial evidence supporting the 

PTAB’s finding of motivation to combine, see J.A. (-1550) 

21–24. 

D. Reasonable Expectation of Success

To render a claim obvious, a PHOSITA must have had 

not only a “reason to combine the teaching of the prior art 

references to achieve the claimed invention,” but also “a 

reasonable expectation of success from doing so.” In re 

Cyclobenzaprine Hydrochloride Extended-Release Capsule 

Patent Litig., 676 F.3d 1063, 1069 (Fed. Cir. 2012) 

(internal quotation marks and citation omitted). 

Columbia University challenges the PTAB’s finding that a 

PHOSITA “would have had a reasonable expectation of 

success in combining Tsien with Prober or with Seela to 

synthesize a 3’-OH-capped nucleotide with a label 

attached to a deazapurine base (via a cleavable linker, for 

claim 15).” Appellant’s Br. 45. Specifically, it cites Dr. 

Trainor’s testimony that the chemistry for creating a 

nucleotide analogue with the claimed features was 

complex, and a PHOSITA could not have reasonably 

expected to be successful in devising an appropriate 

chemical procedure. Id. at 45–46; see also J.A. 3827. 

Illumina responds “that every step of the synthetic 

process would have been understood to be within the level 

of ordinary skill [in the art],” and that Dr. Trainer 

conceded this to be the case. Appellee’s Br. 39. It cites 

the testimony of Dr. Trainer in which he admits to be 

within the PHOSITA’s skill level: the use of “a starting 

deazaguanine with a 7-iodide for linker attachment;” 

“attaching a cleavable alkynylamino linker to the 7-iodo 

position;” and “attaching a fluorescent label to the 

alkynylamino linker.” Id. at 39–40. Tsien references 

Prober as disclosing a method that would be applicable to 

the synthesis of both ddNTPs and dNTPs. J.A. 3029–30. 

Case: 14-1547 Document: 61-2 Page: 23 Filed: 07/17/2015
24 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

Most significantly, the ’869 patent explains a “7 deazaalkynylamino-dGTP[6] is prepared using well-established

procedures,” and does not provide additional guidance 

with respect to chemical procedures. ’869 patent col. 23 ll. 

37–38 (emphasis added). Taken together, these 

disclosures constitute substantial evidence supporting the 

PTAB’s finding that a PHOSITA would have had a 

reasonable expectation of success in achieving the claimed 

invention. 

III. Secondary Considerations Do Not Weigh Strongly in 

Favor of Nonobviousness

Both parties present arguments with respect to 

secondary considerations. Illumina argues simultaneous 

invention supports its position that the claimed invention 

was obvious. Columbia University asserts copying, 

attempted licensing, commercial success, and unexpected 

results support the nonobviousness of the claimed 

invention. 

A. Simultaneous Invention Weighs Modestly in Favor of 

Obviousness

“Independently made, simultaneous inventions, made 

within a comparatively short space of time, are persuasive 

evidence that the claimed apparatus was the product only 

of ordinary mechanical or engineering skill.” George M. 

Martin Co. v. Alliance Mach. Sys. Int’l LLC, 618 F.3d 

1294, 1305 (Fed. Cir. 2010) (internal quotation marks and 

citation omitted). Illumina asserts two entities, Solexa 

and Amersham, each separately conceived of an SBS 

approach as early as December 2001, i.e., before Dr. Ju’s 

patent applications were published, containing the novel 

features of Dr. Ju’s patent claims.” Appellee’s Br. 47. 

6 The notation “dGTP” refers to a 

deoxyribonucleoside triphosphate in which guanine is the 

base. 

 

Case: 14-1547 Document: 61-2 Page: 24 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 25

Columbia University first responds that the activities 

of Solexa and Amersham “are not prior art.” Reply Br. 6. 

This response reflects confusion over the difference 

between simultaneous invention on the one hand and 

anticipation and obviousness on the other. If 

simultaneous invention were only relevant where the 

object of the simultaneous invention constituted prior art, 

it would be analyzed under 35 U.S.C. § 102 and as part of 

the second Graham factor (i.e., as part of a determination 

of the “differences between the prior art and the claims at 

issue”) under 35 U.S.C. § 103. Graham, 383 U.S. at 17. 

As a secondary consideration, however—which falls under 

the fourth Graham factor—simultaneous invention is 

relevant when it occurs within a short space of time from 

the date of invention, and “is strong evidence of what 

constitutes the level of ordinary skill in the art.” 

Ecolochem v. S. Cal. Edison Co., 227 F.3d 1361, 1379 

(Fed. Cir. 2000). Unlike the ultimate determination of 

obviousness, which requires courts to answer the 

hypothetical question of whether an invention “would 

have been obvious,” 35 U.S.C. § 103, simultaneous 

invention demonstrates what others in the field actually 

accomplished. 

