UC Opp No. 3CRISPR Patent

Filed on behalf of Senior Party
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA,

UNIVERSITY OF VIENNA, AND EMMANUELLE CHARPENTIER
By:
Todd R. Walters, Esq.

Erin M. Dunston, Esq.
Travis W. Bliss, Ph.D., Esq.
BUCHANAN INGERSOLL & ROONEY PC
1737 King Street, Suite 500
Alexandria, Virginia 22314-2727
Telephone (703) 836-6620
Facsimile (703) 836-2021
todd.walters@bipc.com
erin.dunston@bipc.com
travis.bliss@bipc.com
By: Li-Hsien Rin-Laures, M.D., Esq.

Sandip H. Patel, Esq.
Greta Noland
MARSHALL GERSTEIN & BORUN LLP
6300 Willis Tower
233 South Wacker Drive
Chicago, Illinois 60606
Telephone (312) 474-6300
Facsimile (312) 474-0448
lrinlaures@marshallip.com
spatel@marshallip.com
gnoland@marshallip.com
UNITED STATES PATENT AND TRADEMARK OFFICE

____________________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________________
THE BROAD INSTITUTE, INC., MASSACHUSETTS INSTITUTE OF
TECHNOLOGY, and PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Patents 8,697,359; 8,771,945; 8,795,965; 8,865,406; 8,871,445; 8,889,356;
8,895,308; 8,906,616; 8,932,814; 8,945,839; 8,993,233; 8,999,641; and Application 14/704,551,
Junior Party,
v.
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, UNIVERSITY
OF VIENNA, AND EMMANUELLE CHARPENTIER,
Application 13/842,859,
Senior Party.
____________________
Patent Interference 106,048 (DK)
____________________
UC et al. OPPOSITION 3
(Opposing Broad et al.s Request for Benefit for Count 1)
Interference No. 106,048

TABLE OF CONTENTS
Page
I.
INTRODUCTION ...............................................................................................................1
II.
THE EVIDENCE .................................................................................................................2
III.
STATEMENT OF MATERIAL FACTS.............................................................................2
IV.
ARGUMENT .......................................................................................................................2
A.
Broads Priority Chains........................................................................................... 3
B.
It Was Broads Burden to Show That Benefit Should Be Awarded ....................... 4
C.
Broad Failed to Establish Continuity of Disclosure ............................................... 5
D.
E.
1.
Example 1 of Zhang B1 Is Not Found in the 406 Patent, the 308

Patent, or the 977 Application ................................................................... 7
2.
Example 1 of Zhang B1 Is Not Found in the 641 Patent or the 736

Application.................................................................................................. 8
Broad Failed to Establish That Intervening Applications for Ten Patents and
One Application Set Forth the Subject Matter of Count 1...................................... 8
1.
Benefit for the 945 and 839 Patents Should Not Be Awarded ................. 9
2.
Benefit for the 965 and 445 Patents Should Not Be Awarded ............... 10
3.
4.
5.
Benefit for the 616 Patent Should Not Be Awarded ............................... 15
6.
Benefit for the 641 Patent Should Not Be Awarded ............................... 17
7.
Benefit for the 551 Application Should Not Be Awarded....................... 18
Broads Alleged Embodiment from Zhang B1 Fails to Describe and Enable

Every Element of Count 1..................................................................................... 20
1.
Broad Motion 3 Does Not Demonstrate Possession in Zhang B1 of

DNA-targeting RNA of Count 1 ........................................................... 20
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2.
V.
Broad Motion 3 Does Not Demonstrate Possession in Zhang B1 of the

DNA-targeting RNA forms a complex with the Cas9 protein, thereby
targeting the Cas9 protein to the target DNA molecule of Count 1 ........ 22
CONCLUSION ..................................................................................................................25
APPENDIX 1 - LIST OF EXHIBITS

APPENDIX 2 STATEMENT OF FACTS
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TABLE OF AUTHORITIES
Cases
Page(s)
Encyclopaedia Britannica, Inc. v. Alpine Elecs. of Am., Inc.,

609 F.3d 1345 (Fed. Cir. 2010).................................................................................. passim
Hillman v. Shyamala,
55 U.S.P.Q.2d 1220 (B.P.A.I. 2000)................................................................................4, 5
Hollmer v. Harari,
681 F.3d 1351 (Fed. Cir. 2012).................................................................................. passim
Hyatt v. Boone,
146 F.3d 1348 (Fed. Cir. 1998)............................................................................................5
Lockwood v. Am. Airlines, Inc.,
107 F.3d 1565 (Fed. Cir. 1997).................................................................................. passim
Reiffin v. Microsoft Corp.,
214 F.3d 1342 (Fed. Cir. 2000).................................................................................. passim
Stevens v. Tamai,
366 F.3d 1325 (Fed. Cir. 2004)............................................................................................5
Winter v. Fujita,
53 U.S.P.Q.2d 1234 (B.P.A.I. 1999)....................................................................................5
Zenon Envtl., Inc. v. U.S. Filter Corp.,
506 F.3d 1370 (Fed. Cir. 2007)............................................................................................6
Statutes
35 U.S.C. 102(g)(1) ......................................................................................................................4
35 U.S.C. 112 ...................................................................................................................... passim
35 U.S.C. 119 ................................................................................................................................4
35 U.S.C. 119(e) ...........................................................................................................................8
35 U.S.C. 120 ...................................................................................................................... passim
35 U.S.C. 121 ................................................................................................................................4
35 U.S.C. 165 ................................................................................................................................4
35 U.S.C. 386 ................................................................................................................................4
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Rules
37 C.F.R. 41.121(b) ..................................................................................................................4, 5
37 C.F.R. 41.201 ................................................................................................................. passim
Additional
Standing Order, 121.3 ...................................................................................................................5
Standing Order, 121.5.2 ................................................................................................................5
Standing Order, 122.5 ...................................................................................................................5
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2
I.
INTRODUCTION
At the outset of this interference, and again when it was re-declared, neither Junior nor
Senior Party was accorded any benefit for Count 1. See Paper No. 1, p. 13; see also Paper No.
32, p. 13. In Broad et al. Substantive Motion 3 (Broad Motion 3), Junior Party (Broad)
requests to be accorded benefit of U.S. Patent Application No. 61/736,527, filed on December
12, 2012 (Zhang B1) (Ex. 2101), for the subject matter of Count 1. Because Broad failed to
meet its burden of establishing its right to benefit of Zhang B1, Senior Party (UC) requests that
Broad Motion 3 be denied.
In requesting benefit, Broad argues that Embodiment E1 satisfies all the elements of
10
Count 1, and thus is a constructive reduction to practice of the subject matter of Count 1. Broad
11
Motion 3, p. 4, ll. 13-14. Embodiment E1 is from Example 1 of Broads earliest provisional, i.e.,
12
Zhang B1. Because Example 1 is what Broad is attempting to rely upon to satisfy 35 U.S.C.
13
120 (and 35 U.S.C. 112, first paragraph), Broad Motion 3 must fail at least because it does
14
not explain continuity of disclosure from Zhang B1 to its involved patents and application. It is
15
neither UCs nor the Boards responsibility to determine whether continuity of disclosure exists.
16
Broad simply failed to meet its burden of proof.
17
Moreover, unlike UCs involved application, which has a direct claim to each of its
18
earlier-filed provisional applications, the applications that matured as Broads involved U.S.
19
Patent Nos. 8,771,945 (the 945 Patent) (Ex. 1008), 8,795,965 (the 965 Patent) (Ex. 1012),
20
8,871,445 (the 445 Patent) (Ex. 1013), 8,889,356 (the 356 Patent) (Ex. 1010), 8,932,814
21
(the 814 Patent) (Ex. 1011), and 8,945,839 (the 839 Patent) (Ex. 1009), U.S. Patent Nos.
22
8,865,406 (the 406 Patent) (Ex. 1014), 8,895,308 (the 308 Patent) (Ex. 1015), 8,906,616
23
(the 616 Patent) (Ex. 1016), and 8,999,641 (the 641 Patent) (Ex. 1018), and Broads
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involved U.S. Patent Application No. 14/704,551 (the 551 Application) (Ex. 1019) each has at
least one intervening application in its priority chain. Another reason Broad Motion 3 fails to
meet its burden of proof is because it fails to substantively address those intervening
applications. Thus, Broad Motion 3 fails to establish Broads ability to claim priority under 35
U.S.C. 120 (and 35 U.S.C. 112, first paragraph) through those intervening applications to
reach back and obtain benefit of Zhang B1.
Broad Motion 3 also fails to establish that Zhang B1 describes and enables the DNA-
targeting RNA and the DNA-targeting RNA forms a complex with the Cas9 protein, thereby
targeting the Cas9 protein to the target DNA molecule elements of Count 1. The passages cited
10
by Broad simply do not support those elements.
11
Because Broad failed to make the required showings for benefit, Broad Motion 3 should
12
be denied.
13
II.
14
15
THE EVIDENCE
A list of exhibits upon which this Opposition relies is set forth in Appendix 1.
III.
16
STATEMENT OF MATERIAL FACTS

