Chen, Lin et al.

Patent Trials and Appeals Board

Mar 19, 2020

12782616 - (D) (P.T.A.B. Mar. 19, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/782,616 05/18/2010 Lin Chen 374634-000077 5004
73230 7590 03/19/2020
DLA Piper LLP (US)
550 South Hope Street
Suite 2300
Los Angeles, CA 90071-2678
EXAMINER
POHNERT, STEVEN C
ART UNIT PAPER NUMBER
1634
NOTIFICATION DATE DELIVERY MODE
03/19/2020 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
GTDocket@dlapiper.com
joshua.gibbs@dlapiper.com
laccprosecution@dlapiper.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte LIN CHEN and REZA KALHOR
____________

Appeal 2019-003807
Application 12/782,616
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, DEBORAH KATZ, and JOHN G. NEW,
Administrative Patent Judges.

KATZ, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 seeks our review,2 under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 1, 2, 5–18, 21, 22, 24–26, 28, 37, and
41–43.3 (Appeal Brief filed date (“Appeal Br.”) 6.)
We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as the
University of Southern California. (See Appeal Br. 4.)
2 We consider the Non-Final Office Action issued January 19, 2018 (“Non-
Final Act.”), the Appeal Brief filed December 21, 2018 (“Appeal Br.”), the
Examiner’s Answer issued on February 19, 2019 (“Ans.”), and the Reply
Brief filed April 17, 2019 (“Reply Br.”).
3 Claims 39–36 and 44–51 were withdrawn; claims 3, 4, 19, 20, 23, 27, and
38–40 were cancelled. (Appeal Br. 6.)
Appeal 2019-003807
Application 12/782,616

2
INTRODUCTION
Appellant’s Specification provides a method for determining the
three-dimensional structure of chromatin in eukaryotic cells. (Specification
dated May 18, 2010 (“Spec.”) ¶ 2.) The Specification describes known
chromosome conformation capture (3C) techniques. (Spec. ¶¶ 5–7.) These
methods include crosslinking chromatin complexes to maintain existing
structural relationships, then ligating DNA loci to identify spatial proximity.
(Id.) Ligation frequency between DNA loci reveals the spatial arrangement
of chromatin at a molecular level. (Id.)
The Specification states that prior techniques use low concentrations
of crosslinked chromatin complexes in dilute solutions to minimize
intermolecular ligation. (Id. ¶ 7.) In contrast, the Specification states that
the described process promotes intramolecular ligation by immobilizing the
crosslinked chromatin complexes. (Id. ¶ 12.)
Appellant’s claim 1 recites:
A method of determining structural organization of
chromatin, comprising:
cross-linking DNAs of the chromatin with
proteins;
cutting the DNAs of the chromatin with restriction
enzymes to form cross-linked protein:DNA complexes
comprising DNAs with 5ʹ-overhangs;
tethering the cross-linked protein:DNA complexes
to at least one support;
blunting the 5 ʹ-overhangs of the tethered
protein:DNA complexes with a biotinylated nucleotide to
produce blunt DNA ends;
ligating the blunt DNA ends on the same cross-
linked protein:DNA complexes while the complexes are
still tethered to the support medium; and
Appeal 2019-003807
Application 12/782,616

3
characterizing the DNA of the protein:DNA
complexes to identify structural organization of the
chromatin.

(Appeal Br. 45.)
The Examiner rejects the claims as follows:
Claims
Rejected
35 U.S.C. § References/Basis Non-Final
Office Action
1, 2, 5–18, 21,
22, 24–26, 28,
37, 41–43
112, second
paragraph
Indefiniteness 3–5
41–43 112, second
paragraph
Indefiniteness 5
1, 2, 5–18, 21,
22, 24–26, 28,
37, 41–43
103(a) Cai,4 Dekker,5 Lee,6
Wartiovaara7
6–17
8–10, 13, 14 103(a) Cai, Dekker, Lee,
Wartiovaara,
Morrison,8 Shiio9
17–18
11, 12, 15–17 103(a) Cai, Dekker, Lee,
Wartiovaara,
18–20

