BROAD Et Al. REPLY 3

Filed on behalf of: Junior Party, Broad
By: Steven R. Trybus

Harry J. Roper
Paul D. Margolis
Jenner & Block LLP
353 North Clark Street
Chicago, IL 60654
Telephone: 312-222-9350
Facsimile: 312-527-0484
strybus@jenner.com
By: Raymond N. Nimrod

Quinn Emanuel Urquhart & Sullivan, LLP
51 Madison Avenue
New York, NY 10010
Telephone: 212-849-7000
Facsimile: 212-849-7100
raynimrod@quinnemanuel.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 No. 106,048 (DK)
BROAD et al. REPLY 3
TABLE OF CONTENTS
Page
I.
INTRODUCTION AND SUMMARY ................................................................................1
II.
STATEMENT OF PRECISE RELIEF REQUESTED ........................................................2
III.
DESCRIPTION OF APPENDICES ....................................................................................2
IV.
ARGUMENT .......................................................................................................................2
A.
B.
V.
Broad Has Demonstrated Possession of All Elements of Count 1 in Zhang

B1 .............................................................................................................................2
1.
Broad has Demonstrated Possession of Element [6] ...................................2
2.
Broad has Demonstrated Possession of Element [10] .................................5
3.
Benefit is Proper for the 359 and 233 Patents ...........................................7
Broad Has Satisfied 35 U.S.C. 120 for All its Involved Patents and
Application...............................................................................................................8
1.
Zhang B1 is Incorporated by Reference into the 406 Patent, the

308 Patent, and the 977 Application .......................................................10
2.
Zhang B1 is Incorporated by Reference into the 641 Patent and

the 736 Application ..................................................................................11
3.
Benefit for the 945 and 839 Patents Should be Awarded .......................12
4.
Benefit for the 965 and the 445 Patents Should be Awarded..................12
5.
Benefit for the 356 and the 814 Patents Should be Awarded..................14
6.
Benefit for the 616 Patent Should be Awarded ........................................14
7.
Benefit for the 641 Patent Should be Awarded ........................................15
8.
Benefit for the 551 Application Should be Awarded ...............................15
CONCLUSION ..................................................................................................................16
TABLE OF AUTHORITIES
Page(s)
CASES
Harari v Lee,
656 F. 3d 1331 (Fed. Cir. 2011)...............................................................................................10
Symantec Corp. v Finjan, Inc.,
2016 WL 1081973 ...................................................................................................................10
Zenon Envtl., Inc. v U.S. Filter Corp.,
506 F.3d 1370 (Fed. Cir. 2007)............................................................................................9, 10
STATUTES
35 U.S.C. 112 ................................................................................................................................1
35 U.S.C. 120 ...................................................................................................................... passim
ii
1
2
I.
INTRODUCTION AND SUMMARY

UC Opposition 3 essentially presents two arguments, neither of which has merit. First,
UC argues that Broad failed to show continuity of disclosure from Zhang B1 (Exhibit 2101) to
the involved patents and the one involved application. This argument is unavailing. As Broad
pointed out in its Motion 3 (page 18), Zhang B1 was incorporated by reference into all involved
patents and the involved application, as well as into all intervening patent applications, such that
there unquestionably has been continuity of disclosure. Moreover, this argument is inapplicable
to, and UC does not present it against, U.S. Patent Nos. 6,697,359 (the 359 patent) or 8,993,233
(the 233 patent).
10
Second, UC asserts that Zhang B1 fails to describe two of the 11 elements of Count 1,
11
namely, [6] (a DNA-targeting RNA) and [10] (wherein the DNA-targeting RNA forms a
12
complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule).
13
UCs argument is unavailing, as Zhang B1 indisputably shows both of these elements.
14
Broad will address UCs second argument first, because it is the only argument that
15
applies to all of the involved patents and application. UC does NOT dispute that the 359 Patent
16
(Ex. 1007) and the 233 patent (Ex. 1017) satisfy 35 U.S.C. 120. The 359 and 233 Patents
17
claim priority directly to Zhang B1--without any intervening application. Furthermore, as the
18
Board made clear in its Order Authorizing Motions (PN 33), benefit to the applications that
19
became the involved patents has already been accorded to Broad based on the involvement of
20
the patents that issued from these applications. Therefore, Broads argument need not refer to
21
them. PN 33, Order page 5, lines 10-12. Broad Motion 3 should be granted at least with
22
respect to these two involved patents and, with that determination, no decision needs to be made
23
regarding benefit for the other involved patents and application.
II.
STATEMENT OF PRECISE RELIEF REQUESTED
Broad requests that Motion 3 be granted and Broad be accorded benefit of US
Application No. 61/736,527, filed December 12, 2012 (Zhang B1), Ex. 2101, for Count 1.
III.
DESCRIPTION OF APPENDICES
Appendix 1 includes a list of the exhibits cited in this reply. Appendix 2 includes a
Statement of Material Facts and responses. Appendix 3 includes a chart showing Broads priority
claims and incorporation by reference statements for each involved patent and application.
IV.
9
10
ARGUMENT
A.
Broad Has Demonstrated Possession of All Elements of Count 1 in Zhang B1
The only elements for which UC argues Broad failed to demonstrate possession are
11
elements [6] and [10] in Count 1. Tellingly, UC does not introduce any evidence showing that
12
Zhang B1 fails to demonstrate possession of those elements. Rather, UC merely relies on
13
attorney argument. In addition, as detailed below, UC repeatedly cherry-picks isolated phrases
14
from Broads Motion 3, and then argues that Broad failed to meet its burden because these
15
isolated phrases, taken completely out of context, lack proper evidentiary supportall the while
16
overlooking Broads evidence and argument in other paragraphs that provide the very support
17
that UC claims is lacking.
18
1.
Broad has Demonstrated Possession of Element [6]
19
UC asserts that Broad has not demonstrated possession of the DNA-targeting RNA
20
component (element [6]) of Count 1. UC Opp. 3 p. 20 l. 10p. 22 l. 7. Broads response is
21
that it has demonstrated possession of elements [7] and [8] and that those elements form a duplex
22
with each other. Therefore, Broad necessarily demonstrated possession of element [6] of Count
23
1 because together element [7] and element [8] form element [6] - the DNA-targeting RNA.
Said another way, in this instance the DNA-targeting RNA of element [6] comprises no more
than the combination of elements [7] and [8] such that showing possession of both elements [7]
and [8] can and does necessarily show possession of element [6].
UC does not deny that Broad has demonstrated possession of element [8]. See, e.g., UC
Opp. 3, Appendix 2, p. 2-7. In fact, UC has admitted Broads possession of element 8. See UC
Opp. 3, Material Fact 38 (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 5.16. Response: Admitted). Indeed, a comparison of admitted Material Fact
38 to the language of element [8] (an activator-RNA or tracr sequence that hybridizes with the
10
targeter-RNA to form a double-stranded RNA duplex of a protein binding segment) shows that
11
there can be no dispute; Broads Embodiment E1 discloses element [8] of Count 1.
12
UC also does not deny Broad has demonstrated possession of element [7]. See, e.g., UC
13
Opp. 3 p. 21 l. 24p. 22 l. 1 and UC Opp. 3 p. 2-7, Material Fact 35. Nor can it. As set forth in
14
detail at page 9, lines 8-16 of Broad Motion 3, Embodiment E1 uses a crRNA that includes a
15
guide sequence. Ex. 2101 162, 172-173 and Fig. 1D (DR-EMX1-DR). Furthermore, Figure
16
1E of Zhang B1 (reproduced in part below) depicts the guide sequence of a crRNA hybridizing
17
to a target RNA (identified as target locus in the figure). Zhang B1 describes Figure 1E as a
18
schematic representation of base pairing between target locus (double stranded DNA) and
19
EMX1-targeting crRNA. Ex. 2101, 175. Figure 1E therefore depicts element [7]: the guide
20
sequence is identified as the blue nucleotides of the strand identified as crRNA and the figure
21
shows that sequence hybridized to the target sequence (the bottom sequence of the target
22
locus); the hybridization is indicated by the vertical dashes,|.
23
Excerpt from Figure 1E