Material Facts 1-102 alleged in Broad Motion 3 are repeated in Appendix 2, along with
17
Senior Partys concise responses thereto. Additional Material Facts 103-145 relied upon in
18
support of this Opposition are also set forth in Appendix 2.
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IV.
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ARGUMENT
At page 1, lines 2-6 of Broad Motion 3, it is argued that Broad should receive the benefit
21
of the filing date of Zhang B1, December 12, 2012, for the subject matter of Count 1. The
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response is that Broad Motion 3 fails to meet its burden of proof. Broad Motion 3 fails to
23
establish continuity of disclosure from Zhang B1 to each of its involved patents and application.
24
Broad Motion 3 also fails to establish that Broad may properly claim priority under 35 U.S.C.
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120 (and 35 U.S.C. 112, first paragraph) through intervening applications to reach back and
obtain benefit to Zhang B1. Broad Motion 3 also fails to establish description and enablement of
elements [6] and [10] of Count 1. Because Broad Motion 3 does not meet its burden of proof, it
should be denied and benefit for Broad should remain as set forth in the Declaration and Re-
Declaration of this interference. See Paper No. 1, p. 13; see also Paper No. 32, p. 13; see also
Exs. 1008-1016, 1018, 1019, 2111-2117, 2119-2121.
A.
The following diagram depicts the relationships among involved Broad patents and
Broads Priority Chains
application, intervening applications, and Zhang B1:
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11
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Green, blue, and pink represent involvement in this interference. Pink represents an
involved Broad patent that does not include Example 1 of Zhang B1. Green and no color
represent intervening applications about which Broad Motion 3 offers no substantive content.
B.
It Was Broads Burden to Show That Benefit Should Be Awarded
The party filing [a] motion has the burden of proof to establish that it is entitled to the
requested relief. 37 C.F.R. 41.121(b). Thus, the burden was on Broad to explain every reason
why the relief it requested should be granted. See, e.g., Hillman v. Shyamala, 55 U.S.P.Q.2d
1220, 1221 (B.P.A.I. 2000).
The relief Broad Motion 3 requests is to be accorded benefit of Zhang B1 for the
10
subject matter of Count 1. Broad Motion 3, p. 1, ll. 2-6. The Rules make clear that [a]ccord
11
benefit means Board recognition that a patent application provides a proper constructive
12
reduction to practice under 35 U.S.C. 102(g)(1). 37 C.F.R. 41.201 (emphasis original). The
13
Rules also make clear that:
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15
16
17
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21
22
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Constructive reduction to practice means a described and enabled

anticipation under 35 U.S.C. 102(g)(1), in a patent application of
the subject matter of a count. Earliest constructive reduction to
practice means the first constructive reduction to practice that has
been continuously disclosed throughout a chain of patent
applications including in the involved application or patent. For
the chain to be continuous, each subsequent application must
comply with the requirements of 35 U.S.C. 119-121, 165, or 386.
37 C.F.R. 41.201 (emphasis original).
Broads requested relief hinges on its priority chains, and priority is not appropriate
24
unless the relied-upon prior-filed application discloses the subject matter of the later-filed
25
application in the manner provided by the first paragraph of 35 U.S.C. 112. 35 U.S.C. 120;
26
see also Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1571 (Fed. Cir. 1997) (In order to gain
27
the benefit of the filing date of an earlier date of an earlier application under 35 U.S.C. 120,
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each application in the chain leading back to the earlier application must comply with the written
description requirement of 35 U.S.C. 112.); see also Reiffin v. Microsoft Corp., 214 F.3d
1342, 1346 (Fed. Cir. 2000) (claims to subject matter in a later-filed application not supported
by an ancestor application in terms of 112 1 . . . do not receive the benefit of the earlier
applications filing date). Further, the requirements of 35 U.S.C. 120 apply to each
application in a chain of priority. See Encyclopaedia Britannica, Inc. v. Alpine Elecs. of Am.,
Inc., 609 F.3d 1345, 1350-52 (Fed. Cir. 2010). Broad Motion 3 failed to properly establish
priority under 35 U.S.C. 120 from Broads involved patents and application through their
respective intervening applications back to Zhang B1. See 37 C.F.R. 41.201.
10
Broads procedural and substantive errors are fatal to Motion 3, as Broad may not make
11
out its prima facie case for the first time in its Reply. See Standing Order, 121.3, 121.5.2,
12
122.5; see Winter v. Fujita, 53 U.S.P.Q.2d 1234, 1249-51 (B.P.A.I. 1999); see also Stevens v.
13
Tamai, 366 F.3d 1325, 1330-5 (Fed. Cir. 2004). Due to at least these deficiencies, Broad failed
14
to meet its burden for obtaining benefit to Zhang B1 and Broad Motion 3 should be denied.
15
C.
Broad Failed to Establish Continuity of Disclosure
16
Broad Motion 3 fails to establish a description of the subject matter of Count 1
17
warranting priority back to Zhang B1 for every involved patent and application. See 37 C.F.R.
18
41.201. This alone is fatal to Broads request for relief. See 37 C.F.R. 41.121(b); see also
19
Hillman, 55 U.S.P.Q.2d at 1221. An application in an interference is entitled to the filing date
20
of an earlier-filed U.S. patent application if the earlier application meets the requirements of 35
21
U.S.C. 120 and 35 U.S.C. 112, paragraph 1, for the subject matter of the count. Hollmer v.
22
Harari, 681 F.3d 1351, 1355 (citing Hyatt v. Boone, 146 F.3d 1348, 1352 (Fed. Cir. 1998)). To
23
gain the benefit of the filing date of an earlier application under 35 U.S.C. 120, each
24
application in the chain leading back to the earlier application must comply with the written
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description requirement of 35 U.S.C. 112. Hollmer, 681 F.3d at 1355 (citing Zenon Envtl.,
Inc. v. U.S. Filter Corp., 506 F.3d 1370, 1378 (Fed. Cir. 2007)). Thus, if any application in the
priority chain fails to make the requisite disclosure of subject matter, the later-filed application is
not entitled to the benefit of the filing date of applications preceding the break in the priority
chain. Hollmer, 681 F.3d at 1355. Broad Motion 3 should be denied because it fails to
establish that the requisite disclosure of subject matter was made.
At page 4, lines 12-14 of Broad Motion 3, it is argued that Embodiment E1 satisfies all
the elements of Count 1, and thus is a constructive reduction to practice of the subject matter of
Count 1 and that Embodiment E1 is one of the experiments described in Example 1 of Zhang
10
B1. The response is that if Example 1, or even Embodiment E1 thereof, of Zhang B1 is what
11
Broad is attempting to rely upon for the description of the invention when required by 35 U.S.C.
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120, no showing regarding Example 1, or even Embodiment E1 thereof, has been made. An
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additional response is that Example 1 of Zhang B1, upon which Broad Motion 3 relies, is not
14
even contained in the 406 Patent, the 308 Patent, and the 641 Patent, nor is Example 1 in the
15
intervening applications of these patents, i.e., U.S. Patent Application 14/104,977 (the 977
16
Application) and International Patent Application PCT/US2013/74736 (the 736 Application).
17
Although the involved 406, 308, and 641 Patents contain language attempting to incorporate
18
the content of Zhang B1 by reference, Broad Motion 3 fails to include a substantive analysis
19
regarding possible incorporation by reference. See Hollmer, 681 F.3d at 1355-8; see also Zenon,
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506 F.3d at 1378-9 (noting that to incorporate material by reference, the host document must
21
identify with detailed particularity what specific material it incorporates and clearly indicate
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where that material is found in the various documents and that [w]hether material has been
23
incorporated by reference into a host document, and the extent to which it has been incorporated
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is analyzed from the viewpoint of one reasonably skilled in the art) (emphasis original). Thus,
for at least these additional reasons, Broad failed to meet its burden for obtaining benefit to
Zhang B1 and Broad Motion 3 should be denied.
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5
1.
Example 1 of Zhang B1 Is Not Found in the 406 Patent, the 308

Patent, or the 977 Application
On page 4, lines 12-14 of Broad Motion 3, it is argued that Embodiment E1 satisfies all
Count 1 and that Embodiment E1 is from Example 1 of Broads earliest provisional, i.e., Zhang
B1. The response is that Example 1 is not found in the 406 Patent or in the 308 Patent.
10
Compare Ex. 2101 at pp. 260-268, 00150-00184 (Example 1 of Zhang B1) with Exs. 1014
11
(the 406 Patent) and 2114 (the application that matured as the 406 Patent) and with Exs. 1015
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(the 308 Patent) and 2121 (the application that matured as the 308 Patent); see Additional
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Facts (AF) 103-104. An additional response is that Example 1 of Zhang B1 is not found in
14
the 977 Application, the intervening parent application for both the 406 Patent and the 308
15
Patent. Compare Ex. 2101 at pp. 260-268, 00150-00184 (Example 1 of Zhang B1) with Ex.
16
2106; see AFs 105-106.
17
At least because Broad failed to show its entitlement to benefit back to Zhang B1 for the
18
subject matter of Count 1 and because a description of the subject matter relied upon by Broad
19
from Zhang B1 is not even present in the 406 Patent, 308 Patent, and intervening 977
20
Application, benefit should not be awarded. See 37 C.F.R. 41.201, 35 U.S.C. 120, Hollmer,
21
681 F.3d at 1355; Encyclopaedia Britannica, 609 F.3d at 1350-52; Reiffin, 214 F.3d at 1346;
22
Lockwood, 107 F.3d at 1571.
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2
2.
Example 1 of Zhang B1 Is Not Found in the 641 Patent or the 736

Application
On page 4, lines 12-14 of Broad Motion 3, it is argued that Embodiment E1 satisfies all
Count 1 and that Embodiment E1 is from Example 1 of Broads earliest provisional, i.e., Zhang
B1. The response is that Example 1 of Zhang B1 is not found in the 641 Patent. Compare Ex.
2101 at pp. 260-268, 00150-00184 (Example 1 of Zhang B1) with Exs. 1018 (the 641 Patent)
and 2119 (the application that matured as the 641 Patent); see AF 107. An additional response
is that Example 1 of Zhang B1 is not found in the 736 Application, the intervening parent
10
application for the 641 Patent. Compare Ex. 2101 at pp. 260-268, 00150-00184 (Example 1
11
of Zhang B1) with Ex. 2122 (the 736 Application); see AFs 108-109.
12
At least because Broad failed to show its entitlement to benefit back to Zhang B1 for the
13
subject matter of Count 1 and because a description of the subject matter relied upon by Broad
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from Zhang B1 is not even present in the 641 Patent and the intervening 736 Application,
15
benefit should not be awarded. See 37 C.F.R. 41.201, 35 U.S.C. 120, Hollmer, 681 F.3d at
16
1355; Encyclopaedia Britannica, 609 F.3d at 1350-52; Reiffin, 214 F.3d at 1346; Lockwood, 107
17
F.3d at 1571.
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D.
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At page 18, lines 11-17 of Broad Motion 3, it is argued that:
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Broad Failed to Establish That Intervening Applications for Ten Patents and
One Application Set Forth the Subject Matter of Count 1
Broad . . . has satisfied the requirements for claiming priority to