4 Cai, S. et al., SATB1 packages densely looped, transcriptionally active
chromatin for coordinated expression of cytokine genes, 38 NATURE
GENETICS 1278–1288 (2006).
5 Dekker et al., WO 2008/024473 A2, published February 28, 2008.
6 Lee, T. I. et al., Chromatin immunoprecipitation and microarray-based
analysis of protein location, 1 NATURE PROTOCOLS 729–748 (2006).
7 Wartiovaara et al., US 2007/0277251 A1, published November 29, 2007.
8 Morrison, A. J. et al., Retinoblastoma Protein Transcriptional Repression
through Histone Deacetylation of a Single Nucleosome, 22 MOLECULAR
CELLULAR BIO. 856–865 (2002).
9 Shiio, Y. and Aebersold, R., Quantitative proteome analysis using isotope-
coded affinity tags and mass spectrometry, 1 NATURE PROTOCOLS 139–145
(2006).
Appeal 2019-003807
Application 12/782,616

4
Claims
Rejected
35 U.S.C. § References/Basis Non-Final
Office Action
Morrison, Shiio,
Blander,10 Fujita11
1, 2, 5–7, 18,
21, 22, 24–26,
28, 37, 38, 40,
41
103(a) Cai, Dekker, Lee,
Wartiovaara,
Morrison, GE
Healthcare12
20–31
8–17 103(a) Cai, Dekker, Lee,
Wartiovaara,
Morrison, GE
Healthcare, Blander,
Fujita
31–33

ANALYSIS
35 U.S.C. § 112, second paragraph — Indefiniteness
The Examiner rejects claim 1 as indefinite for reciting “characterizing
the DNA of the protein:DNA complexes to identify structural organization
of the chromatin.” (Non-Final Act. 4.) The Examiner finds the
Specification does not teach a limiting definition of “characterizing.” (Id.)
The Examiner concludes that Appellant had “the opportunity to limit the
claims to sequencing, but wants the breadth of ‘characterizing’ without a
clear written indication of what is required and how it relates to chromatin
structure.” (Ans. 31–32.)

10 Blander, G. et al., SIRT1 Shows No Substrate Specificity in Vitro, 280 J.
BIO. CHEM. 9780–9785 (2005).
11 Fujita et al., EP 1967582 A1, published September 10, 2008.
12 GE Healthcare, Instructions 71-7106-00 AF Affinity Media, Activated
Thiol Sepharose 4B, Sepharose™ (2008).
Appeal 2019-003807
Application 12/782,616

5
Appellant argues that the plain meaning of the claim terms, read in
view of the Specification, would be readily understood by one of skill in the
art. (Appeal Br. 15.) Appellant argues that the Specification defines
characterizing as by “sequencing or other methods suitable to identify
structural organization of the chromatin.” (Id. at 14, citing Spec. ¶¶ 14, 29.)
We are persuaded by Appellant’s argument. “A claim is indefinite if,
when read in light of the specification, it does not reasonably apprise those
skilled in the art of the scope of the invention.” Amgen, Inc. v. Hoechst
Marion Roussel, Inc., 314 F.3d 1313, 1342 (Fed. Cir. 2003). The
Specification discloses that ligation frequency of DNAs in protein:DNA
complexes, i.e., intramolecular ligation, indicates structural organization of
chromatin. (Spec. ¶ 7.) The Specification states that ligation frequency can
be measured by various techniques. (Id.) These techniques include
sequencing or other methods. (See id. ¶¶ 14, 30, 55, 59.)
We agree with the Examiner that the claim is broader than the specific
sequencing techniques disclosed in the Specification. However, “breadth is
not to be equated with indefiniteness.” In re Miller, 441 F.2d 689, 693
(CCPA 1971). Because the claim, read in light of the specification,
reasonably apprises a person of ordinary skill in the art of the step of
“characterizing . . . to identify structural organization of the chromatin,” we
reverse the Examiner’s rejection of claim 1 as indefinite. The rejection of
the dependent claims falls with claim 1.
The Examiner also rejects claim 41 as indefinite. (Non-Final Act. 5.)
The Examiner determines that the claim and Specification do not provide a
standard for ascertaining the requisite degree of separation distance between
a majority of individual protein:DNA complexes. (Id.)
Appeal 2019-003807
Application 12/782,616