The tendency of simultaneous invention to weigh in 

favor of obviousness would, of course, be negated if the 

purported simultaneous invention was not made 

independently of the claimed invention. Perhaps with 

this in mind, Columbia University asserts the Solexa 

patent was filed “months after features of Dr. Ju’s SBS 

method were disclosed in a public National Science 

Foundation Grant Announcement.” Reply Br. 6–7. 

However, Columbia University asserts that at the time of 

Solexa’s disclosure, “Solexa . . . thought that a nucleotide 

with the requisite combination of features was 

patentable.” Id. It makes a similar assertion with respect 

to Amersham. Id. In so asserting, Columbia University 

undermines its own argument: If Solexa and Amersham 

Case: 14-1547 Document: 61-2 Page: 25 Filed: 07/17/2015
26 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

had copied their purported simultaneous inventions from 

the grant announcement, they would have had no basis to 

believe their simultaneous inventions were patentable.

Columbia University also argues Amersham’s 

activities did not constitute simultaneous invention 

because the chemical configuration it described was 

“useless as a chain terminator.” Reply Br. 7. It points out 

that Illumina did not present its simultaneous invention 

argument to the PTAB. Because the record is not fully 

developed, the evidence of simultaneous invention as a 

whole weighs only modestly in favor of obviousness. 

B. Copying Does Not Favor Nonobviousness

Columbia University asserts “Manteia, a company 

whose intellectual property was later acquired by 

Illumina’s predecessor-in-interest Solexa, copied Dr. Ju’s 

invention” as reflected in a 2003 presentation. 

Appellant’s Br. 12. The 2003 presentation cites Dr. Ju’s 

publication. See J.A. 3894. Illumina responds that the 

asserted copying is irrelevant because the only elements 

shown to be copied were disclosed in Tsien, Dower, and 

Stemple, and that the presentation does not disclose a 

deazapurine and therefore does not reflect copying of the 

claimed invention. Appellee’s Br. 57. 

Illumina further responds that Solexa did not copy 

Dr. Ju’s invention, citing a December 2001 patent 

application filed by Solexa that discloses “a base that is 

linked to a detectable label via a cleavable linker,” and a 

removable “protecting group” at the 3’ position that “is 

intended to prevent nucleotide incorporation.” J.A. 3750, 

3755; see also Appellee’s Br. 11–14, 58. The PTAB 

considered Columbia University’s evidence of copying and 

did not find it persuasive. J.A. 29. Because the record is 

inconclusive as to whether any party in fact copied Dr. 

Ju’s invention, because the PTAB did not make an explicit 

factual finding in this regard, and because it is unclear 

whether the asserted actions represent copying or 

Case: 14-1547 Document: 61-2 Page: 26 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 27

independent invention, the asserted copying does not 

weigh in favor of nonobviousness. 

C. Attempted Licensing Weighs Modestly in Favor of 

Nonobviousness 

Columbia University cites several emails from 

Illumina showing an interest in “collaborating with Dr. Ju 

from Columbia University on his reversible terminators,” 

and stating “Professor Jingyue Ju purportedly has solved 

the reversible terminator cleavable dye label issue.” J.A. 

3993–95. Although these emails demonstrate an interest 

in Dr. Ju’s work, none of the emails mentions the ’698, 

’575, or ’869 patents or clearly indicates the subject 

matter sought to be licensed fell within the claims of those 

patents. In re GPAC, 57 F.3d 1573, 1580 (Fed. Cir. 1995) 

(“Because, in affidavits reciting the licensing history of 

the ’111 patent, GPAC did not establish which claim(s) of 

the patent the licensing program incorporates, GPAC has 

not shown that licensing . . . arose out of recognition and 

acceptance of the subject matter claimed in the ’111 

patent.”). This factor therefore provides only modest 

evidence of nonobviousness. 

D. Commercial Success Does Not Favor Nonobviousness

Commercial success of a product embodying an 

invention tends to show nonobviousness when “the 

commercial success . . . results from the claimed 

invention” and is “due to the merits of the claimed 

invention beyond what was readily available in the prior 

art.” J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 

1563, 1571 (Fed. Cir. 1997). “When a patentee can 

demonstrate commercial success, usually shown by 

significant sales in a relevant market, and that the 

successful product is the invention disclosed and claimed 

in the patent, it is presumed that the commercial success 

is due to the patented invention.” Id. 

Case: 14-1547 Document: 61-2 Page: 27 Filed: 07/17/2015
28 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

Columbia University asserts Illumina’s sales were 

significant and embody the claims of the ’698, ’869, and 

’575 patents. Appellant’s Br. 59 (citing J.A. 3879–85); 

Appellant’s Br. (-1548) 57; Appellant’s Br. (-1550) 57. 