Zhang B1, pursuant to 35 U.S.C. 119(e), and 120, for all the
applications that issued as the Broad patents and application in this
interference, each filed within twelve months of Zhang B1 or with
benefit to an application filed within twelve months of Zhang B1
and, further, each including at least one common inventor (Feng
Zhang) and a specific reference to Zhang B1 and incorporating
Zhang B1 by reference. Facts 99-102; Exs. 1007-1019, 2101,
2105-2121 and 2122-2123; Ex. 2001, Simons 5.2.
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The response is that these conclusory assertions do not meet Broads burden of establishing
benefit to Zhang B1, especially because the intervening applications are not addressed at all. See
AFs 110-116. By failing to address those intervening applications, Broad failed to establish its
right to benefit back to Zhang B1. See 37 C.F.R. 41.201, 35 U.S.C. 120, Hollmer, 681 F.3d
at 1355; Encyclopaedia Britannica, 609 F.3d at 1350-52; Reiffin, 214 F.3d at 1346; Lockwood,
107 F.3d at 1571.
1.
8
9
Benefit for the 945 and 839 Patents Should Not Be Awarded
As shown in the diagram above, Broads involved 945 and 839 Patents have as their
parent and grandparent application, respectively, U.S. Patent Application No. 14/054,414 (the
10
414 Application) (Ex. 2105). See AFs 117-118. The 414 Application is not substantively
11
addressed in Broad Motion 3. See AF 110. The cited paragraph from the Declaration by Dr.
12
Simons, 5.2, does not mention the 414 Application, let alone analyze its contents. See AFs
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119-120; Ex. 2001, 5.2.
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15
The only mention in Broad Motion 3 of intervening applications is in alleged Facts 100102:
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100. There is a common inventor, (Feng Zhang) among B1, each

of the Broad patents and application in the interference and each
intervening application. Ex. 2001, Simons 5.61.
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101. Each of the Broad patents and application in the interference

and each intervening application includes a specific reference to
Zhang B1. Ex. 2001, Simons 5.61.
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102. Each of the applications that issued as Broad patents and

application in the interference, as well each of the intervening
applications, incorporated Zhang B1 by reference. Exs. 1007-1019,
2101, 2105-2121 and 2122-2133; Ex. 2001, Simons 5.61.
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See Broad Motion 3, p. A2-15; see AF 121. Alleged Facts 100-102 are as conclusory as the
paragraph for which they are cited. Alleged Facts 100-102 lack any substantive analysis of the
414 Application.
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Alleged Facts 100-102 cite to one paragraph from the Declaration of Dr. Simons, 5.61,
which states:
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Indeed, Zhang B1 provides a method for adapting the CRISPRCas9 system for function in a eukaryotic cell, including working
examples, that is carried through all of the Involved Broad Patents
and Application of inventor Zhang and co-inventors (Patents
8,697,359 (Ex. 1007); 8,771,945 (Ex. 1008); 8,795,965 (Ex. 1012);
8,865,406 (Ex. 1014); 8,871,445 (Ex. 1013); 8,889,356 (Ex. 1010);
8,895,308 (Ex. 1015); 8,906,616 (Ex. 1016); 8,932,814 (Ex. 1011);
8,945,839 (Ex. 1009); 8,993,233 (Ex. 1017); 8,999,641 (Ex. 1018);
and Application 14/704,551 (Ex. 1019).) For the reasons discussed
above Zhang B1 describes and enables multiple embodiments that
fall within the scope of Count 1. In my opinion, the work in Zhang
B1 shows and provides details sufficient to describe and enable use
of CRISPR-Cas9 in a method in a eukaryotic cell as described by
Count 1 of the Interference.
20
Ex. 2001, 5.61. Paragraph 5.61 of Dr. Simons Declaration fails to provide any analysis of the
21
414 Application and does not even cite the 414 Application (Ex. 2105). Id.
22
Because Broad Motion 3 lacks any substantive analysis of the 414 Application, which is
23
an intervening application for both the 945 and 839 Patents, benefit should not be awarded for
24
those patents. See 37 C.F.R. 41.201, 35 U.S.C. 120, Hollmer, 681 F.3d at 1355;
25
Encyclopaedia Britannica, 609 F.3d at 1350-52; Reiffin, 214 F.3d at 1346; Lockwood, 107 F.3d
26
at 1571.
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2.
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parent application U.S. Patent Application No. 14/105,035 (the 035 Application) (Ex. 2110).
30
See AFs 122-123. The 035 Application is not substantively addressed in Broad Motion 3. See
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AF 111. The cited paragraph from the Declaration by Dr. Simons, 5.2, does not mention the
035 Application, let alone analyze its contents. See AFs 124-125. In fact, the 035 Application
is not even listed as a document reviewed by Dr. Simons. See AF 126; Ex. 2001, 3.4; pp. 84-
85 (Table II).
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2101, 2105-2121 and 2122-2133; Ex. 2001, Simons 5.61.
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035 Application.
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which states:
8,697,359 (Ex. 1007); 8,771,945 (Ex. 1008); 8,795,965 (Ex. 1012);
8,865,406 (Ex. 1014); 8,871,445 (Ex. 1013); 8,889,356 (Ex. 1010);
8,895,308 (Ex. 1015); 8,906,616 (Ex. 1016); 8,932,814 (Ex. 1011);
8,945,839 (Ex. 1009); 8,993,233 (Ex. 1017); 8,999,641 (Ex. 1018);
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at 1571.
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3.
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See AF 105. The 977 Application is not substantively addressed in Broad Motion 3. See AF
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112. The cited paragraph from the Declaration by Dr. Simons, 5.2, does not mention the 977
15
Application, let alone analyze its contents. See AFs 127-128. In fact, the 977 Application is not
16
even listed as a document reviewed by Dr. Simons. See AF 129; Ex. 2001, 3.4; pp. 84-85
17
(Table II).
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2

2101, 2105-2121 and 2122-2133; Ex. 2001, Simons 5.61.
977 Application.
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which states:
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20
21
8,697,359 (Ex. 1007); 8,771,945 (Ex. 1008); 8,795,965 (Ex. 1012);
8,865,406 (Ex. 1014); 8,871,445 (Ex. 1013); 8,889,356 (Ex. 1010);
8,895,308 (Ex. 1015); 8,906,616 (Ex. 1016); 8,932,814 (Ex. 1011);
8,945,839 (Ex. 1009); 8,993,233 (Ex. 1017); 8,999,641 (Ex. 1018);
22
23
24
25
26
27
28
at 1571.
29
- 13 -

1
4.
See AFs 130-131. The 031 Application is not substantively addressed in Broad Motion 3. See
AF 113. The cited paragraph from the Declaration by Dr. Simons, 5.2, does not mention the
031 Application, let alone analyze its contents. See AFs 132-133. In fact, the 031 Application
is not even listed as a document reviewed by Dr. Simons. See AF 134; Ex. 2001, 3.4; pp. 84-
85 (Table II).
9
10
11
12
13

14
15
16

17
18
19
20

2101, 2105-2121 and 2122-2133; Ex. 2001, Simons 5.61.
21
See Broad Motion 3, p. A2-15; AF 121. Alleged Facts 100-102 are as conclusory as the paragraph
22
for which they are cited. Alleged Facts 100-102 lack any substantive analysis of the 031
23
Application.
24
25
26
27
28
29
which states:
- 14 -

1
2
3
4
5
6
7
8
9
10
8,697,359 (Ex. 1007); 8,771,945 (Ex. 1008); 8,795,965 (Ex. 1012);

8,865,406 (Ex. 1014); 8,871,445 (Ex. 1013); 8,889,356 (Ex. 1010);
8,895,308 (Ex. 1015); 8,906,616 (Ex. 1016); 8,932,814 (Ex. 1011);
8,945,839 (Ex. 1009); 8,993,233 (Ex. 1017); 8,999,641 (Ex. 1018);
11
12
13
14
15
16
17
at 1571.
18
5.
19
Benefit for the 616 Patent Should Not Be Awarded
As shown in the diagram above, Broads involved 616 Patent has as its parent
20
application U.S. Patent Application No. 14/104,990 (the 990 Application) (Ex. 2107). See AF
21
135. The 990 Application is not substantively addressed in Broad Motion 3. See AF 114. The
22
cited paragraph from the Declaration by Dr. Simons, 5.2, does not mention the 990
23
Application, let alone analyze its contents. See AFs 136-137. In fact, the 990 Application is not
24
even listed as a document reviewed by Dr. Simons. See AF 138; Ex. 2001, 3.4; pp. 84-85
25
(Table II).
26
27
- 15 -

1
2
3

4
5
6

7
8
9
10

2101, 2105-2121 and 2122-2133; Ex. 2001, Simons 5.61.
11
12
13
990 Application.
14
15
which states:
16
17
18
19
20
21
22
23
24
25
26
27
28
29
8,697,359 (Ex. 1007); 8,771,945 (Ex. 1008); 8,795,965 (Ex. 1012);
8,865,406 (Ex. 1014); 8,871,445 (Ex. 1013); 8,889,356 (Ex. 1010);
8,895,308 (Ex. 1015); 8,906,616 (Ex. 1016); 8,932,814 (Ex. 1011);
8,945,839 (Ex. 1009); 8,993,233 (Ex. 1017); 8,999,641 (Ex. 1018);
30
31
32
33
an intervening application for the 616 Patent, benefit should not be awarded for that patent. See
- 16 -

1
37 C.F.R. 41.201, 35 U.S.C. 120, Hollmer, 681 F.3d at 1355; Encyclopaedia Britannica, 609
F.3d at 1350-52; Reiffin, 214 F.3d at 1346; Lockwood, 107 F.3d at 1571.
6.
Benefit for the 641 Patent Should Not Be Awarded
As shown in the diagram above, Broads involved 641 Patent has as its parent
application International Patent Application PCT/US2013/74736 (the 736 Application) (Ex.
2122). See AF 108. The 736 Application is not substantively addressed in Broad Motion 3.
See AF 115. The cited paragraph from the Declaration by Dr. Simons, 5.2, does not mention
the 736 Application, let alone analyze its contents. See AFs 139-140. In fact, the 736
Application is not even listed as a document reviewed by Dr. Simons. See AF 141; Ex. 2001,
10
3.4; pp. 84-85 (Table II).
11
12
13
14
15

16
17
18

19
20
21
22

2101, 2105-2121 and 2122-2133; Ex. 2001, Simons 5.61.
23
See Broad Motion 3, p. A2-15. Alleged Facts 100-102 are as conclusory as the paragraph for
24
which they are cited. Alleged Facts 100-102 lack any substantive analysis of the 736
25
Application.
26
27
which states:
- 17 -

1
2
3
4
5
6
7
8
9
10
11
12
13
14
8,697,359 (Ex. 1007); 8,771,945 (Ex. 1008); 8,795,965 (Ex. 1012);
8,865,406 (Ex. 1014); 8,871,445 (Ex. 1013); 8,889,356 (Ex. 1010);
8,895,308 (Ex. 1015); 8,906,616 (Ex. 1016); 8,932,814 (Ex. 1011);
8,945,839 (Ex. 1009); 8,993,233 (Ex. 1017); 8,999,641 (Ex. 1018);
15
16
17
18
an intervening application for the 641 Patent, benefit should not be awarded for that patent. See
19
37 C.F.R. 41.201, 35 U.S.C. 120, Hollmer, 681 F.3d at 1355; Encyclopaedia Britannica, 609
20
F.3d at 1350-52; Reiffin, 214 F.3d at 1346; Lockwood, 107 F.3d at 1571.
21
7.
22
Benefit for the 551 Application Should Not Be Awarded
As shown in the diagram above, Broads involved 551 Application has as its parent
23
application International Patent Application PCT/US2013/74819 (the 819 Application) (Ex.
24
2123). See AF 142. The 819 Application is not substantively addressed in Broad Motion 3.
25
See AF 116. The cited paragraph from the Declaration by Dr. Simons, 5.2, does not mention
26
the 819 Application, let alone analyze its contents. See AFs 143-144. In fact, the 819
27
Application is not even listed as a document reviewed by Dr. Simons. See AF 145; Ex. 2001,
28
3.4; pp. 84-85 (Table II).
29
30
- 18 -