6
Appellant argues the claim recites relative terminology defining a
distance in which a majority of protein:DNA complexes are less likely to
form intermolecular ligation events. (Appeal Br. 20–21, citing Spec. ¶¶ 42–
43.) Appellant contends a number of approaches may be used to determine
the claimed distance. (Id. at 21.) For example, one of skill in the art could
predict fragment length based on the particular restriction enzyme and
incubation conditions. (Id.; see also Spec. ¶¶ 98–101.) Likewise, the
distance between tethered protein:DNA complexes can be determined by
using a support with a well-defined surface area. (Id.; see also Spec. ¶ 43.)
Appellant argues that a person of ordinary skill in the art could determine the
distance by “calculating the length of fragments generated by a particular
restriction enzyme, the concentration of protein:DNA complexes, and the
surface area of the supports used in the method.” (Id.)
We are persuaded by Appellant’s argument. The definiteness
requirement is not a demand for unreasonable precision, but rather invokes
some standard of reasonable precision in the use of language in the context
of the circumstances. In re Packard, 751 F.3d 1307, 1313 (Fed. Cir. 2014).
Appellant’s claim, read in light of the Specification, provides reasonable
precision for defining a distance between protein:DNA complexes.
Accordingly, we reverse the Examiner’s rejection of claim 41 as indefinite.
The rejections of dependent claims 42 and 43 fall with claim 41.

35 U.S.C. § 103(a)
Claims 1, 2, 5–18, 21, 22, 24–26, 28 and 37
The Examiner finds Cai teaches using two existing assays, 3C and
chromatin immunoprecipitation (ChIP)-loop assay, to determine the
Appeal 2019-003807
Application 12/782,616

7
structural organization of chromatin. (Non-Final Act. 7.) The ChIP assay
includes the steps of (1) cross-linking DNAs of chromatin with proteins; (2)
cutting the DNAs of chromatin with restriction enzymes; (3) tethering cross-
linked protein:DNA complexes to at least one support (Sepharose beads); (4)
ligating DNA ends on the same cross-linked protein:DNA complexes while
the complexes are still tethered to the support; and (5) characterizing the
DNA to identify structural organization of chromatin. (Id. at 10–11.)
The Examiner finds further that Lee teaches a method of using the
ChIP assay including the steps of blunting the 5ʹ-overhangs of the tethered
protein:DNA complexes and ligating the blunt DNA ends. (Id. at 16.) In
addition, the Examiner finds Dekker teaches high-throughput sequencing for
identifying and quantifying the structural organization of chromatin. (Id. at
13–15.)
The Examiner acknowledges that Cai and Dekker do not teach
blunting with biotinylated nucleotides. (Id. at 15.) But, because
Wartiovaara teaches using biotin-modified nucleotides as polynucelotide
labels, the Examiner determines that one of ordinary skill in the art would
have been motivated to blunt the sticky ends of the DNAs with a
biotinylated nucleotide. (Id. at 16.) The Examiner also determines that
using biotinylated nucleotides to blunt the 5ʹ-overhangs would have been a
mere substitution of one nucleotide for another known in the field. (Id.)
Accordingly, the Examiner concludes claim 1 would have been prima facie
obvious over the prior art.
Appellant argues the Examiner failed to provide a “clear articulation
of the reasons(s) why the claimed invention would have been obvious.”
(Appeal Br. 36, citing MPEP § 2143.) Particularly, Appellant objects to the
Appeal 2019-003807
Application 12/782,616