Illumina responds that “the very features proclaimed by 

Columbia [University] to be the reason for Illumina’s 

commercial success (attachment of the label to the base 

via a cleavable linker) were already known in Tsien, 

Dower, and Stemple,” and that Columbia University did 

not assert the deazapurine contributed to commercial 

success. Appellee’s Br. 54. 

Commercial success does not favor nonobviousness. 

“[I]f the feature that creates the commercial success was 

known in the prior art, the success is not pertinent.” 

Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1312 

(Fed. Cir. 2006). Here, each of the features claimed to be 

responsible for the commercial success of the invention 

was disclosed in a single prior art reference, Tsien. 

In addition, Columbia University does not itself sell 

its patented invention. Although reliance on a 

defendant’s or third party’s sale of a patented invention to 

demonstrate commercial success may be probative of 

nonobviousness in some cases, it is not particularly 

helpful in the present matter because it is unclear 

whether any success was attributable to developments in 

the field that led to simultaneous invention (which would 

tend to show the invention was obvious) or to copying 

(which would tend to show the invention was nonobvious). 

E. Unexpected Results Do Not Favor Nonobviousness

Evidence of “some superior property or advantage 

that a person of ordinary skill in the relevant art would 

have found surprising or unexpected” tends to indicate 

nonobviousness. In re Soni, 54 F.3d 746, 750 (Fed. Cir. 

1995). Columbia University asserts, as evidence of 

unexpected results, Dr. Trainor’s testimony that the 

claimed nucleotides are unexpectedly better than 

Case: 14-1547 Document: 61-2 Page: 28 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 29

pyrosequencing. Appellant’s Br. 53; see also J.A. 30. 

According to the ’698 patent, pyrosequencing is a “widely 

used” process that “employs four natural nucleotides . . . 

for sequencing DNA by synthesis” and “is based on the 

pyrophosphate (PPi) released during the DNA polymerase 

reaction, the quantitative conversion of pyrophosphate to 

adenosine triphosphate (ATP) by sulfurylase, and the 

subsequent production of visible light by firefly 

luciferase.” ’698 patent col. 2 ll. 19–28. 

Unexpected results “‘must be shown to be unexpected 

compared with the closest prior art.’” Kao Corp. v. 

Unilever U.S., Inc., 441 F.3d 963, 970 (Fed. Cir. 2006) 

(quoting In re Baxter Travenol Labs., 952 F.2d 388, 392 

(Fed. Cir. 1991)). The PTAB found pyrosequencing was 

not the closest prior art. Columbia University argues 

pyrosequencing was the closest prior art because it was 

“the only commercial embodiment of SBS at the time of 

Dr. Ju’s invention.” Appellant’s Br. 63. However, there is 

no requirement that the closest prior art be 

commercialized. See In re Merchant, 575 F.2d 865, 869 

(CCPA 1978) (“In In re Wright . . . , failure of a particular 

reference to constitute the commercial standard did not 

diminish its position as the closest prior art.”) (internal 

quotation marks and citation omitted); see also In re 

Chupp, 816 F.2d 643, 644 (Fed. Cir. 1987) (“To rebut the 

prima facie case of obviousness, Chupp submitted a 

declaration discussing the results of tests comparing the 

herbicidal activity of the claimed compound with that of 

the closest prior art compounds and with two commercial 

herbicides . . . . It is undisputed that the claimed 

compound gave superior results . . . .”) (emphases added). 

Evidence of unexpected results in comparison to 

pyrosequencing is therefore not probative of 

nonobviousness. 

Case: 14-1547 Document: 61-2 Page: 29 Filed: 07/17/2015
30 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

IV. The PTAB Did Not Err in Determining Certain 

Challenged Claims Were Anticipated

“Anticipation is a question of fact that we review for 

clear error . . . .” Forest Labs., Inc. v. Ivax Pharm., Inc., 

501 F.3d 1263, 1268 (Fed. Cir. 2007). In Appeal 2014-

1548, Columbia University argues the PTAB erred in 

rejecting claims 12, 13, 17, 20–26, 28, 29, 31, and 33 as 

anticipated because “the references are non-enabling” and 

do not “‘disclose all elements of the claim within the four 

corners of the document . . . arranged as in the claim.’” 

Appellant’s Br. (-1548) 64 (quoting Net MoneyIN, Inc. v. 

VeriSign, Inc., 545 F.3d 1359, 1369 (Fed. Cir. 2008)). 

(Columbia University makes a similar argument with 

respect to claims 1–3 of the ’575 patent. See Appellant’s 

Br. (-1550) 64.) Specifically, it identifies as elements 

common to the listed claims, “a [1] 3’-OH-capped 

nucleotide, [2] base-label, and [3] cleavable linker.” 