3
1
2
UC argues that Embodiment E1 merely shows the use of a pre-crRNA, not a mature crRNA....
UC Opp. 3, p. 21 ll. 19-20. Broads response is that the use of the term pre-crRNA in
Embodiment E1 is irrelevant and was explained in footnote 4 of Broad Motion 3, a fact UC
apparently overlooked. The mature crRNA is processed from the pre-crRNA: Zhang B1
teaches that tracrRNA hybridizes to the direct repeats of pre-crRNA, which is then processed
into mature crRNAs containing individual spacer sequences. Footnote 4 of Broad Motion 3.
See also, for example, Ex. 2101 150, 172-175 and Figures 1C and 1E. See also Ex. 2001
5.14, 5.15, 5.27, 5.28 and 5.37. Therefore, a person of ordinary skill in the art would have
10
understood that pre-crRNA is processed into mature crRNA in vivo. Ex. 2001 2.9, 5.6. In
11
fact, UCs expert Dr. Carol Greider testified to this point. (Q. ...What do you mean by pre-
12
CRISPR RNA? A. The pre-CRISPR RNA that is made, its the term pre-CRISPR RNA, and it
13
needs to be processed into CRISPR RNAs. Q. Processed that it gets cut? A. Theres a cleavage
14
event, an RNA cleavage event and Q. So pre-CRISPR RNA differs from crRNA in that this
15
pre-CRISPR RNA gets cut to make crRNA? A. Yes, in several different steps. Greider
16
transcript, Ex. 2013, p. 133, ll. 3-9; and p. 134, ll. 12-15. Also, pre-crRNA is in the scope of
17
element [7] as it comprises the necessary guide sequence that hybridizes to a target sequence.
18
See, e.g., Broad Motion 3, p. 16, ll. 13-14, Appendix 3-6; Ex. 2001. Figure 1C.
19
Moreover, Broad has shown that elements [7] and [8] are duplexed to form element [6].
20
See UCs admission of Material Fact 38, which states that Broads Embodiment E1 discloses a
21
tracr sequence [i.e., element 8] that hybridizes with the targeter RNA [i.e., element 7] . UC
22
Opp. 3, Appendix 2, p. 2-7. See also the discussion below regarding element [10].
4
1
2
2.
Broad has Demonstrated Possession of Element [10]
UC further asserts that Broad has not demonstrated possession of element [10] the
DNA-targeting RNA forms a complex with the Cas9 protein, thereby targeting the Cas9 protein
to the target DNA molecule[.] UC Opp. 3 p. 22 l. 8p. 25 l. 4. The response is that Broad has
sufficiently demonstrated possession of element [10] of the Count. UC argues that B1 only
discusses, at most, a complex between the crRNA (targeter-RNA) and the Cas9 protein and that
[i]t does not, however, mention or explain the role for the activator RNA or tracr sequence.
UC Opp. 3, p. 24, ll. 3-6. However, as noted above, UC admitted Material Fact 38. See UC
Opp. 3, Appendix 2, p. 2-7. Because UC admits that the targeter RNA is bound to the tracr, the
10
targeter RNA must form a complex with the Cas9 protein and the tracr that is part of a duplex
11
must also be part of the complex.
12
Again, UC overlooks the evidence set forth by Broad showing possession of element
13
[10]. See, e.g., Broad Motion 3 p. 11 l. 12p.12 l. 13, p. 13 l. 1p. 14 l. 5; Ex. 2101 Figs. 1A and
14
1D-1F, 1, 24, 64, 150, 154-156, 173-175; Ex. 2001 5.18-5.19, 5.22-5.24, 5.26-5.30, 5.35-
15
5.37. Zhang B1 states:
16
17
18
19
[T]he CRISPR complex comprises a CRISPR enzyme complexed with a guide

sequence hybridized to a target sequence within said target polynucleotide,
wherein said guide sequence is linked to a tracr mate sequence which in turn
hybridizes to a tracr sequence.
20
Ex. 2101 11. UC, relying on merely a portion of a single sentence in Zhang B1 11, concludes
21
that 11 fails to describe a complex comprising a DNA targeting RNA and a Cas9 protein. UC
22
Opp. 3, p. 23, ll. 26-34. Broads response is that, consistent with Broads Motion 3 at p. 11, ll.
23
15-16, this sentence, taken in the context of the entire disclosure of B1 (including, e.g., 4-8,
24
150, 168, 170, 175, 178 and the claims), discloses the DNA-targeting RNA in a complex with
25
the Cas9 protein. See, e.g., Ex. 2001 5.40-5.41.