1
2
3

4
5
6

7
8
9
10

2101, 2105-2121 and 2122-2133; Ex. 2001, Simons 5.61.
11
12
13
819 Application.
14
15
which states:
16
17
18
19
20
21
22
23
24
25
26
27
28
29
8,697,359 (Ex. 1007); 8,771,945 (Ex. 1008); 8,795,965 (Ex. 1012);
8,865,406 (Ex. 1014); 8,871,445 (Ex. 1013); 8,889,356 (Ex. 1010);
8,895,308 (Ex. 1015); 8,906,616 (Ex. 1016); 8,932,814 (Ex. 1011);
8,945,839 (Ex. 1009); 8,993,233 (Ex. 1017); 8,999,641 (Ex. 1018);
30
31
32
33
an intervening application for the 551 Application, benefit should not be awarded for that
- 19 -

1
application. See 37 C.F.R. 41.201, 35 U.S.C. 120, Hollmer, 681 F.3d at 1355; Encyclopaedia
Britannica, 609 F.3d at 1350-52; Reiffin, 214 F.3d at 1346; Lockwood, 107 F.3d at 1571.
3
4
E.
An independent reason to deny Broad Motion 3 is its failure to show that each and every
element of Count 1 is described and enabled by Zhang B1. At a minimum, Broad Motion 3 fails
to establish support in Zhang B1 for the DNA-targeting RNA and the DNA-targeting RNA
forms a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA
molecule elements of Count 1.
10
11
1.
12
Broads Alleged Embodiment from Zhang B1 Fails to Describe and Enable

Every Element of Count 1

DNA-targeting RNA of Count 1
At page 2, line 17 of Broad Motion 3, Broad designates the DNA-targeting RNA
13
component of Count 1 as element [6]. The response is that Count 1 clearly states that the
14
DNA-targeting RNA includes: (i) a targeter-RNA or guide sequence and (ii) an activator-RNA
15
or tracr sequence:
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
[1] A method, in a eukaryotic cell, of cleaving or editing a target DNA

molecule or modulating transcription of at least one gene encoded thereon,
the method comprising:
[2] contacting,
[3] in a eukaryotic cell,
[4] a target DNA molecule having a target sequence
[5] with an engineered and/or non-naturally-occurring Type II Clustered
Regularly lnterspaced Short Palindromic Repeats (CRISPR)CRISPR associated (Cas) (CRISPR-Cas) system comprising:
[6] a) a DNA-targeting RNA comprising
[7]
i) a targeter-RNA or guide sequence that hybridizes with the
get sequence, and
[8]
ii) an activator-RNA or tracr sequence that hybridizes with the
targeter-RNA to form a double-stranded RNA duplex
of a protein binding segment, and
[9] b) a Cas9 protein,
[10] wherein the DNA-targeting RNA forms a complex with the Cas9
protein, thereby targeting the Cas9 protein to the target DNA molecule,
- 20 -

1
2
3
[11] whereby said target DNA molecule is cleaved or edited or

transcription of at least one gene encoded by the target DNA molecule is
modulated.
See Paper No. 1, pp. 10-11; see also Paper No. 32, p. 10 (Broad bracketing and emphasis
added).
At page 9, lines 6-7 of Broad Motion 3, it is argued that [t]he CRISPR-Cas system of
Embodiment E1 comprises a mature crRNA:tracrRNA complex (i.e., a DNA-targeting RNA)
and therefore satisfies the element [6] of Count 1. To support this argument, Broad cites
Alleged Fact 33 and Paragraph 5.14 of the Simons Declaration (Ex. 2001). The response is that
10
neither Alleged Fact 33 nor Paragraph 5.14 of the Simons Declaration support Broads argument.
11
Alleged Fact 33 reads: The CRISPR-Cas9 system of Embodiment E1 comprises a
12
mature crRNA:tracrRNA complex (i.e., a DNA-targeting RNA) and therefore satisfies element
13
[6] of Count 1. Ex. 2001, Simons 5.14. Broad Motion 3, p. A2-6. This fact is simply a
14
conclusion and is identical to the first sentence of Paragraph 5.14, but for the omission of the
15
word Embodiment: The CRISPR-Cas9 system of E1 comprises a mature crRNA:tracrRNA
16
complex (i.e., a DNA-targeting RNA) and therefore satisfies element [6] of Count 1. Ex. 2001,
17
5.14. Nothing in Alleged Fact 33 or in Paragraph 5.14 of the Simons Declaration provides
18
evidence showing why Embodiment E1 comprises a mature crRNA:tracrRNA complex (i.e., a
19
DNA-targeting RNA). Id. (emphasis added). In addition, Embodiment E1 merely shows the
20
use of a pre-crRNA, not a mature crRNA, let alone a mature crRNA:tracrRNA complex, as
21
Broad alleges in Fact 33 and Paragraph 5.14 of the Simons Declaration. In Appendix 3 of Broad
22
Motion 3, Broad provides a table that alleges portions of Paragraphs 162 and 175 and Figure 1E
23
of Zhang B1 provide written description support for a DNA-targeting RNA comprising a
24
targeter-RNA or guide sequence and an activator RNA or tracr sequence. The response is that
25
the cited portions of Zhang B1, at most, describe or depict a crRNA (or the guide sequence of the
- 21 -

1
crRNA), but do not describe the presence of an activator RNA or tracr sequence. Accordingly,
these cited portions of Zhang B1 do not describe a DNA-targeting RNA as required by
element [6] of Count 1.
Thus, Broad Motion 3 fails to establish possession in Zhang B1 of element [6] of Count
1. Because Broad failed to show an embodiment with each and every element of Count 1, i.e., a
described and enabled anticipation of Count 1, Broad Motion 3 should be denied. See 37 C.F.R.
41.201.
8
9
10
11
2.
12

the DNA-targeting RNA forms a complex with the Cas9 protein,
thereby targeting the Cas9 protein to the target DNA molecule of
Count 1
Count 1 requires that the DNA-targeting RNA forms a complex with the Cas9 protein,
13
thereby targeting the Cas9 protein to the target DNA molecule and Broad characterizes that
14
requirement as element [10] of Count 1. At page 11, line 12 through page 12, line 13 of Broad
15
Motion 3, it is argued that that Zhang B1 teaches a DNA-targeting RNA forming a complex with
16
the Cas9 protein, and therefore, [e]lement [10] of Count 1 is satisfied. To support this
17
argument, Broad cites Alleged Facts 47,1 48, and 49, specific portions of Paragraphs 11, 173,
18
175, and Figure 1E of Zhang B1 (Ex.2101), and Paragraph 5.18 and 5.19 of the Simons
19
Declaration (Ex. 2001). The response is that none of this purported evidence supports Broads
20
arguments.
21
22
Alleged Facts 47-49 are simply conclusions and do not explain why element [10] is
satisfied:
1
Reference to Fact 41 on Page 11, Line 21 of Broad Motion 3 is believed to be a typographical
error because Fact 41 is cited to support element [8] of Count 1. See Broad Motion 3, p. 10, l.
16.
- 22 -

1
2
3
4
5
6
7
8
9
10
47. For Embodiment E1, Zhang B1 teaches that the CRISPR

complex comprises a CRISPR enzyme [e.g. Cas9] complexed with
a guide sequence. Ex. 2101, Zhang B1 11. See also, Ex. 2101,
Zhang B1 175 ([m]ature crRNA processed from the direct
repeat-spacer array directs Cas9 to genomic targets consisting of
complimentary protospacers and a protospacer-adjacent motif
(PAM). Upon target-spacer base pairing, Cas9 creates a doublestrand break in the target DNA. . . . Fig 1E, illustrates a schematic
representation of base pairing between target locus and EMX1targeting crRNA). Ex. 2001, Simons 5.18.
11
12
13
14
15
16
17
18
19
48. The CRISPR-Cas system used in Embodiment E1 target a

DNA molecule having a target sequence, and the experiment
resulted in a successful cleavage and editing of the human EMX1
genomic locus. See, e.g., Ex. 2101, Zhang B1 173 (Cotransfection of all CRISPR components minus SpRNaseIII also
induced up to 4.7% indel in the protospacer . . . Sanger
sequencing of amplicons containing the target locus verified the
cleavage activity in 43 sequenced clones, 5 mutated alleles
(11.6%) were found (emphasis added)). Ex. 2001, Simons 5.18.
20
21
22
23
24
49. The skilled artisan having read the Zhang B1 specification and
considered the successful experiment of Embodiment E1 and the
Figures of Zhang B1 would conclude that the DNA-targeting
RNA form[ing] a complex with the Cas9 protein occurred. Ex.
2001, Simons 5.19.
25
As for the specific portions of Paragraphs 11, 173, 175, and Figure 1E of Zhang B1 cited
26
by Broad, that, too, fails to establish that element [10] is satisfied. Specifically, Broad cites to
27
language in Paragraph 11 of Zhang B1, which states that the CRISPR complex comprises a
28
CRISPR enzyme complexed with a guide sequence and language in Paragraph 173 of Zhang B1
29
(also relied upon by Alleged Fact 48), which states that [c]o-transfection of all CRISPR
30
components minus SpRNaseIII also induced up to 4.7% indel in the protospacer. In addition,
31
Broad Motion 3 cites to language in Paragraph 175 of Zhang B1 that states that [m]ature crRNA
32
processed from the direct repeat-spacer array directs Cas9 to genomic targets. None of the
33
language of Zhang B1 cited by Broad Motion 3 describes a complex comprising a DNA-
34
targeting RNA and a Cas9 protein (the CRISPR enzyme of cited Paragraph 11 is not Cas9,
- 23 -