Appellant’s Br. (-1548) 64. Tsien explains an approach in 

which: 

a [1] 3’-blocked dNTP analogue containing a [2] 

label such as a fluorescent group [is] coupled to a 

remote position such as the base. This dNTP can 

be incorporated . . . according to the methods 

described below.

One method involves the use of a fluorescent tag

attached to the base moiety. . . . 

In another type of remote labeling the . . . label 

can be attached to the dNTP through a spacer or 

tether. The [3] tether can be cleavable if 

desired . . . . 

J.A. 3028–29 (emphases added). 

It is true Tsien provides that elements 1 and 2 may be 

combined with either a label that is directly attached to 

the base or one that is attached via a cleavable or nonCase: 14-1547 Document: 61-2 Page: 30 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 31

cleavable tether. However, “when a genus is so limited 

that a person of ordinary skill in the art can at once 

envisage each member of this limited class, . . . a 

reference describing the genus anticipates every species 

within the genus.” Abbvie Inc. v. Mathilda & Terrence 

Kennedy Inst. of Rheumatology Trust, 764 F.3d 1366, 1379 

(Fed. Cir. 2014) (internal quotation marks and citation 

omitted). This court agrees with the PTAB that an 

embodiment comprising a 3’-OH-capped nucleotide, baselabel, and cleavable linker could be “envisaged clearly by 

one of ordinary skill in the art upon reading the Tsien 

disclosure.” J.A. (-1548) 10.

Columbia University also argues Tsien does not 

“enable[] a skilled artisan to make a base-labeled, 

3’-OH-capped nucleotide without undue experimentation,” 

because “[t]he references do not teach the necessary 

synthetic chemistry.” Appellant’s Br. (-1548) 64–65. In 

Appeal 2014-1550, Columbia University similarly argues 

“Tsien does not enable a skilled artisan to make a baselabeled, 3’-OH-capped nucleotide [as claimed in claims 1–

3 of the ’575 patent] without undue experimentation.” 

Appellant’s Br. (-1550) 67. However, as already 

explained, if novel and nonobvious chemistry was needed 

to practice the claimed inventions, Dr. Ju would have 

been obligated to disclose this chemistry in the patent. 

See 35 U.S.C. § 112(1) (2000).7

The PTAB’s denial of a procedural motion is reviewed 

for abuse of discretion. See Bilstad v. Wakalopulos, 386 F. 

3d 1116, 1121 (Fed. Cir. 2004). The PTAB abuses its 

discretion when its decision: “(1) is clearly unreasonable, 

7 Section 112 has since been amended. See AIA 

§ 4(c), 125 Stat. at 296. However, because the 

applications that led to the ’698, ’869, and ’575 patents 

were filed before Sept. 16, 2012, the pre-AIA § 112

applies. See AIA § 4(e), 125 Stat. at 297. 

 

Case: 14-1547 Document: 61-2 Page: 31 Filed: 07/17/2015
32 TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

arbitrary, or fanciful; (2) is based on an erroneous 

conclusion of law; (3) rests on clearly erroneous fact 

finding; or (4) involves a record that contains no evidence 

on which the [PTAB] could rationally base its decision.” 

Id. 

In Appeal 2014-1548, Columbia University argues the 

PTAB’s denial of its motion to amend its claims was 

erroneous, and that the error was not harmless: 

Columbia’s amendments would have rewritten 

claim 15 in independent form and added the 

deazapurine limitation to the other challenged 

claims. . . . 

The [PTAB’s] failure to enter Columbia’s 

amendment led it to address the critical dispute 

over the scope of Tsien’s and Stemple’s disclosures 

first in the context of anticipation, where the 

issues were (in the [PTAB’s] mistaken view) 

uncontested. When the [PTAB] turned to the 

obviousness of claims 15 and 16, it had already 

decided that Tsien and Stemple disclosed a 

nucleotide with a 3’-OH cap and a label attached 

to the base by a cleavable linker, and it asked 

whether adding a deazapurine was obvious.

Appellant’s Br. (-1548) 62–63. Columbia University 

makes a similar argument with respect to claims 1–3 of 

the ’575 patent. See Appellant’s Br. (-1550) 60–63. 

Because the PTAB did not clearly err in its determination 

of what Tsien teaches, Columbia University’s argument 

based on its contrary assertion does not establish 

patentability over the prior art, and is therefore rejected. 

See Microsoft Corp. v. Proxyconn, Inc., No. 2014-1542, 

2015 WL 3747257, at *13 (Fed. Cir. June 16, 2015) 

(explaining that motions to amend may properly be 

denied where the patentee has failed to establish 

patentability over the prior art of record). 

Case: 14-1547 Document: 61-2 Page: 32 Filed: 07/17/2015
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC. 33

CONCLUSION

For these reasons, the decisions of the PTAB are 

AFFIRMED

Case: 14-1547 Document: 61-2 Page: 33 Filed: 07/17/2015