5
UC also asserts that the CRISPR enzyme of cited paragraph 11 is not Cas9[.] UC
Opp. 3, p. 23 l. 34. Broads response is, B1 recites CRISPR enzyme in 11 and B1
unequivocally describes Cas9 as such a CRISPR enzyme: [i]n some embodiments, the CRISPR
enzyme is a Cas9 enzyme. Ex. 2101 4-8. Moreover, every experiment described in B1 uses
Cas9, and Cas9 is recited in the B1 claims as filed (see claims 8, 20, 24, 35 and 53). Although in
one embodiment, the CRISPR enzyme of B1 can encompass enzymes other than Cas9 ([i]n
some embodiments, the CRISPR enzyme is a Type II CRISPR enzyme system Ex. 2101 5),
Cas9, the prototypical Type II CRISPR enzyme, is described as being directed to the target by
the complex, and only Cas9 is described as mediating cleavage. See, e.g., Ex. 2101 173, 175,
10
176. Further, as recognized by UCs own experts, Cas9 is the only CRISPR enzyme required for
11
cleavage by the CRISPR system. Ex. 1022 50; Ex. 1024 44.
12
Notably, UCs argument here is in direct conflict with its position in UC Motion 4 at p. 8,
13
where UC argues that Figure 1 of UCs provisional application P1 supports the DNA-targeting
14
RNA forms a complex with the Cas9 protein element of Count 1. But, Figure 1 of P1 does not
15
refer to Cas9 but rather to a site-directed modifying polypeptidea term that is broader than
16
CRISPR enzyme and that is defined in UCs P1 as a polypeptide that binds RNA and is
17
targeted to a specific DNA sequence. Ex. 1001 126.
18
UC also asserts that Paragraph 150 of Zhang B1, when taken in context, is referencing
19
the natural CRISPR-Cas system and is not a description of experiments performed in Zhang B1.
20
UC Opp. 3, p. 24 ll. 14-18. Broads response is that UC has overlooked the last sentence of
21
150 (which must be considered in its entirety): This example [Example 1] describes an
22
example process for adapting this RNA-programmable nuclease system to direct CRISPR
23
complex activity in the nuclei of eukaryotic cells.

6
Dr. Simons, Broads expert, explained that Example 1 of B1 describes a process of
adapting the natural CRISPR-Cas system in eukaryotic cells. See, e.g., Ex. 2001 5.19, as well
as 5.22-5.25. This testimony is unrebutted by UC and its experts.
A person of ordinary skill in the art would also understand that the DNA-targeting RNA
of Embodiment 1 forms a complex with the Cas9 protein, thereby targeting the Cas9 protein to
the target DNA molecule in eukaryotic cells, because the target-specific DNA-targeting RNA
and Cas9 protein were shown by Zhang B1 to induce indel formation in the chosen DNA target.
Ex. 2001 5.16 and 5.19; Ex. 2101 173. Moreover, UC also entirely overlooks page 13, line
1 to page 14, line 5 of Broads Motion 3, which offers additional argument in support of
10
possession of element [10] based on the detection of DNA cleavage using the Surveyor assay,
11
demonstrating that Cas9 is targeted to the target DNA. Ex. 2101 173; Ex. 2001 5.22-5.25.
12
As UCs expert Dr. Carroll testified, one of skill in the art in 2012 knew that for cleavage to take
13
place (as demonstrated in Zhang B1), Cas9 had to be bound to a crRNA and tracrRNA complex,
14
and such binding was required to direct the complex to the target DNA. (Q. ... In 2012, a
15
person of ordinary skill in the art knew that in order for cleavage to take place, Cas9 had to be
16
bound to a CRISPR RNA[targeter RNA] and tracrRNA complex; correct? A: Yes. Q: And in
17
2012, a person [of] ordinary skill[] in the art knew that binding between the CRISPR RNA
18
tracrRNA hybrid and Cas9 was required to direct the complex to the target DNA; correct? A:
19
Yes. Carroll transcript Ex. 2012, p. 163, lines 16-25.
20
21
3.
Benefit is Proper for the 359 and 233 Patents
Because the only arguments that UC raised with regard to the 359 and 233 patents were
22
the alleged absence of proof on elements [6] and [10], and because those arguments have been
23
shown to be wrong, Broad should be accorded benefit of the December 12, 2012, filing date of
Zhang B1 for Count 1. Moreover, because Broad has shown that UC is not entitled to the benefit
of any filing date prior to December 12, 2012 (see Broad Opposition 4, PN #725), the
interference should be redeclared with Broad as the Senior Party.
Below, Broad shows why UCs arguments regarding 120, made with respect to the
involved patents and application (other than the involved 359 and 233 patents), are incorrect,
entitling Broad to the December 12, 2012, date for all of those involved patents and for the
involved application as well.

B.
8
9
Broad Has Satisfied 35 U.S.C. 120 for All its Involved Patents and
Application 1
10
In UC Opp. 3, Senior Party UC does not dispute any of the assertions set forth in Broad
11
Motion 3 at p. 18, lines 11-17, that for all the applications that issued as the Broad patents and
12
application in this interference, each was filed within twelve months of Zhang B1 or claimed
13
benefit to an application filed within twelve months of Zhang B1, each included at least one
14
common inventor (Feng Zhang), each included (including the 359 and the 233 patents) a
15
specific reference to Zhang B1, and each included a statement reciting that Zhang B1 was
16
incorporated by reference. In fact, UC admits that the 406 (Ex. 1014), 308 (Ex. 1015) and 641
17
(Ex. 1018) Patents contain language attempting to incorporate the content of Zhang B1 by
18
reference (UC Opp. 3, p. 6, lines 17- 18).
19
Nonetheless, on page 6, line 17 through page 7, line 3 of UC Opp. 3, UC asserts that
20
Broad Motion 3 should be denied because Broad motion 3 fails to include a substantive analysis
21
regarding possible incorporation by reference. In support of this assertion, UC relies upon
22
Zenon Envtl., Inc. v U.S. Filter Corp., 506 F.3d 1370, 1378 (Fed. Cir. 2007) for the proposition
The analysis presented herein is supported by Appendix 3.

8
that the host document must identify with detailed particularity what specific material it
incorporates and clearly indicate where that material is found in the various documents and
that [w]hether material has been incorporated by reference into a host document, and the extent
to which it has been incorporated is analyzed from the viewpoint of one reasonably skilled in
the art. The response is that UC misstates the law and that Broad has met its burden by the
showing in Motion 3 on page 18, lines 11-17. In addition, Zenon does not apply to the facts of
the present interference. As stated in Broad Motion 3 on page 18, lines 11-17, and not denied by
UC, each of the involved Broad patents and application, as well as the intervening applications
from which priority is claimed, contains an explicit statement incorporating the previous
10
applications by reference in their entirety. This incorporation by reference statement, along with
11
compliance with the other requirements of 35 U.S.C. 120, which UC does not deny have been
12
met, are all that is required to incorporate the contents of Zhang B1, including Example 1 upon
13
which Broad relies, into each involved application and patent and to provide the required
14
continuity of disclosure.
15
This was made clear by a recent decision of the PTAB rejecting essentially the same
16
argument presented by UC, and distinguishing Zenon and other similar cases on the basis that in
17
Zenon there was a lack of continuity of disclosure in a priority chain because the priority
18
references were not incorporated in their entirety, but only with respect to specific portions.
19
Symantec Corp. v Finjan, Inc., 2016 WL 1081973 (IPR2015-01897 (PTAB February 26, 2016)).
20
In contrast, in the Broad applications, as in Symantec, the boilerplate language used in the
21
[Broad] patents, broadly stating without further qualification that the earlier-filed patents are
22
incorporated by reference, is sufficient in view of Federal Circuit precedent to incorporate the
23
disclosure of at least the [Zhang B1] patent into each later-filed patent (citing Harari v Lee, 656
9
F. 3d 1331, 1335 (Fed. Cir. 2011). In Harari, the Federal Circuit found that the entire
application disclosure was incorporated by the broad and unequivocal language: The disclosures
of the two applications are hereby incorporated by reference. Harari, 656 F.3d at 1335.
Accordingly, because all of Broads involved patents and application, and all applications
from which they claim priority, contain such boilerplate language as noted on page 18, lines
11-17 of Broad Motion 3, Broad has satisfied its burden, as will discussed more fully below.
7
8
9
1.
Zhang B1 is Incorporated by Reference into the 406 Patent, the 308