1
which is a requirement of element [10]). As explained above, Count 1 clearly states that a DNA-
targeting RNA includes a targeter-RNA or guide sequence and an activator-RNA or tracr
sequence. See Broad Motion 3, p. 2, ll. 17-20. Significantly, the relied-upon language of Zhang
B1 only discusses, at most, a complex between the crRNA (targeter-RNA) and the Cas9 protein.
It does not, however, mention or explain the role for the activator RNA or tracr sequence. Thus,
the portions of Zhang B1 cited in Broad Motion 3 fail to describe a DNA-targeting RNA
form[ing] a complex with the Cas9 protein as required by element [10] of Count 1.
8
9
Paragraphs 5.18 and 5.19 of the Simons Declaration fare no better in terms of supporting
the argument that element [10] is satisfied by Zhang B1. Paragraph 5.18 quotes portions of
10
Paragraphs 173 and 175 of Zhang B1. See Ex. 2001, 5.18. The quoted portion of Paragraph
11
173 does not disclose tracr as part of the complex and the quoted portion of Paragraph 175,
12
which includes a description of Figure 1E, does not discuss tracr. Id. Paragraph 5.19 of the
13
Simons Declaration and Appendix 3 of Broad Motion 3 cite to Paragraph 150 of Zhang B1 in an
14
attempt to demonstrate support for element [10]. Paragraph 150 of Zhang B1, however, when
15
taken in context, is referencing the natural CRISPR-Cas system as it exists in bacteria and is not
16
a description of experiments purportedly performed in Zhang B1. Furthermore, Paragraph 150
17
fails to describe a DNA-targeting RNA form[ing] a complex with the Cas9 protein even in a
18
natural CRISPR-Cas system ([a]n example of type II CRISPR system is the type II CRISPR
19
locus from Streptococcus pyogenes SF370 . . . . In this system, targeted DNA double-strand
20
break (DSB) is generated in four sequential steps . . . . Third, the mature crRNA:tracrRNA
21
complex directs Cas9 to the target DNA . . . .). Once again, the cited portions of Zhang B1 fail
22
to describe a DNA-targeting RNA form[ing] a complex with the Cas9 protein as required by
23
element [10] of Count 1.
- 24 -

1
Broad Motion 3 fails to establish possession in Zhang B1 of element [10] of Count 1.
Because Broad failed to show an embodiment with each and every element of Count 1, i.e., a
described and enabled anticipation of Count 1, Broad Motion 3 should be denied. See 37 C.F.R.
41.201.
V.
6
7
CONCLUSION
For at least the foregoing reasons, Broads Motion 3 should be denied.
Respectfully submitted,
By /Todd R. Walters/
Registration No. 34,040
Alexandria, Virginia 22314
Telephone (703) 836-6620
Facsimile (703) 836-2021
Counsel for UC and Vienna
By: / Sandip H. Patel /

Sandip H. Patel, Esq.
MARSHALL GERSTEIN & BORUN LLP
6300 Willis Tower
233 South Wacker Drive
Telephone (312) 474-6300
Facsimile (312) 474-0448
spatel@marshallip.com
Counsel for EC
Date: August 15, 2016
- 25 -

APPENDIX 1 LIST OF EXHIBITS
EXHIBIT
DESCRIPTION
NO.
U.S. Patent No. 8,697,359, issued on April 15, 2014, to Feng Zhang (the 359
1007
Patent)
1008
U.S. Patent No. 8,771,945, issued on July 8, 2014, to Feng Zhang (the 945 Patent)
U.S. Patent No. 8,945,839, issued on February 3, 2015, to Feng Zhang (the 839
1009
Patent)
U.S. Patent No. 8,889,356, issued on November 18, 2014, to Feng Zhang (the 356
1010
Patent)
U.S. Patent No. 8,932,814, issued on January 13, 2015, to Le Cong and Feng Zhang
1011
(the 814 Patent)
U.S. Patent No. 8,795,965, issued on August 5, 2014, to Feng Zhang (the 965
1012
Patent)
U.S. Patent No. 8,871,445, issued on October 28, 2014, to Le Cong and Feng Zhang
1013
(the 445 Patent)
U.S. Patent No. 8,865,406, issued on October 21, 2014, to Feng Zhang and Fei Ran
1014
(the 406 Patent)
U.S. Patent No. 8,895,308, issued on November 25, 2014, to Feng Zhang and Fei Ran
1015
(the 308 Patent)
U.S. Patent No. 8,906,616, issued on December 9, 2014, to Feng Zhang et al. (the
1016
616 Patent)
1-1

EXHIBIT
DESCRIPTION
NO.
U.S. Patent No. 8,993,233, issued on March 31, 2015 to Feng Zhang et al. (the 233
1017
Patent)
U.S. Patent No. 8,999,641, issued on April 7, 2015 to Feng Zhang et al. (the 641
1018
Patent)
U.S. Patent Application No. 14/704,551, filed on May 5, 2015 to Feng Zhang et al.
1019
(the 551 Application)
2001
Declaration of Dr. Paul Simons, executed May 23, 2016.
2101
U.S. Provisional Patent Application No. 61/736,527, filed December 12, 2012.
2105
U.S. Patent Application No. 14/054,414, filed October 15, 2013.
2106
U.S. Patent Application No. 14/104,977, filed December 12, 2013.
2107
U.S. Patent Application No. 14/104,990 filed December 12, 2013.
2108
2109
2110
2111
U.S. Patent Application No. 14/183,429, filed February 18, 2014.
2112
U.S. Patent Application No. 14/183,471, filed February 18, 2014.
2113
U.S. Patent Application No. 14/183,486, filed February 18,2014.
2114
U.S. Patent Application No. 14/222,930, filed March 24, 2014.
2115
U.S. Patent Application No. 14/256,912, filed April 18, 2014.
2116
1-2

EXHIBIT
DESCRIPTION
NO.
2117
2118
U.S. Patent Application No. 14/703,511, filed May 4, 2015.
2119
2120
2121
U.S. Patent Application No. 14/293,498, filed June 2, 2014.
2122
Zhang et al., WO 2014/093655, filed December 12, 2013.
2123
Zhang et al., WO 2014/093712, filed December 12, 2013.

Godwin et al., Spontaneous and restriction enzyme-induced chromosomal
2212
recombination in mammalian cells, 91 Proc. Natl Acad. Sci. USA 12554-12558

(1994).
Guschin et al., A rapid and general assay for monitoring endogenous gene
2214
modification, 649 Methods Molecular Biology 247-256 (2010).
Perez et al., Establishment of HIV-1 resistance in CD4+ T cells by genome editing
2232
using zinc-finger nucleases, 26 Nature Biotechnology 808-816 (2008).
1-3

APPENDIX 2 - STATEMENT OF MATERIAL FACTS
Junior Party Alleged Facts 1-102
1.
Count 1 is directed to a method of use in a eukaryotic cell by way of CRISPR-
Cas9-mediated action. Redeclaration, Paper No. 32, p. 10. Ex. 2001, Simons 4.2. Response:
Denied.
2.
The CRISPR-Cas9 systems disclosed in B1 are based on engineered prokaryotic
CRISPR immune systems, and these inventive systems can be used to perform useful operations
in eukaryotic cells, such as gene editing. Ex. 2001, Simons 5.6. Response: Denied.
3.
During the relevant time period, a person of ordinary skill in the art would have a
broad background that includes a strong understanding of the molecular biology and
biochemistry techniques needed to clone, express, isolate, purify, and manipulate proteins and
nucleic acids in the context of both in vitro and in vivo experiments in both prokaryotes and
eukaryotes; a Ph.D. degree in a life sciences discipline, e. g., chemistry, biochemistry,
neurobiology; and at least one year of relevant post-doctoral experience. Ex. 2001, Simons 4.1.
Response: Denied.
4.
Zhang B1 describes in detail engineering of the Cas9 protein, targeter RNA and
activator-RNA, for cleaving a target DNA molecule, in a eukaryotic cell, through multiple
enabled embodiments. Ex. 2101, Zhang B1 170, 173 and 175; Ex. 2001, Simons 5.1.
Response: Insufficient information, therefore unable to admit or deny.
5.
Targeter-RNA and guide sequence are alternative terms in Count 1. Ex. 2001,
Simons 4.2. Response: Denied.

6.
Targeter-RNA consists of both the guide sequence and also the tracr mate
sequence operably linked as described in the language of Zhang B1. Ex. 2001, Simons 5.1,
5.6. Response: Insufficient information, therefore unable to admit or deny.
2-1

7.
Activator-RNA and tracr sequence are alternative terms in Count 1. Ex. 2001,

8.
The Zhang B1 embodiments are referred to in the Simons Declaration (Ex. 2001,
Simons 5.2) as E1-E29 and are constructive reductions to practice of Count 1 as of the
December 12, 2012 filing date of Zhang B1. Response: Denied.
9.
The experiments discussed in Zhang B1 that resulted in 4.7% and 5.0% indels
illustrated in Zhang B1 Figure 1D, lanes 4 and 5, respectivelyare hereafter referred to as

Embodiments E1 and E2. See Ex. 2101, Zhang B1 173. Ex. 2001, Simons 5.2. Response:
Denied.
10.
Zhang B1 sufficiently teaches and enables each embodiment such that a skilled
person would be able to use each embodiment successfully, without undue experimentation. See,
e.g., Example 1 (Ex. 2101, Zhang B1 150-184); Example 2 (Ex. 2101, Zhang B1 185).
11.
Embodiment E1 is a CRISPR-Cas9-based method for cleaving or editing a target
DNA molecule or modulating transcription of at least one gene encoded thereon in a

eukaryotic cell. See Ex. 2101, Zhang B1 175 (Figure 1D illustrates surveyor nuclease assay
for SpCas9-mediated minor insertions and deletions.). Ex. 2001, Simons 5.4. Response:
Admitted only that the quoted text appears in the cited paragraph, otherwise denied.
12.
E1 demonstrates efficient cleavage and editing of the human EMX1 locus in
eukaryotic cells transfected with vectors expressing the components of an engineered CRISPRCas system (SpCas9, tracr RNA and pre-crRNA). Ex. 2101, Zhang B1 173; Figure 1D, lane 4.
Ex. 2001, Simons 5.4. Response: Denied.
2-2

13.
E1 therefore satisfies element [1] of Count 1. Ex. 2001, Simons 5.4. Response:
Insufficient information, therefore unable to admit or deny.