8
Examiner’s use of block quotes, for example, arguing that the Examiner
does not show where Cai teaches the step of tethering. (Id. at 37–38.)
We are not persuaded by Appellant’s argument. Appellant’s own
citation to the Examiner’s rejection includes the Examiner’s description of
Cai’s teaching that “[t]he use of the protein A sepharose is a method of
tethering.” (Appeal Br. 38.) The Examiner has positively included the
references in the statement of the rejection, In re Hoch, 428 F.2d 1341, 1342
n.3 (CCPA 1970), and has articulated “an apparent reason to combine the
known elements in the fashion claimed by the patent at issue.” KSR Int'l Co.
v. Teleflex Inc., 550 U.S. 398, 418 (2007). Accordingly, we find that the
Examiner has adequately explained the perceived shortcomings of the claims
so that Appellant is properly notified and able to respond. In re Jung, 637
F.3d 1356, 1362 (Fed. Cir. 2011).
Appellant argues generally that combining Cai with the other
references cited by the Examiner would render Cai unsuitable for its
intended purpose.13 (Reply Br. 7.) More specifically, Appellant argues that
Cai’s intended purpose is the targeted analysis of an individual protein,
SATB1, on chromatin structure in response to a stimulus. (Appeal Br. 29.)
Thus, Cai specifically analyzes a single chromatin constituent with an
antibody and locus-specific PCR. (Id. at 30–32.) In contrast, Appellant

13 Appellant repeatedly emphasizes the number of references cited by the
Examiner. (See Reply Br. 6–7.) The Examiner’s citation of up to nine
references does not weigh against a holding of obviousness as “[t]he
criterion . . . is not the number of references, but what they would have
meant to a person of ordinary skill in the field of the invention. In re
Gorman, 933 F.2d 982, 986 (Fed. Cir. 1991)
Appeal 2019-003807
Application 12/782,616

9
argues that combining Cai with Dekker, Wartiovaara, and Lee would negate
the specificity of the process taught in Cai. (See id. at 30–35.)
For example, Appellant contends that Dekker relates to a high-
throughput analysis of the genome, in which information regarding the effect
of SATB1 would be lost. (Id. at 30.) Appellant contends that “Wartiovaara
teaches methods for amplifying or hybridizing the biotinylated DNA that are
independent of any proteins bound to the DNA.” (Id. at 34.) Because
Wartiovaara’s isolation by biotin is not sequence-specific, Appellant
contends that isolation by biotin adds unnecessary complexity and reduces
the specificity of Cai’s process. (Id. at 35.) Appellant contends that Lee’s
blunting of nucleic acid fragments by adding universal primer binding sites
dilutes Cai’s desired signal in noise from the rest of the genome. (Id. at 36.)
Accordingly, Appellant argues “the combination of Lee with Cai renders Cai
unsuitable for its intended purpose of specific examination of particular
fragments of a specific locus differentially bound by SATB1.” (Id.)
We are not persuaded by Appellant’s argument. We begin with
Appellant’s argument limiting Cai’s teachings to determining the structural
organization of chromatin only as it relates to SATB1. When determining
obviousness, “the prior art as a whole must be considered. The teachings are
to be viewed as they would have been viewed by one of ordinary skill.” In
re Hedges, 783 F.2d 1038, 1041 (Fed. Cir. 1986).
Cai teaches that, at the time of the invention, there were at least two
different known assays, 3C and ChIP, for examining chromatin structure.
(See Ans. 38–39.) Both Cai and Lee teach using the ChIP assay for
determining the structural organization of chromatin. (See above.) The
combined references teach that the ChIP assay may provide information
Appeal 2019-003807
Application 12/782,616