Patent, and the 977 Application
On page 7, line 9 of UC Opp. 3, UC asserts that Example 1 is not found in the 406 or the
10
308 Patents. On page 7, lines 13-14 of UC Opp. 3, UC asserts that Example 1 of Zhang B1 is
11
not found in the 977 Application, the intervening parent application for both the 406 and 308
12
Patents. The response is that the entire disclosure of Zhang B1, including Example 1, is
13
incorporated by reference into the 977 Application, and the 406 and 308 Patents.
14
The 977 Application claims priority to Zhang B1, and both the 406 and 308 Patents
15
claim priority to the 977 Application. Specifically, paragraph [0001] of the 977 Application
16
claims priority to U.S. provisional patent application[] 61/736,527 filed on December 12,
17
2012.... (Ex. 2106). This statement is followed by paragraph [0003] which states that:
18
19
20
21
22
23
24
25
26
27
The foregoing applications, and all documents cited therein or during their
prosecution (appln cited documents) and all documents cited or referenced in
the appln cited documents, and all documents cited or referenced herein (herein
cited documents), and all documents cited or referenced in herein cited
documents, together with any manufacturers instructions, ... are hereby
incorporated herein by reference, and may be employed in the practice of the
invention. More specifically, all referenced documents are incorporated by
reference to the same extent as if each individual document was specifically and
individually indicated to be incorporated by reference. (hereinafter incorporation
by reference statement).
10
The 406 Patent issued from Application 14/222,930 (930 Application) (Ex. 2114)
which states in paragraph [0001] This application is a continuation of U.S. application
14/104,977, filed December 12, 2013 and This application also claims priority to U.S.
provisional application[] 61/736,527 filed on December 12, 2012. (Ex. 2114). Paragraph
[0003] of the 930 Application contains the incorporation by reference statement set forth above.
(Ex. 2114). The 308 Patent issued from Application 14/293,498 (498 Application) (Ex.2121),
which contains in paragraph [0001] a claim of priority to Zhang B1 and the 977 Application and
in paragraph [0003] the incorporation by reference statement set forth above.
9
10
11
12
13
Example 1 is present in the disclosure of the 406 Patent, the 308 Patent and the 977
Application because the entire Zhang B1 specification is incorporated by reference therein.
2.
Zhang B1 is Incorporated by Reference into the 641 Patent and the

736 Application
On page 8, line 6 of UC Opp. 3, it is asserted that Example 1 of Zhang B1 is not found in
14
the 641 Patent. Also, on page 8, lines 9-10, of UC Opp. 3, it is asserted that Example 1 of
15
Zhang B1 is not found in the 736 Application, the intervening parent application for the 641
16
Patent. The response to both assertions is similar to that noted above regarding the 406 and
17
308 Patents and the 977 Application: the entire disclosure of Zhang B1, including Example 1,
18
is incorporated by reference into both the 641 Patent and the intervening 736 Application.
19
U.S. application 14/226,274 (274 Application) (Ex. 2119) which issued as the 641
20
Patent, claims priority to the 736 Application and Zhang B1 in paragraph [0001] and contains in
21
Paragraph [0003] the incorporation by reference statement set forth above. Ex. 2119. Paragraph
22
[0001] of the 736 Application (Ex. 2122) claims priority to Zhang B1 and paragraph [0003] of
23
the 736 Application as filed contains the incorporation by reference statement. Ex. 2122.
11
1
2
3.
Benefit for the 945 and 839 Patents Should be Awarded
At page 10, lines 22-24 of UC Opp. 3, it is asserted that because Broad Motion 3 lacks
any substantive analysis of the 414 application, which is an intervening application for both the
945 and 839 Patents, benefit should not be awarded for those patents. The response is that
benefit was awarded to the 414 application that issued as the 359 Patent and Broad so noted in
its motion. See 359 patent (Ex. 1007), 5.61 Simons Declaration (Ex. 2001), Facts 100-102,
lines 11-17 of page 18 of Broad Motion 3. Accordingly, the 414 Application is specifically
discussed by Broad Motion 3 and by Dr. Simons.
The 839 Patent (Ex. 1009) issued from application No. 14/256,912 (912 Application)
10
(Ex. 2115) which claims priority in paragraph [0001] to the intervening Application 14/183,429
11
(429 Application) (Ex. 2111), the 414 Application (Ex. 2105) as well as Zhang B1 and contains
12
in paragraph [0002] the incorporation by reference statement. The 429 Application, which
13
issued as the 945 Patent (Ex. 1008), claims priority to the 414 Application and Zhang B1 in
14
paragraph [0001] and contains the incorporation by reference statement in paragraph [0002]. Ex.
15
2111. The 414 Application (and the 359 Patent) claim priority to Zhang B1 in paragraph
16
[0001], and include the incorporation by reference statement in paragraph [0002]. Ex. 2105,
17
1-2; Ex. 1007, Col. 1 ll. 1-30. The 414, 429 and 912 Applications as filed all explicitly
18
disclose Example 1 of Zhang B1 in 130-160. Exs. 2105, 2111 and 2115.
19
20
4.
Benefit for the 965 and the 445 Patents Should be Awarded
On page 12, lines 5-7 of UC Opp. 3, it is argued that because Broad Motion 3 lacks any
21
substantive analysis of the 035 Application, an intervening application for both the 965 and
22
445 Patents, benefit should not be awarded for those patents. The response is that the 035
23
Application (Ex. 2110) is cited in Fact 102 and in lines 11-17 of page 18 of Broad Motion 3.
12
1
2
3
In particular, the 035 Application claims priority to Zhang B1 in paragraph [0001] and
includes the incorporation by reference statement in paragraph [0003]. Ex. 2110 1, 3.
Furthermore, Application 14/183,486 (486 Application), which issued as the 965 Patent
(Ex. 1012), contains in paragraph [0003] the incorporation by reference statement, and in
paragraph [0001] a claim of priority to the 035 Application and Zhang B1. Ex. 2113.
Application 14/259,420 (420 Application), which issued as the 445 Patent (Ex. 1013), contains
in paragraph [0001] a claim of priority to the 035 Application and Zhang B1 and contains in
paragraph [0003] the incorporation by reference statement. Ex. 2117. The response also is that
the 035, the 486 and the 420 Applications as filed all contain Example 1 from Zhang B1 in
10
186-220. Exs. 2110, 2113 and 2117.
11
Benefit for the 406 and 308 Patents Should be Awarded
12
On page 13, lines 24-26 of UC Opp. 3, it is asserted that because Broad Motion 3 lacks
13
any substantive analysis of the 977 Application, an intervening application for both the 406 and
14
308 Patents, benefit should not be awarded for those patents. The response is that the 977
15
16
The 977 Application claims priority to Zhang B1 in paragraph [0001] and includes the
17
incorporation by reference statement in paragraph [0003]. Ex. 2106. The 406 Patent (Ex. 1014)
18
was filed as Application 14/222,930 (930 Application), which includes in paragraph [0001] a
19
claim of priority to the 977 Application and Zhang B1, and includes in paragraph [0003] the
20
incorporation by reference statement. Ex. 2114. Also, the 308 Patent (Ex. 1015) issued from
21
Application 14/293,498 (498 Application), which contains a priority claim in paragraph [0001]
22
to the 977 Application and Zhang B1, and contains in paragraph [0003] the incorporation by
23
reference statement. Ex. 2121.