14.
In Embodiment E1, the CRISPR-Cas system was successfully used to cleave
DNA in a eukaryotic cell, establishing the contacting of a target DNA molecule, as required by
element [2] of Count 1. Ex. 2001, Simons 5.5. Response: Denied.
15.
The CRISPR-Cas system used in E1 targets a DNA molecule in a eukaryotic cell
having a target sequence, and the experiment resulted in successful cleavage and editing of the
human EMX1 genomic locus. See, e.g., Ex. 2101, Zhang B1 173 (Co-transfection of all four
CRISPR components minus SpRNase III also induced up to 4.7% indel[s] in the protospacer...
Sanger sequencing of amplicons containing the target locus verified the cleavage activity: in 43
sequenced clones, 5 mutated alleles (11.6%) were found (emphasis added)); Ex. 2001, Simons
5.5. Response: Denied.
16.
Zhang B1 discusses that Cas9 in natural prokaryotic systems cleaves invading
DNA as part of a complex that includes Cas9 and the DNA-targeting targeter RNA with a tracr
mate segment hybridized to an activator RNA. Ex. 2001, Simons 5.6. Response: Denied.
17.
Zhang B1 further shows that when in the complex, the guide sequence of the
targeter RNA directs the complex to contact the invading DNA target at the directed site,
forming a DNA-RNA heteroduplex with the target DNA sequence adjacent to the PAM. Ex.
2001, Simons 5.6. Response: Denied.
18.
Zhang B1 states that an adapted system with this mechanism was used in the
eukaryotic system of the examples:
2-3

This example [Example 1] describes an example process for adapting this
RNA-programmable nuclease system to direct CRISPR complex activity in the
nuclei of eukaryotic cells.
(Ex. 2101, Zhang B1 150). Ex. 2001, Simons 5.6. Response: Denied.
19.
A modified version of Figure 1A of Zhang B1 showing the specific contacting of
the adapted CRISPR-Cas9 system with a target DNA in a eukaryotic cell as directed by the
targeter RNA in Embodiment E1 is as follows:
Ex. 2001, Simons 5.6. Response: Admitted only that the graphic is a modification of
Figure 1A from Zhang B1, otherwise denied.
20.
The skilled artisan, having considered the Zhang B1 specification, figures and
successful experiment of Embodiment E1, would understand contacting occurred with the
target DNA site. Ex. 2001, Simons 5.7. Response: Insufficient information, therefore
unable to admit or deny.
21.
Embodiment E1 satisfies element [2] of Count 1. Ex. 2001, Simons 5.7.

22.
Embodiment E1 uses the CRISPR-Cas system in a eukaryotic cell. Ex. 2101,
Zhang B1 p. 260, ln 12. Ex. 2001, Simons 5.8. Response: Insufficient information,
therefore unable to admit or deny.
2-4

23.
The heading to the section discussing Example 1 reads: Example 1: CRISPR
Complex Activity in the Nucleus of a Eukaryotic Cell (emphasis added); Ex. 2101, Zhang B1
p. 260, ln 12; Ex. 2001 Simons 5.8. Response: Admitted.
24.
The method of Embodiment E1 is performed in the eukaryotic Human
embryonic kidney (HEK) 293FT cell line[.] Ex. 2101, Zhang B1 152; see also Ex. 2101,
Zhang B1 173 (To test in mammalian cells can achieve targeted cleavage of mammalian
chromosomes, HEK 293FT cells were transfected with combinations of CRISPR components
(emphasis added)); Ex 2001, Simons 5.8. Response: Admitted only that the quoted text
appears in the cited paragraph, otherwise denied.
25.
In Embodiment E1, Figure 1D, lane 4, shows cleavage in the presence of 3
components: SpCas9, tracr RNA and pre-crRNA in a eukaryotic cell. Ex. 2101, Zhang B1 Fig.
4D. Response: Insufficient information, therefore unable to admit or deny.
26.
Embodiment E1 therefore satisfies the eukaryotic cell requirement of element
[3] of Count 1. Ex. 2001, Simons 5.8. Response: Insufficient information, therefore unable
to admit or deny.
27.
A CRISPR-Cas system was used in Embodiment E1 to contact, cleave and edit a
target DNA molecule having a target sequence, as required by element [4] of Count 1. See
e.g., Ex. 2101, Zhang B1 172 (The initial spacer was designed to target a 33-base-pair (bp)
target site (30-bp protospacer plus a 3-bp CRISPR motif (PAM) sequence satisfying the NGG
recognition motif of Cas9) in the human EMX1 locus (Figure 1C) (emphasis added)); see also
Ex. 2101, Zhang B1 173 (the Surveyor assay was used to detect potential cleavage activity at
the target EMX1 locus ... Co-transfection of the CRISPR components induced up to 4.7% indel
2-5

in the protospacer (emphasis added)); Ex. 2101, Zhang B1 57; Ex. 2001, Simons 5.8.
Response: Denied.
28.
The target DNA molecule having a target sequence requirement of element [4]
of Count 1 is therefore satisfied by Embodiment E1. Ex. 2001, Simons 5.9. Response:
29.
The CRISPR-Cas system used in Embodiment E1 has elements that are distinct
from the naturally-occurring prokaryotic Type II CRISPR-Cas system of S. pyogenes SF370. Ex.
2001, Simons 5.10. Response: Insufficient information, therefore unable to admit or deny.
30.
A spacer selected to hybridize with the EMX1 protospacer in the human EMX1
genetic locus (not present in the naturally occurring system) is incorporated, and is therefore
engineered and/or non-naturally-occurring as required by element [5] of Count 1. Ex. 2101,
Zhang B1 172-173; Ex. 2001, Simons 5.10. Response: Insufficient information, therefore
31.
Additionally, the components of the CRISPR-Cas system of Embodiment E1 are
provided as engineered expression vectors. Ex. 2001, Simons 5.10. Response: Insufficient
information, therefore unable to admit or deny.
32.

33.
The CRISPR-Cas9 system of Embodiment E1 comprises a mature
crRNA:tracrRNA complex (i.e., a DNA-targeting RNA) and therefore satisfies element [6] of
Count 1. Ex. 2001, Simons 5.14. Response: Denied.
2-6

34.
The crRNA used in Embodiment E1 comprises a guide sequence. See, e.g., Ex.
2101, Zhang B1 162 (Spacers (also referred to as guide sequences) were inserted into the
crRNA array between BsaI sites); see also Fig 1E. Ex. 2001, Simons 5.14.
Excerpt from Figure 1E
Response: Admitted.
35.

36.
The DNA-targeting RNA portion of the CRISPR-Cas system used in Embodiment
E1 also comprises an activator-RNA or tracr sequence as required by Count 1. Ex. 2101,

Zhang B1 7; see, e.g., Ex. 2101, Zhang B1 172 (To promote precise transcriptional initiation,
the RNA polymerase III-based U6 promoter was selected to drive the expression of tracrRNA
(Figure 1C) (emphasis added)); see also Ex. 2101, Zhang B1 173 (To test whether
heterologous expression of the CRISPR system (SpCas9, SpRNase III, tracrRNA and precrRNA) in mammalian cells can achieve targeted cleavage of mammalian chromosomes, HEK
293FT cells were transfected with combinations of CRISPR components (emphasis added));
Ex. 2101, Zhang B1, Figure 1D. Ex. 2001, Simons 5.15. Response: Denied.
37.
Embodiment E1 provides an activator-RNA or tracr sequence. Ex. 2001, Simons
5.15. Response: Admitted.

38.
Embodiment E1 discloses a tracr sequence that hybridizes with the targeter RNA
to form a double stranded RNA duplex of a protein binding segment. Ex. 2001, Simons
2-7

39.
The CRISPR-Cas9 system used in E1 targets a DNA molecule having a target
sequence, and caused successful cleavage and editing of the human EMX1 genomic locus. See,
e.g., Ex. 2101, Zhang B1 173. Ex. 2001, Simons 5.16. Response: Insufficient information,
40.
Zhang B1 discusses that Cas9 in natural prokaryotic systems cleaves invading
DNA as part of a complex that includes Cas9, the DNA-targeting targeter RNA with a tracr mate
segment hybridized to an activator RNA. Ex. 2001, Simons 5.16. Response: Denied.
41.
Zhang B1 further discusses that in the complex, the guide sequence of the targeter
RNA directs the complex to specifically contact the DNA target by forming a DNA-RNA
heteroduplex between the target DNA sequence and the complementary RNA sequence in the
targeter RNA. Ex. 2001, Simons 5.16. Response: Denied.
42.
Zhang B1 clearly states that an adapted system with this mechanism was used in
the examples. Ex. 2001, Simons 5.16. Response: Denied.

43.
A skilled artisan having considered the successful cleavage of DNA in a
eukaryotic cell presented in E1 and the Figures of Zhang B1, and, in light of the B1 specification,
would therefore conclude that a DNA-targeting RNA comprising ... an activator-RNA or tracr
sequence that hybridizes with the targeter-RNA to form a double stranded RNA duplex of a
protein binding segment occurred. Ex. 2001, Simons 5.16. Response: Insufficient
44.

45.
The CRISPR-Cas system used in Embodiment E1 comprises a Cas9 protein, as
required by Count 1. See, e.g., Ex. 2101, Zhang B1 173 (To test whether heterologous
2-8

expression of the CRISPR system (SpCas9, tracrRNA, and pre-crRNA) in mammalian cells
can achieve targeted cleavage of mammalian chromosomes, HEK 293FT cells were transfected
with combinations of CRISPR components (emphasis added)); see also Ex. 2101, Zhang B1
Figure 1D. Ex. 2001, Simons 5.17. Response: Denied.
46.
E1 satisfies element [9] of Count 1. Ex. 2001, Simons 5.17. Response:

47.
For Embodiment E1, Zhang B1 teaches that the CRISPR complex comprises a
CRISPR enzyme [e.g. Cas9] complexed with a guide sequence. Ex. 2101, Zhang B1 11. See
also, Ex. 2101, Zhang B1 175 ([m]ature crRNA processed from the direct repeat-spacer array
directs Cas9 to genomic targets consisting of complimentary protospacers and a protospaceradjacent motif (PAM). Upon target-spacer base pairing, Cas9 creates a double-strand break in
the target DNA. Fig 1E, illustrates a schematic representation of base pairing between target
locus and EMX1-targeting crRNA). Ex. 2001, Simons 5.18. Response: Denied.
48.
The CRISPR-Cas system used in Embodiment E1 targets a DNA molecule having
a target sequence, and the experiment resulted in a successful cleavage and editing of the human
EMX1 genomic locus. See, e.g., Ex. 2101, Zhang B1 173 (Co-transfection of all CRISPR
components minus SpRNase III also induced up to 4.7% indel in the protospacer ... Sanger
sequencing of amplicons containing the target locus verified the cleavage activity in 43
sequenced clones, 5 mutated alleles (11.6%) were found (emphasis added)). Ex. 2001, Simons
49.
The skilled artisan having read the Zhang B1 specification and considered the
successful experiment of Embodiment E1 and the Figures of Zhang B1 would conclude that the
2-9

DNA-targeting RNA form[ing] a complex with the Cas9 protein occurred. Ex. 2001, Simons
50.
Element [10] of Count 1 is satisfied. Ex. 2001, Simons 5.19. Response:
Denied.
51.
In Embodiment E1, the target DNA molecule [was] cleaved or edited or
transcription of at least one gene encoded by the target DNA molecule [was] modulated, as
required by Count 1. See, e.g., Ex. 2101, Zhang B1 173 (Co-transfection of all CRISPR
components minus SpRNase III also induced up to 4.7% indel in the protospacer ... Sanger
sequencing of amplicons containing the target locus verified the cleavage activity in 43
sequenced clones, 5 mutated alleles (11.6%) were found (emphasis added)). Ex. 2001, Simons
52.
Thus, Embodiment E1 satisfies Count 1, element [11]. Ex. 2001, Simons 5.20.