10
about site-specific chromatin structure (Cai), as well as “a whole-genome
view of protein-DNA interactions when combined with DNA microarray
analysis.” (Lee 729.) Nothing in the prior art teaches that the proposed
modification of Cai with Lee would result in an inoperable ChIP assay. See
In re Urbanski, 809 F.3d 1237, 1244 (Fed. Cir. 2016). Therefore, we find
that one of ordinary skill in the art would have been motivated to pursue the
desirable genome-wide properties taught by Lee, even if that meant
foregoing the specificity taught by Cai. See id.; see also Medichem S.A. v.
Rolabo S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (“The fact that the
motivating benefit comes at the expense of another benefit, however, should
not nullify its use as a basis to modify the disclosure of one reference with
the teachings of another. Instead, the benefits, both lost and gained, should
be weighed against one another.”)
Likewise, a person of ordinary skill in the art would have been
motivated to apply Dekker’s genome-wide analysis to the genome-wide
ChIP assay taught by Cai and Lee. As for substituting Lee’s “universal PCR
priming sites” (Appeal Br. 35–36) with Wartiovaara’s non-specific
biotinylated primers (id. at 34), we find that a person of ordinary skill in the
art would have made the substitution of known nucleotides given the desire
for a non-specific, genome-wide assay. Accordingly, we agree with the
Examiner that it would have been obvious to a person of ordinary skill in the
art to combine the ChIP assay of Cai with the teachings of Dekker, Lee, and
Wartiovaara, and we sustain the rejection of claim 1.
Appellant applies the same argument against the combination of Cai
and the additional references cited by the Examiner as to claims 2, 5–18, 21,
Appeal 2019-003807
Application 12/782,616

11
22, 24–26, 28, and 37. (See Appeal Br. 39–43.) For the reasons set forth
above, we sustain the Examiner’s rejection of these claims.

Claims 41–43
The Examiner rejects claim 41 as obvious over Cai, Dekker, Lee,
Wartiovaara, and Morrison as evidenced by GE Healthcare. (Final Act. 20.)
Claim 41 recites:
The method of claim 1, wherein the crosslinked protein:DNA
complexes are tethered such that a majority of the individual
protein:DNA complexes are separated from each other by a distance
greater than about twice the greatest length from a 5'-overhang on a
DNA of the chromatin to the nearest site of the crosslinking event on
the DNA.

(Appeal Br. 49.)
The Examiner finds Morrison teaches non-antibody based alternatives
to ChIP assays, as well using various beads for these assays. (Final Act.
28–29.) The Examiner cites GE Healthcare as teaching activated thiol
Sepharose allows for covalent tethering. (Id. at 29.)
Appellant contends the Examiner does not point to any teaching of the
elements in claims 41–43. (Appeal Br. 24–25.) Appellant argues that
claims 41 recite active steps rather than mere intended results because they
recite “observable, structural characteristics of practicing the claimed
method.” (Id. at 25–26.) As such, Appellant argues that the wherein clause
of claim 41 is relevant to patentability and must be found in the art before
the method of claim 41 is determined to be obvious. (See id.)
We are not persuaded by Appellant’s argument because even when
the wherein clause of claim 41 is given weight, the claimed method would
Appeal 2019-003807
Application 12/782,616

12
have been obvious. We begin with interpreting the claims. As discussed
above, we agree with Appellant that claims 41–43 are not indefinite. Rather,
claim 41 recites a distance between individual protein:DNA complexes that
could be readily determined by a person of ordinary skill in the art. (See
above.) The distance results from the choice of restriction enzyme,
concentration of complexes, and surface area of the substrate used in the
method. (Id.)
Because the distance depends on the restriction enzyme and substrate,
we review the Specification’s description of each feature. The Specification
lists suitable restriction enzymes, including: MboI, which recognizes the
sequence 5ʹ-GATC, HindIII which recognizes the sequence 5ʹ-AAGCTT,
and BsrGI, which recognizes 5ʹ-TGTACA. (Spec. ¶ 38.) The Specification
teaches MboI is expected to produce fragments of 401 bp average size and
HindIII is expected to produce fragments of 3461 bp average size. (Id.
¶ 99.) The Specification describes the substrate as “media, such as beads,
colloids, and matrices with a well-defined surface area.” (Id. ¶ 43.) The
Specification does not describe the appropriate surface area, however, lists
DynaBeads MyOne Streptavidin T1 Magnetic Beads as suitable beads for
the process. (Id. ¶ 48.)
The Examiner cites prior art teaching surface-immobilized
conformation capture assays using the same or similar restriction enzymes
and supports. For example, Cai teaches performing a ChIP assay by
digesting chromatin with Sau3AI and tethering to Sepharose 4B beads.
(Non-Final Act. 10.) Lee teaches performing a ChIP assay with DNA
fragments ranging from 200–600 bp and tethering to Dynabeads. (Lee 732,
Appeal 2019-003807
Application 12/782,616