13
1
2
5.
Benefit for the 356 and the 814 Patents Should be Awarded
any substantive analysis of the 031 Application, an intervening application for both the 356 and
814 Patents, benefit should not be awarded for these patents. The response is that the 031
More particularly, the 031 Application contains in paragraph [0001] a claim of priority
to Zhang B1 and in paragraph [0003] the incorporation by reference statement. Ex. 2109. The
356 Patent (Ex. 1010) issued from Application 14/183,471 (471 Application) which contains in
paragraph [0001] a priority claim to the 031 Application and Zhang B1, and in paragraph [0003]
10
the incorporation by reference statement. Ex. 2112. The 814 Patent (Ex. 1011) issued from
11
Application 14/258,458 (458 Application), which contains in paragraph [0001] a priority claim
12
to the 031 Application and Zhang B1, and in paragraph [0003] the incorporation by reference
13
statement. Ex. 2116. The response is that all of the 031, the 471 and the 458 Applications as
14
filed contain Example 1 of Zhang B1 in paragraphs 186-220. Exs. 2109, 2112 and 2116.
15
6.
Benefit for the 616 Patent Should be Awarded
16
On page 16, lines 32 and 33 of UC Opp. 3, it is asserted that, because Broad Motion 3
17
lacks any substantive analysis of the 990 Application, an intervening application for the 616
18
Patent, benefit should not be awarded for that patent. The response is that the 990 Application
19
(Ex. 2107) is cited in Fact 102 and in lines 11-17 of page 18 of Broad Motion 3.
20
More particularly, the 990 Application claims priority to Zhang B1 in paragraph [0001]
21
and contains in paragraph [0003] the incorporation by reference statement. Ex. 2107. The 616
22
Patent (Ex. 1016) issued from Application 14/290,575 (575 Application) which contains in
23
paragraph [0001] a priority claim to the 990 Application and Zhang B1 and in paragraph [0003]
14
the incorporation by reference statement. Ex. 2120. The response also is that the 990 and 575
Applications both contain Example 1 of Zhang B1 in paragraphs 156-171. Exs. 2107 and 2120.
3
4
7.
Benefit for the 641 Patent Should be Awarded
any substantive analysis of the 736 Application, an intervening application for the 641 Patent,
benefit should not be awarded for that patent. The response is that the 736 Application (Ex.
2122) is cited in Fact 102 and in lines 11-17 of page 18 of Broad Motion 3.
10
641 Patent (Ex. 1018) issued from Application 14/226,274 (274 Application), which contains
11
in paragraph [0001] a priority claim to the 736 Application and Zhang B1 and in paragraph
12
[0003] the incorporation by reference statement. Ex. 2119.
13
14
8.
Benefit for the 551 Application Should be Awarded
On page 19 line 32 through page 20 line 1 of UC Opp. 3, it is asserted that because Broad
15
Motion 3 lacks any substantive analysis of the 819 Application, an intervening application for
16
the 551 Application, benefit should not be awarded for that application. The response is that the
17
819 Application (Ex. 2123) is cited in Fact 102 and lines 11-17 of page 18 of Broad Motion 3.
18
19
20
551 Application contains in paragraph [0001] a claim of priority to the 819 Application and to
21
Zhang B1 and includes in paragraph [0003] the incorporation by reference statement. Ex. 1019.
22
The response also is that both the 819 and 551 Applications contain Example 1 of Zhang B1 in
23
153-168. Exs. 2123 and 1019.
15
As demonstrated above, the entire disclosure of Zhang B1, including Example 1, upon
which Broad relies, is incorporated by reference into each involved Broad patent and application
and each intervening application through the use of a proper priority claim and a non-limiting
incorporation by reference statement in each and every one of the applications as filed. UC does
not dispute that the other requirements of 35 U.S.C. 120 are satisfied, namely that Feng Zhang
is a common inventor, that one of the applications in the priority chain was filed within twelve
months of the filing date of Zhang B1 and that each subsequent application was filed during the
pendency of the previous application; thus, Broad has demonstrated entitlement to the benefit of
Zhang B1 for Count 1 with respect to each of the involved patents and application.
10
V.
CONCLUSION
11
For all the reasons discussed above, Broad requests to be accorded benefit of US
12
Application No. 61/736,527, filed December 12, 2012, for the subject matter of Count 1.
13
Dated: September 28, 2016
Respectfully submitted,
14
15
16
17
18
19
20
21
22
/Steven R. Trybus/
Steven R. Trybus
Reg. No. 32,760
Lead Counsel for Broad
Jenner & Block LLP
Chicago, IL 60654
Telephone: (312) 222-9350
Facsimile: (312) 527-0484
strybus@jenner.com
16
APPENDIX 1: LIST OF EXHIBITS

Exhibit
Number
Description
1001
U.S. Patent Application No. 13/842,859, filed on March 15, 2013, to