53.
Zhang B1 provides ample details of how to detect and quantify editing as a
consequence of cleavage via the Surveyor assay. Ex. 2101, Zhang B1 24 and 175. Simons
54.
Zhang B1 explains that since the double strand breaks, including those resulting
from Cas9 cleavage in mammalian nuclei are partially repaired by the non-homologous end
joining (NHEJ) pathway, which leads to the formation of indels, the Surveyor assay was used to
detect potential cleavage activity at the target EMX1 locus. Ex. 2101, Zhang B1 24, 64, 154156, 173. Simons 5.22. Response: Admitted.
2-10

55.
Non-homologous end-joining is a major pathway for repair of DNA double-strand
breaks in mammalian cells, typically resulting in short insertions or deletions (indels) at or very
close to the site of the double strand break (e.g. Perez et al., NAT. BIOTECH. 26:808-816, 2008
(Ex. 2232); Godwin et al., PNAS 91:12554-12558, 1994 (Ex. 2212)). Ex. 2001, Simons 5.23.
56.
The Surveyor assay is a well-established method of detecting single base
substitution and indel mutations (Guschin et al., METH MOL. BIOL. 649:247-256, 2010 (Ex.
2214)). Ex. 2001, Simons 5.23. Response: Insufficient information, therefore unable to
admit or deny.
57.
Although indels do occur spontaneously, the frequency of spontaneous indels is
extremely low and far less than the limit of detection of the Surveyor assay. Ex. 2001, Simons
58.
The creation of double strand breaks increases the frequency of indel formation by
several orders of magnitude. Ex. 2001, Simons 5.23. Response: Denied.

59.
It follows that the detection of indels centered on the target site of an engineered
nuclease following treatment of cells with that engineered nuclease, demonstrates not only that
NHEJ occurs after cleavage by Cas9 but also that there has been cleavage at the nuclease target.
60.
Zhang B1 provides a schematic overview (Figure 7) and a descriptive overview of
the steps of a Surveyor assay. Ex. 2101, Zhang B1 154-156, Figure 7. Ex. 2001, Simons
2-11

61.
Zhang B1 also describes genomic sequencing to verify DNA cleavage and editing.
Ex. 2001, Simons 5.24. Response: Insufficient information, therefore unable to admit or
deny.
62.
Both of these methods verified cleavage of EMX1 target DNA in E1; see, e.g., Ex.
2101, Zhang B1, Figures 1D, 1F. Ex. 2001, Simons 5.24. Response: Insufficient
63.
Zhang B1 describes the components sufficient to practice the method of the
Count. Ex. 2001, Simons 5.44. Response: Insufficient information, therefore unable to
admit or deny.
64.
The working examples of Zhang B1 teach the sequences of S. pyogenes-based and
S. thermophilus-based CRISPR-Cas components. Ex. 2001, Simons 5.44. Response:

65.
Embodiment E1 describes three separate expression vectors containing different
CRISPR-Cas components based on the S. pyogenes Type II CRISPR-Cas system (in Figure 1C
reproduced below), namely: (V1), an hSpCas9; (V4), tracrRNA and (V3), a vector containing the
30 nucleotide spacer sequence GGAAGGGCCTGAGTCCGAGCAGAAGAAGAA integrated
between direct repeats (DR; Fig. 1C, grey font). Ex. 2001, Simons 5.44. Response:
66.
The spacer sequence hybridizes to the human EMX1 protospacer sequence (note
the spacer contains the identical sequence to the coding strand of the EMX1 protospacer; also
shown above in more detail in Ex. 2101, Zhang B1 Figure 1E). Ex. 2001, Simons 5.44.
2-12

67.
The downstream direct repeat contains the tracr mate sequence (Ex. 2101, Zhang
B1 170, 175). Ex. 2001, Simons 5.44. Response: Denied.

68.
Zhang B1 provides the sequences that a skilled artisan would need to make each
vector. Ex. 2001, Simons 5.44. Response: Denied.

69.
The DNA sequence for the human EF1 promoter was well known in the art, and
the Zhang B1 specification also provides the amino acid sequence encoded by the NLShSpCas9-NLS portion of Vector 1 (V1). Ex. 2101, Zhang B1 197, 199; Ex. 2001, Simons
5.44. Response: Admitted that the DNA sequence for the human EF1 promoter was well
known in the art, and the Zhang B1 specification also provides the amino acid sequence
encoded by the NLS- hSpCas9-NLS portion of Vector 1 (V1); denied that Paragraph 199
of Zhang B1 supports the alleged fact.
70.
From this information, a skilled artisan could construct the vectors, as shown in
Figure 1C, reproduced below. Ex. 2001, Simons 5.45.
Response: Denied.
71.
The DNA sequence for the U6-DR-EMX1-DR vector (Vector 3 or V3) was
taught through the combination of Zhang B1s disclosure of the U6-DR-BbsI backbone-DR
sequence in Ex. 2101, Zhang B1 192 and the spacer sequence (blue font) in Figure 1C, as a
skilled artisan would readily be able to put these two sequences together to obtain V3. Ex. 2001,
Simons 5.45-5.46. Response: Denied
2-13

72.
The DNA sequence for U6-short tracrRNA vector (Vector 4 or V4) was
provided in Ex. 2101, Zhang B1 190. Response: Admitted.

73.
Zhang B1 describes and enables how to make the components of the method of
Count 1 sufficiently for the skilled person to practice the Count 1 method. Ex. 2001, Simons
5.45-5.46. Response: Denied.
74.
The CRISPR-Cas vectors of E1 and other embodiments were engineered
specifically for use in eukaryotic cells, and thus differ in several important respects from the
CRISPR-Cas system as it exists in nature. Ex. 2001, Simons 5.47. Response: Denied.
75.
The Cas9 vectors of Embodiment E1 and other embodiments contain either an
EF1 promoter or a U6 promoter (Ex. 2101, Zhang B1, Figure 1C, 11B). Ex. 2001, Simons
76.
The EF1 promoter direct[s] constitutive expression of a nucleotide sequence in
many cell types and in this context drives expression of Cas9 in the HEK293FT cells. Ex.
2101, Zhang B1 48. Ex. 2001, Simons 5.47. Response: Insufficient information, therefore
77.
The U6 promoter in Zhang B1, Figure 1C, 11B, promote[s] precise transcription
initiation of the crRNA and tracrRNA. Ex. 2101, Zhang B1 185. Response: Denied.
78.
Neither promoter is in the CRISPR-Cas systems of S. pyogenes or S. thermophilus
as they exist in nature. Ex. 2001, Simons 5.47. Response: Insufficient information,
79.
Vector 1 of E1 contains nuclear localization signals (NLSs) for importation of
Cas9 from the cytosol, into the nucleus of the eukaryotic cell, where it carried out cleavage of the
2-14

target DNA. Ex. 2101, Zhang B1 62, 170, 175; Figure 1C. Ex. 2001, Simons 5.47.
Response: Denied.
80.
Zhang B1 discloses the sequences for the N-terminal NLS and the C-terminal
NLS used in E1. Ex. 2101, Zhang B1 170. Ex. 2001, Simons 5.47. Response: Denied.
81.
E1 teaches a skilled artisan that an hSpCas9 with an NLS on both the amino and
carboxy termini shows robust nuclear localization in HEK293FT cells. Ex. 2101, Zhang B1
170; Figure 1B. Ex. 2001, Simons 5.47. Response: Denied.
82.
Vector 3 in E1 has a spacer designed to hybridize with the EMX1 protospacer in
the human EMX1 genomic locus, as shown in Figure 1C. Ex. 2101, Zhang B1 175. Ex. 2001,
83.
Zhang B1 describes and enables how to make the CRISPR-Cas9 system in
eukaryotic cells as called for by the Count 1 method. Ex. 2001, Simons 5.47. Response:
Denied.
84.
Zhang B1 teaches a skilled artisan how to grow the eukaryotic cells in which the
CRISPR-Cas system can be utilized. Ex. 2101, Zhang B1 151-153. Ex. 2001, Simons 5.48.
85.
Zhang B1 explains how HEK 293FT cells were transfected with DNA vectors
(plasmids) containing CRISPR-Cas components. Ex. 2001, Simons 5.48. Response: Denied.
86.
Zhang B1 describes and enables how to make the CRISPR-Cas9 system in
eukaryotic cells as called for by the Count 1 method. Ex. 2001, Simons 5.47-5.48. Response:
Denied.
87.
Zhang B1 provides considerable direction and guidance for making and using the
invention of Count 1. Ex. 2001, Simons 5.53. Response: Denied.
2-15

88.
Embodiment E1 is one among many successful reductions to practice of the
method recited in Count 1. Ex. 2001, Simons 5.53. Response: Denied.