13
745.) Morrison teaches performing a ChIP assay with protein A/G-agarose
beads or activated thiol-Sepharose 4B beads. (Morrison 857.)
In sum, the Examiner finds that the combined prior art teaches the
claimed process using similar components that would have been expected to
give the same results. (Ans. 45.) “Where . . . the claimed and prior art
products are identical or substantially identical . . . the PTO can require an
applicant to prove that the prior art products do not necessarily or inherently
possess the characteristics of his claimed product. . . . [The] fairness [of the
burden-shifting] is evidenced by the PTO’s inability to manufacture products
or to obtain and compare prior art products.” In re Best, 562 F.2d 1252,
1255 (CCPA 1977). Because Appellant fails to direct us to evidence that the
actual distances would be different, we sustain the Examiner’s rejection of
claim 41 over the combined prior art.
Claims 42 and 43 expressly recite the purpose and intended result of
the claimed method, i.e., that intramolecular ligation is more frequent than
intermolecular ligation (less than 36% of total ligation). (Appeal Br. 49–50.)
The Specification discloses that the resulting intramolecular ligation occurs
by using the claimed surface-immobilized conformation capture assay as
opposed to a solution-based assay (e.g., HiC). (Spec. ¶¶ 95–101, Examples
3 and 4.) Appellant provides no evidence that more frequent intramolecular
ligation, as compared to intermolecular ligation, results from variations
within the surface-immobilized assay itself. Therefore, the recitations of
claims 42 and 43 do not result in a manipulative difference in the steps of the
claim. See Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc., 246
F.3d 1368, 1375–1376 (Fed. Cir. 2018). Accordingly, we are not persuaded
that claims would not have been obvious over the combined prior art
Appeal 2019-003807
Application 12/782,616

14
teaching the same method, and we sustain the Examiner’s rejection of claims
42 and 43 over the prior art.
CONCLUSION
Upon consideration of the record and for the reasons given, we
reverse the Examiner’s rejection under 35 U.S.C. § 112, first paragraph.
We affirm the Examiner’s rejection under 35 U.S.C. § 103(a).
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 2, 5–18,
21, 22, 24–
26, 28, 37,
41–43
112, second
paragraph
Indefiniteness 1, 2, 5–18,
21, 22, 24–
26, 28, 37,
41–43
41–43 112, second
paragraph
Indefiniteness 41–43
1, 2, 5–18,
21, 22, 24–
26, 28, 37,
41–43
103(a) Cai, Dekker, Lee,
Wartiovaara
1, 2, 5–18,
21, 22, 24–
26, 28, 37,
41–43

8–10, 13,
14
103(a) Cai, Dekker, Lee,
Wartiovaara,
Morrison, Shiio
8–10, 13,
14

11, 12, 15–
17
103(a) Cai, Dekker, Lee,
Wartiovaara,
Morrison, Shiio,
Blander, Fujita
11, 12, 15–
17

1, 2, 5–7,
18, 21, 22,
24–26, 28,
37, 38, 40,
41
103(a) Cai, Dekker, Lee,
Wartiovaara,
Morrison, GE
Healthcare
1, 2, 5–7,
18, 21, 22,
24–26, 28,
37, 38, 40,
41

Appeal 2019-003807
Application 12/782,616

15
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
8–17 103(a) Cai, Dekker, Lee,
Wartiovaara,
Morrison, GE
Healthcare,
Blander, Fujita
8–17
Overall
Outcome
1, 2, 5–18,
21, 22, 24–
26, 28, 37,
41–43

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136.

AFFIRMED