Jennifer Doudna et al. (the 859 Application)
1007
Zhang, U.S. Patent 8,697,359, April 15, 2014.
1008
Zhang, U.S. Patent 8,771,945, July 8, 2014.
1009
Zhang. U.S. Patent 8,945,839, February 3, 2015.
1010
Zhang, U.S. Patent 8,889,356, November 18, 2014.
1011
Cong et al., U.S. Patent 8,932,814, January 13, 2015.
1012
Zhang, U.S. Patent 8,795,965, August 5, 2014.
1013
Cong et al., U.S. Patent 8,871,445, October 28, 2014.
1014
Zhang et al., U.S. Patent 8,865,406, October 21, 2014.
1015
Zhang et al., U.S. Patent 8,895,308, November 25, 2014.
1016
Zhang et al., U.S. Patent 8,906,616, December 9, 2014.
1017
Zhang et al., U.S. Patent 8,993,233, March 31, 2015.
1018
Zhang et al., U.S. Patent 8,999,641, April 7, 2015.
1019
U.S. Patent Application No. 14/704,551, filed May 5, 2015.
1022
Declaration of Dr. Carol Greider, executed May 23, 2016.
1024
Declaration of Dr. Dana Carroll, executed May 23, 2016.
2001
Declaration of Dr. Paul Simons, executed May 23, 2016.
2012
Deposition transcript of Dr. Dana Carroll from September 13, 2016.
2013
Deposition transcript of Dr. Carol Greider from September 16, 2016.
2101
U.S. Provisional Patent Application No. 61/736,527, filed December

12, 2012.
A1-1
Exhibit
Number
Description
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.
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
2117
2119
U.S. Patent Application No. 14/226,274, filed March 26, 2013.
2120
U.S. Patent Application No. 14/290,575, filed May 29, 2014.
2121
U.S. Patent Application No. 14/293,498, filed June 2, 2014.
2122
Zhang et al., International Patent Application No.

PCT/US2013/074736 (WO 2014/093655)
2123
Zhang et al., International Patent Application No.

PCT/US2013/074819 (WO 2014/093712)
A1-2
APPENDIX 2: STATEMENT OF MATERIAL FACTS

Broads Facts with UCs Responses
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
A2-1
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.
7.
Activator-RNA and tracr sequence are alternative terms in Count 1. Ex.

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

A2-2
CRISPR- Cas system (SpCas9, tracr RNA and pre-crRNA). Ex. 2101, Zhang B1 173; Figure
1D, lane 4. Ex. 2001, Simons 5.4. Response: Denied.
13.
E1 therefore satisfies element [1] of Count 1. Ex. 2001, Simons 5.4.

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
A2-3
the eukaryotic system of the examples:

... 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. Response: Insufficient information, therefore unable to admit or deny.

A2-4
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.
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,
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
A2-5
Ex. 2101, Zhang B1 173 (the Surveyor assay was used to detect potential cleavage activity at
the targetEMX1 locus ... Co-transfection of the CRISPR components induced up to 4.7% indel
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:
Insufficient information, therefore unable to admit or deny.
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
unable to admit or deny.
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
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
A2-6
Count 1. Ex. 2001, Simons 5.14. Response: Denied.

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 Bsal sites); see also Fig 1E. Ex. 2001, Simons 5.14.
Excerpt from Figure IE
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 pre- crRNA) 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

A2-7
RNA to form a double stranded RNA duplex of a protein binding segment. Ex. 2001, Simons
5.16. Response: Admitted.
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
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 DNARNA 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.
44.

A2-8
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
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
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 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 5.18. Response: Insufficient information, therefore unable to admit or deny.
A2-9
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. Response: Denied.
50.
Element [10] of Count 1 is satisfied. Ex. 2001, Simons 5.19. Response:
51.
In Embodiment E1, the target DNA molecule [was] cleaved or edited or
Denied.
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,
52.
Thus, Embodiment E1 satisfies Count 1, element [11]. Ex. 2001, Simons

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.
54.
Zhang B1 explains that since the double strand breaks, including those
resulting from Cas9 cleavage in mammalian nuclei are partially repaired by the nonhomologous 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.
A2-10
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. 26:808816, 2008 (Ex. 2232); Godwin et al., PNAS 91:12554-12558, 1994 (Ex. 2212)). Ex. 2001,
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,
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. Ex. 2001, Simons 5.23. Response: Denied.
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
5.24. Response: Admitted.
61.
Zhang B1 also describes genomic sequencing to verify DNA cleavage and
editing. Ex. 2001, Simons 5.24. Response: Insufficient information, therefore unable to
A2-11
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 information,
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.
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
A2-12
each vector. Ex. 2001, Simons 5.44. Response: Denied.

69.
The DNA sequence for the human EF1a 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 B1's 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
72.
The DNA sequence for U6-short tracrRNA vector (Vector 4 or V4)
A2-13
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,
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,
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
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
A2-14
the 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.
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
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.
A2-15
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, Simons 5.53. Response: Denied.
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. Ex. 2001, Simons 5.53. Response: Denied.
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.
95.
As of December 12, 2012, editing or modulating transcription of at least one
A2-16
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. Ex. 2001, Simons 5.61. Response: Denied.
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. Ex. 2001, Simons 5.2. Response: Denied.
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
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.
A2-17
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.
A2-18
UCs Alleged Facts with Broads Responses

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).
Answer: Denied
104.
Answer: Denied
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.
Answer: Admitted
106.
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).
Answer: Denied
A2-19
107.
Answer: Denied
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.
Answer: Admitted
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).
Answer: Denied
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).
Answer: Denied
111.
A2-20
Answer: Denied
112.
Answer: Denied
113.
Answer: Denied
114.
Answer: Denied
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).
Answer: Denied
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).
Answer: Denied
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.
A2-21
Answer: Admitted
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.
Answer: Admitted
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.
Answer: Denied
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.
Answer: Denied
121.
The only mention in Broad Motion 3 of intervening applications is in alleged Facts 100-
102. See Broad Motion 3.
Answer: Denied
122.
U.S. Patent Application No. 14/105,035 is the parent of U.S. Patent Application
Answer: Admitted
A2-22
123.
Answer: Admitted
124.
Answer: Admitted
125.
Answer: Denied
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).
Answer: Admitted
127.
Answer: Admitted
128.
A2-23
Answer: Denied
129.
See Ex. 2001, 3.4; pp. 84-85 (Table II).
Answer: Admitted
130.
Answer: Admitted
131.
Answer: Admitted
132.
Answer: Admitted
133.
Answer: Denied
134.
See Ex. 2001, 3.4; pp. 84-85 (Table II).