89.
Over 20 successful experiments in eukaryotic cells are described in Zhang B1. Ex.
2001, Simons 5.53. Response: Insufficient information, therefore unable to admit or deny.
90.
In each Zhang B1 embodiment, eukaryotic cells are transfected with engineered
DNA construct(s) which direct the expression of the crRNA:tracrRNA complex and the Cas9
protein as components (or precursors) of an engineered Type II CRISPR-Cas system. Ex. 2001,
91.
Upon appropriate spatial and temporal expression of the constituents of the
engineered CRISPR-Cas system, the crRNA:tracrRNA forms a complex with the Cas9 protein.
92.
The complex contacts the DNA target and the guide sequence (or spacer) of the
crRNA (or targeter-RNA) hybridizes with the protospacer (or target sequence) of the target DNA
molecule, and Cas9 then mediate cleavage of that DNA. Ex. 2001, Simons 5.53. Response:
Denied.
93.
Each of the working embodiments of Zhang B1 satisfies all the elements of Count
1, and thus is a constructive reduction to practice of Count 1 including Embodiment E1. Ex.
2001, Simons 5.54. Response: Denied.
94.
Zhang B1 and Embodiment E1 of Zhang B1 describe the method of cleaving or
introducing templated and non-templated gene edits or modulating transcription of at least one
gene encoded by a target DNA of Count 1. See, e.g., Ex. 2101, Zhang B1 173; 175; Figure
1D, lane 4. Ex. 2001, Simons 5.49-5.52. Response: Denied.
2-16

95.
As of December 12, 2012, editing or modulating transcription of at least one gene
encoded by target DNA was recognized by those of ordinary skill in the art as having substantial
utility. Ex. 2001, Simons 5.49-5.52. Response: Admitted.
96.
Zhang B1 provides a method for adapting the CRISPR-Cas9 system for function
in a eukaryotic cell, including working examples that is carried through all of the Involved Broad
Patents and Application of inventor Zhang and co-inventors in the Redeclaration of Interference.
97.
As to Count 1, Zhang B1 provides a written description that enables the person
skilled in the art to make and use the claimed invention. Ex. 2001, Simons 5.2. Response:
Denied.
98.
Both the enablement and written description requirements of 35 USC 112 have
been satisfied by Zhang B1, as of the December 12, 2012 filing date of Zhang B1, as to Count 1.
99.
Each and every application that issued as Broad patents and application in the
interference were all filed within twelve months of Zhang B1 or properly claimed the benefit
under 35 U.S.C. 120 of an application that had been filed within twelve months of Zhang B1.
Exs. 1007-1019, 2101, 2105-2121 and 2122-2133; Ex. 2001, Simons 5.61. Response:
100.
There is a common inventor, (Feng Zhang) among B1, each of the Broad patents
and application in the interference and each intervening application. Ex. 2001, Simons 5.61.
2-17

101.
Each of the Broad patents and application in the interference and each intervening
application includes a specific reference to Zhang B1. Ex. 2001, Simons 5.61. Response:
102.
Each of the applications that issued as Broad patents and application in the
interference, as well each of the intervening applications, incorporated Zhang B1 by reference.

Exs. 1007-1019, 2101, 2105-2121 and 2122-2133; Ex. 2001, Simons 5.61. Response:
2-18

Senior Party Facts in Support of Opposition 3
103.
Example 1 of U.S. Provisional Patent Application 61/736,527 is not found in U.S.
Patent No. 8,865,406 or the application from which it issued, U.S. Patent Application
14/222,930. Compare Ex. 2101 at pp. 260-268, 00150-00184 (Example 1 of Zhang B1) with
Ex. 1014 (the 406 Patent) and Ex. 2114 (U.S. Patent Application 14/222,930).
104.
105.
U.S. Patent Application 14/104,977 is the parent application for U.S. Patent
Application 14/222,930, which issued as U.S. Patent No. 8,865,406, and for U.S. Patent
Application 14/293,498, which issued as U.S. Patent No. 8,895,308. See Exs. 1014, 1015, 2106,
2114, 2121.
106.
Patent Application 14/104,977. Compare Ex. 2101 at pp. 260-268, 00150-00184 (Example 1
of Zhang B1) with Ex. 2106 (U.S. Patent Application 14/104,977).
107.
108.
International Patent Application PCT/US2013/74736 is the parent application for
U.S. Patent Application 14/226,274, which issued as U.S. Patent No. 8,999,641. See Exs. 1018,
2119, 2122.
2-19

109.
Example 1 of U.S. Provisional Patent Application 61/736,527 is not found in
International Patent Application PCT/US2013/74736. Compare Ex. 2101 at pp. 260-268,

00150-00184 (Example 1 of Zhang B1) with Ex. 2122 (International Patent Application
PCT/US2013/74736).
110.
Broad Motion 3 does not substantively address the subject matter of U.S. Patent
Application 14/054,414. See Broad Motion 3; see also Ex. 2105 (the 414 Application).
111.
112.
113.
114.
115.
Broad Motion 3 does not substantively address the subject matter of International
Patent Application PCT/US2013/74736. See Broad Motion 3; see also Ex. 2122 (the 736
Application).
116.
Broad Motion 3 does not substantively address the subject matter of International
Patent Application PCT/US2013/74819. See Broad Motion 3; see also Ex. 2123 (the 819
Application).
117.
U.S. Patent Application 14/054,414 is the parent application of U.S. Patent
Application 14/183,429, which issued as U.S. Patent No. 8,771,945. See Exs. 1008, 2105, 2111.
2-20

118.
U.S. Patent Application 14/054,414 is the grandparent application of U.S. Patent
Application 14/256,912, which issued as U.S. Patent No. 8,945,839. See Exs. 1008, 1009, 2105,
2111, 2115.
119.
Paragraph 5.2 from the Declaration by Dr. Simons does not mention U.S. Patent
Application 14/054,414. See Ex. 2001, 5.2.

120.
Paragraph 5.2 from the Declaration by Dr. Simons does not analyze the contents
of U.S. Patent Application 14/054,414. See Ex. 2001, 5.2

121.
The only mention in Broad Motion 3 of intervening applications is in alleged
Facts 100-102. See Broad Motion 3.

122.
U.S. Patent Application No. 14/105,035 is the parent of U.S. Patent Application
14/183,486, which issued as U.S. Patent No. 8,795,965. See Exs. 1012, 2110, 2113.
123.
124.

125.
of U.S. Patent Application 14/105,035. See Ex. 2001, 5.2.

126.
U.S. Patent Application 14/105,035 is not listed as a document reviewed by Dr.
Simons. See Ex. 2001, 3.4; pp. 84-85 (Table II).

127.

128.
2-21

129.

130.
131.
132.

133.

134.

135.
136.

137.

138.

139.
Paragraph 5.2 from the Declaration by Dr. Simons does not mention International
Patent Application PCT/US2013/74736. See Ex. 2001, 5.2.
2-22

140.
of International Patent Application PCT/US2013/74736. See Ex. 2001, 5.2.

141.
International Patent Application PCT/US2013/74736 is not listed as a document
reviewed by Dr. Simons. See Ex. 2001, 3.4; pp. 84-85 (Table II).
142.
International Patent Application PCT/US2013/74819 is the parent of U.S. Patent
Application 14/704,551. See Exs. 1019, 2123.

143.
Paragraph 5.2 from the Declaration by Dr. Simons does not mention International
Patent Application PCT/US2013/74819. See Ex. 2001, 5.2.

144.
of International Patent Application PCT/US2013/74819. See Ex. 2001, 5.2.

145.
International Patent Application PCT/US2013/74819 is not listed as a document
reviewed by Dr. Simons. See Ex. 2001, 3.4; pp. 84-85 (Table II).
2-23

CERTIFICATE OF FILING AND SERVICE
I hereby certify that on this 15th day of August, 2016, the foregoing UC et al.
OPPOSITION 3 is being filed, via the Interference Web Portal, by 5:00 PM Eastern Time.
Pursuant to agreement by the parties, service copy is being sent, via electronic mail by 8:00 PM
Eastern Time today, to Junior Partys counsel as follows:
Steven R. Trybus, Esq.
Harry J. Roper, Esq.
Paul D. Margolis, Esq.
JENNER & BLOCK LLP
353 North Clark Street
(312) 222-9350
strybus@jenner.com
hroper@jenner.com
pmargolis@jenner.com
/Todd R. Walters/
Alexandria, Virginia 22314
Telephone (703) 836-6620
Facsimile (703) 836-2021
Counsel for UC and Vienna

UC Opp No. 3CRISPR Patent

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Filed on behalf of Senior Party

THE REGENTS OF THE UNIVERSITY OF CALIFORNIA,

Todd R. Walters, Esq.

By: Li-Hsien Rin-Laures, M.D., Esq.

UNITED STATES PATENT AND TRADEMARK OFFICE

Interference No. 106,048

THE EVIDENCE .................................................................................................................2

STATEMENT OF MATERIAL FACTS.............................................................................2

Broads Priority Chains........................................................................................... 3

It Was Broads Burden to Show That Benefit Should Be Awarded ....................... 4

Broad Failed to Establish Continuity of Disclosure ............................................... 5

Example 1 of Zhang B1 Is Not Found in the 406 Patent, the 308

Example 1 of Zhang B1 Is Not Found in the 641 Patent or the 736

Benefit for the 616 Patent Should Not Be Awarded ............................... 15

Benefit for the 641 Patent Should Not Be Awarded ............................... 17

Benefit for the 551 Application Should Not Be Awarded....................... 18

Broads Alleged Embodiment from Zhang B1 Fails to Describe and Enable

Broad Motion 3 Does Not Demonstrate Possession in Zhang B1 of

Interference No. 106,048

Broad Motion 3 Does Not Demonstrate Possession in Zhang B1 of the

APPENDIX 1 - LIST OF EXHIBITS

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Encyclopaedia Britannica, Inc. v. Alpine Elecs. of Am., Inc.,

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Broad Motion 3 be denied.

Broad simply failed to meet its burden of proof.

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reach back and obtain benefit of Zhang B1.

by Broad simply do not support those elements.

STATEMENT OF MATERIAL FACTS

support of this Opposition are also set forth in Appendix 2.

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Exs. 1008-1016, 1018, 1019, 2111-2117, 2119-2121.

Broads Priority Chains

application, intervening applications, and Zhang B1:

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It Was Broads Burden to Show That Benefit Should Be Awarded

1220, 1221 (B.P.A.I. 2000).

Rules also make clear that:

Constructive reduction to practice means a described and enabled

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respective intervening applications back to Zhang B1. See 37 C.F.R. 41.201.

Broad Failed to Establish Continuity of Disclosure

Broad Motion 3 fails to establish a description of the subject matter of Count 1

Hillman, 55 U.S.P.Q.2d at 1221. An application in an interference is entitled to the filing date

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establish that the requisite disclosure of subject matter was made.

Application) and International Patent Application PCT/US2013/74736 (the 736 Application).

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Zhang B1 and Broad Motion 3 should be denied.

Example 1 of Zhang B1 Is Not Found in the 406 Patent, the 308

2106; see AFs 105-106.

Lockwood, 107 F.3d at 1571.

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Example 1 of Zhang B1 Is Not Found in the 641 Patent or the 736

At page 18, lines 11-17 of Broad Motion 3, it is argued that:

Broad . . . has satisfied the requirements for claiming priority to

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107 F.3d at 1571.

119-120; Ex. 2001, 5.2.

100. There is a common inventor, (Feng Zhang) among B1, each

101. Each of the Broad patents and application in the interference

102. Each of the applications that issued as Broad patents and