A2-24
Answer: Admitted
135.
Answer: Admitted
136.
Answer: Admitted
137.
Answer: Denied
138.
See Ex. 2001, 3.4; pp. 84-85 (Table II).
Answer: Admitted
139.
Paragraph 5.2 from the Declaration by Dr. Simons does not mention International Patent
Application PCT/US2013/74736. See Ex. 2001, 5.2.
Answer: Admitted
140.
Paragraph 5.2 from the Declaration by Dr. Simons does not analyze the contents of
International Patent Application PCT/US2013/74736. See Ex. 2001, 5.2.

A2-25
Answer: Denied
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).
Answer: Admitted
142.
International Patent Application PCT/US2013/74819 is the parent of U.S. Patent
Application 14/704,551. See Exs. 1019, 2123.
Answer: Admitted
143.
Paragraph 5.2 from the Declaration by Dr. Simons does not mention International Patent
Application PCT/US2013/74819. See Ex. 2001, 5.2.
Answer: Admitted
144.
Paragraph 5.2 from the Declaration by Dr. Simons does not analyze the contents of
International Patent Application PCT/US2013/74819. See Ex. 2001, 5.2.
Answer: Denied
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).
Answer: Admitted
A2-26
APPENDIX 3 TABLE OF SUPPORT FOR BROAD PRIORITY AND

INCORPORATION BY REFERENCE STATEMENTS
Patent/Application
discussed in Reply
1
US 8,697,359
Exhibit 1007
USSN 14/054,414
Filed: 10/15/2013
Exhibit 2105
2
3
USSN 14/104,977
Filed: 12/12/2013
Exhibit 2106
Incorporation By
Reference to B1 in
Application as Filed
[0002] The foregoing
applications, and all
documents cited
therein or during their
prosecution (appln
cited documents) and
all documents cited or
referenced in the appln
cited documents, and
referenced herein
(herein cited
documents), and all
documents cited or
referenced in herein
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
herein by reference,
and may be employed
in the practice of the
invention. More
specifically, all
referenced documents
are incorporated by
reference to the same
extent as if each
individual document
was specifically and
individually indicated
to be incorporated by
reference.
documents cited
Priority claim to B1 in Example 1 2, 3

Specification as Filed
[0001] Priority is
also claimed to US
provisional patent
applications
61/736,527.
Paragraphs
00130-00160
[0001] This
application also claims
priority to U.S.
Incorporated by
reference
Paragraph numbers refer to application as filed.

Example 1 includes Embodiment 1.
A3-1
Patent/Application
discussed in Reply
USSN 14/104,990
Filed: 12/12/2013
Exhibit 2107
Incorporation By
Reference to B1 in
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
A3-2

provisional patent
applications
61/736,527 filed on
December 12, 2012.
[0001] This
Paragraphs
application claims
00156-00171
priority to . Priority
is also claimed to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
USSN 14/105,031
Filed: 12/12/2013
Exhibit 2109
Incorporation By
Reference to B1 in
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
A3-3

[0001] This
Paragraphs
application claims
00186-00220
priority to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
USSN 14/105,035
Filed: 12/12/2013
Exhibit 2110
Incorporation By
Reference to B1 in
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
A3-4

[0001] This
Paragraphs
application claims
00186-00220
priority to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
US 8,771,945;
Exhibit 1008
USSN 14/183,429
Filed: 02/18/2014
Exhibit 2111
US 8,889,356
Exhibit 1010
USSN 14/183,471
Exhibit 2112
Incorporation By
Reference to B1 in
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
A3-5

[0001] This
Paragraphs
application is a
00130-00160
continuation of
application 14/054,414
filed October 15, 2013
which claims priority
to US provisional
patent application .
Priority is also claimed
to US provisional
patent applications
61/736,527 filed on
December 12, 2012.
[0001] This
application is a
continuation of US
filed December 12,
Paragraphs
00186-00220
Patent/Application
discussed in Reply
Filed: 02/18/2014
US 8,795,965
Exhibit 1012
USSN 14/183,486
Filed: 02/18/2014
Exhibit 2113
Incorporation By
Reference to B1 in
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
A3-6

2013, which claims
priority to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
[0001] This
Paragraphs
application is a
00186-00220
continuation of US
filed December 12,
2013, which claims
priority to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
US 8,865,406
Exhibit 1014
USSN 14/222,930;
Filed: 03/24/2014
Ex 2114
Incorporation By
Reference to B1 in
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
A3-7

[0001] This
Incorporated by
application is a
reference
continuation of U.S.
filed December 12,
2013 and which claims
priority to US
provisional patent
application. This
priority to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
10
Patent/Application
discussed in Reply
Incorporation By
Reference to B1 in
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.

US 8,999,641
Exhibit 1018

documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
[0001] This
Incorporated by
application is a
reference
continuation of
International
Application No.
PCT/US2013/074736,
filed December 12,
2013, which claims
provisional patent
applications
61/736,527 filed on
December 12, 2012.
USSN 14/226,274;
Filed: 03/26/2014
Exhibit 2119
A3-8
Patent/Application
discussed in Reply
11
US 8,945,839;
Exhibit 1009
USSN 14/256,912
Filed: 04/18/2014
Exhibit 2115
.
12
US 8,932,814
Exhibit 1011
USSN 14/258,458;
Filed: 4/22/2014
Exhibit 2116
Incorporation By
Reference to B1 in
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
A3-9

[0001] This
application is a
filed February 18,
2014, which is a
continuation of US
patent application
14/054,414 filed
October 15, 2013, now
U.S. Patent 8,697,359,
to US provisional
patent application .
Priority is also claimed
to US provisional
patent applications
61/736,527 filed on
December 12, 2012
.
Paragraphs
00130-00160
[0001] This
application is a
continuation of US
filed December 12,
2013, which claims
Paragraphs
00186-00220
Patent/Application
discussed in Reply
13
US 8,871,445
Exhibit 1013
USSN 14/259,420
Filed: 04/23/2014
Exhibit 2117
Incorporation By
Reference to B1 in
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
A3-10

priority to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
[0001] This
Paragraphs
application is a
00186-00220
continuation of US
filed December 12,
2013 which claims
priority to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
14
US 8,906,616
Exhibit 1016
USSN 14/290,575
Filed: 05/29/2014
Exhibit 2120
Incorporation By
Reference to B1 in
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
A3-11

[0001] This
Paragraphs
application is a
00156-00171
filed December 12,
2013 and claims
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
15
US 8,895,308
Exhibit 1015
USSN 14/293,498
Filed: 06/02/2014
Exhibit 2121
Incorporation By
Reference to B1 in
specifically, all
are incorporated by
extent as if each
individual document
reference.
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
A3-12

[0001] This
Incorporated by
application is a
reference
filed December 12,
2013 and which claims
priority to US
provisional patent
application. This
priority to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
16
17
Incorporation By
Reference to B1 in
reference.
USSN 14/704,551;
Filed: 05/05/2015
documents cited
Exhibit 1019
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
PCT/US2013/074736 [003] The foregoing
Filed: 12/12/2013
documents cited
WO 2014/093655
Exhibit 2122
prosecution (appln
A3-13

[0001] This
Paragraphs
application is a
00153-00168
continuation of
International
Application No.
PCT/US2013/074819,
filed December 12,
2013, and published as
PCT Publication No.
WO 2014/093712 on
June 19, 2014 and
to . Priority is also
claimed to US
provisional patent
applications
61/736,527 filed on
December 12, 2012.
[001] ... Priority is

Incorporated by
also claimed to US
reference
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
18
Incorporation By
Reference to B1 in
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
PCT/US2013/074819 [003] The foregoing
Filed: 12/12/2013
documents cited
WO 2014/093712
Exhibit 2123
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
A3-14


Paragraphs
also claimed to US
00156-00168
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
19
US 8,993,233
Exhibit 1017
USSN 14/105,017
Filed: 12/12/2013
Exhibit 2108
Incorporation By
Reference to B1 in
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
are incorporated by
extent as if each
individual document
reference.
[003] The foregoing
documents cited
prosecution (appln
referenced herein
(herein cited
documents), and all
documents cited or
cited documents,
together with any
manufacturers
instructions, are
hereby incorporated
and may be employed
invention. More
specifically, all
A3-15


Incorporated by
also claimed to US
reference
provisional patent
applications
61/736,527 filed on
December 12, 2012.
Patent/Application
discussed in Reply
Incorporation By
Reference to B1 in
are incorporated by
extent as if each
individual document
reference.
A3-16

CERTIFICATE OF FILING AND SERVICE

I hereby certify that on the 28th day of September, 2016, a true and complete copy of the
foregoing BROAD et al. REPLY 3 is being filed by 5:00 pm EST via the Interference Web
Portal. Pursuant to agreement of the parties, service copies are being sent by e-mail by 8:00 pm
EST, to counsel for Senior Party as follows:
Todd R. Walters, Esq.
Erin M. Dunston, Esq.
Travis W. Bliss, Ph.D., Esq.
Christopher L. North, Ph.D., Esq.
BUCHANNAN INGERSOLL & ROONEY PC
1737 King Street, Suite 500
Alexandria, Virginia 22314-2727
(703) 836-6620
todd.walters@bipc.com
erin.dunston@bipc.com
travis.bliss@bipc.com
christopher.north@bipc.com
Date: September 28, 2016
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
(312) 474-6300
lrinlaures@marshallip.com
spatel@marshallip.com
gnoland@marshallip.com
/s/ Steven R. Trybus

Steven R. Trybus
Reg. No. 32,760
Lead Counsel for Broad
Jenner & Block LLP
Chicago, IL 60654
Telephone: (312) 222-9350
Facsimile: (312) 527-0484
strybus@jenner.com

BROAD Et Al. REPLY 3

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Filed on behalf of: Junior Party, Broad

By: Steven R. Trybus

By: Raymond N. Nimrod

UNITED STATES PATENT AND TRADEMARK OFFICE

Patent Interference No. 106,048 (DK)

BROAD et al. REPLY 3

INTRODUCTION AND SUMMARY ................................................................................1

STATEMENT OF PRECISE RELIEF REQUESTED ........................................................2

DESCRIPTION OF APPENDICES ....................................................................................2

Broad Has Demonstrated Possession of All Elements of Count 1 in Zhang

Broad has Demonstrated Possession of Element [6] ...................................2

Broad has Demonstrated Possession of Element [10] .................................5

Benefit is Proper for the 359 and 233 Patents ...........................................7

Zhang B1 is Incorporated by Reference into the 406 Patent, the

Zhang B1 is Incorporated by Reference into the 641 Patent and

Benefit for the 616 Patent Should be Awarded ........................................14

Benefit for the 641 Patent Should be Awarded ........................................15

Benefit for the 551 Application Should be Awarded ...............................15

BROAD et al. REPLY 3

BROAD et al. REPLY 3

INTRODUCTION AND SUMMARY

(the 233 patent).

UCs argument is unavailing, as Zhang B1 indisputably shows both of these elements.

regarding benefit for the other involved patents and application.

BROAD et al. REPLY 3

STATEMENT OF PRECISE RELIEF REQUESTED

Broad requests that Motion 3 be granted and Broad be accorded benefit of US

Broad Has Demonstrated Possession of All Elements of Count 1 in Zhang B1

Zhang B1 fails to demonstrate possession of those elements. Rather, UC merely relies on

attorney argument. In addition, as detailed below, UC repeatedly cherry-picks isolated phrases

that UC claims is lacking.

Broad has Demonstrated Possession of Element [6]

component (element [6]) of Count 1. UC Opp. 3 p. 20 l. 10p. 22 l. 7. Broads response is

BROAD et al. REPLY 3

there can be no dispute; Broads Embodiment E1 discloses element [8] of Count 1.

locus); the hybridization is indicated by the vertical dashes,|.

Excerpt from Figure 1E

BROAD et al. REPLY 3

Embodiment E1 is irrelevant and was explained in footnote 4 of Broad Motion 3, a fact UC

BROAD et al. REPLY 3

Broad has Demonstrated Possession of Element [10]

must also be part of the complex.

5.37. Zhang B1 states:

[T]he CRISPR complex comprises a CRISPR enzyme complexed with a guide

the Cas9 protein. See, e.g., Ex. 2001 5.40-5.41.

BROAD et al. REPLY 3

Opp. 3, p. 23 l. 34. Broads response is, B1 recites CRISPR enzyme in 11 and B1

targeted to a specific DNA sequence. Ex. 1001 126.

complex activity in the nuclei of eukaryotic cells.

BROAD et al. REPLY 3

Dr. Simons, Broads expert, explained that Example 1 of B1 describes a process of

as 5.22-5.25. This testimony is unrebutted by UC and its experts.

Yes. Carroll transcript Ex. 2012, p. 163, lines 16-25.

Benefit is Proper for the 359 and 233 Patents

BROAD et al. REPLY 3

interference should be redeclared with Broad as the Senior Party.

involved application as well.

reference (UC Opp. 3, p. 6, lines 17- 18).

Nonetheless, on page 6, line 17 through page 7, line 3 of UC Opp. 3, UC asserts that

regarding possible incorporation by reference. In support of this assertion, UC relies upon

The analysis presented herein is supported by Appendix 3.

BROAD et al. REPLY 3

incorporated by reference, is sufficient in view of Federal Circuit precedent to incorporate the