Broad Opp. No. 4

Filed on behalf of: Junior Party, Broad
By:
Steven R. Trybus
Paul D. Margolis
Jenner & Block LLP
353 North Clark Street, Chicago, IL 60654
Telephone: 312-222-9350
Facsimile: 312-527-0484
strybus@jenner.com
Paper No. ____
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. OPPOSITION 3
TABLE OF CONTENTS
Page
I.
INTRODUCTION and SUMMARY ...................................................................................1
II.
STATEMENT OF PRECISE RELIEF REQUESTED ........................................................3
III.
DESCRIPTION OF APPENDICES ....................................................................................3
IV.
REASONS WHY THIS MOTION SHOULD BE DENIED ...............................................3

A.
The Subject Matter of Count 1 and Proposed Count 2 ............................................3
B.
Proposed Count 2 is unfair to Junior Party because it excludes Junior

Partys best proofs....................................................................................................5
C.
Count 1 is not unfair to Senior Party .......................................................................7
D.
Count 1 is not deficient ............................................................................................9
E.
Because Eukaryotic CRISPR Methods are Separately Patentable, UCs

Motion 3 Should be Denied. ....................................................................................9
1.
F.
V.
Senior Party fails to prove that CRISPR in Eukaryotic Cells Would

have been obvious over the publication of Single Guide RNA
CRISPR ......................................................................................................10
Proposed Count 2 does not properly define the interfering subject matter............14
1.
Guide RNA is used in the intrinsic evidence to include both twomolecule and single-molecule guide RNA ................................................15
2.
The ordinary meaning of guide RNA in the art includes twomolecule constructs ....................................................................................17
3.
Senior Partys Arguments to the contrary are meritless ............................19
G.
The subject matter of Proposed Count 2 is unpatentable over the prior art ...........20
H.
Any Count Should Allow Junior Party to Present Its Earliest Proofs ...................24
I.
UC Is Not Entitled To Benefit of P1, P2 or P3 ......................................................25
J.
If the Board grants UCs Motion 3, Numerous Junior Party Claims Should
Be De-Designated As Not Obvious Over Proposed Count 2 ................................26
CONCLUSION ..................................................................................................................29
TABLE OF AUTHORITIES
Page(s)
CASES
Crown Operations Intl, Ltd. v. Solutia, Inc.,
289 F.3d 1367 (Fed. Cir. 2002)................................................................................................28
Openwave Sys., Inc. v. Apple Inc.,
808 F.3d 509 (Fed. Cir. 2015)..................................................................................................20
Strelchenko v. Univ. Mass.,
2003 WL 1386644 (BPAI 2003)..............................................................................................15
ii
I.
INTRODUCTION and SUMMARY
Senior Partys (UCs) motion to substitute Count 2 should be denied for five reasons.
First, Senior Partys proposed Count 2 is unfair to Junior Party because it excludes Junior
Partys best proofs. Proposed Count 2 is limited to single molecule guide RNA. However,
Junior Partys earliest proofs use a two-molecule guide RNA. This fact is widely known. In ex
parte prosecution of its involved patents, Junior Party relied on these two-molecule guide RNA
experiments to antedate UCs publications and patent applications. UC is aware of this work and
has repeatedly cited to it in this interference. Consequently, in proposing Count 2, UC intends to
exclude Junior Partys best proofs. For that reason alone, UCs Motion 3 should be denied.
10
Second, UCs complaints that Count 1 is unfair to UC because it excludes UCs best
11
proofs are meritless. Any alleged unfairness is a result of UCs own actions in seeking an
12
interference with over 400 allowed patent claims every single one of which is limited to
13
eukaryotic CRISPR methods and all of which were allowed based on Junior Partys arguments
14
that eukaryotic CRISPR is separately patentable over the prior art.
15
UC has certainly created the impression it is staking a claim to the eukaryotic invention.
16
The vast majority of the examples in its patent application are eukaryotic. UC filed, but then
17
canceled, claims expressly reciting the eukaryotic environment. While this strategy may be
18
acceptable for some purposes, it should not be used to skew the perception of the interfering
19
subject matter by allowing UC to argue that [n]one of Senior Partys claims have a eukaryotic
20
limitation. Moreover, UC actively campaigned in the PTO for the declaration of an interference
21
with a series of patents all of which are limited to eukaryotic CRISPR methods. It is hardly
22
unfair to keep the eukaryotic limitation in the count and limit UCs priority proofs.
23
24
To the extent UC suggests there is any unfairness due to its involved claims covering
embodiments of other patentable inventions that are excluded by Count 1, UCs remedy was to
1
seek to have claims limited to those embodiments designated as not corresponding to the count.
However, for its own tactical reasons, UC has waived such a motion. UCs deliberate, calculated
waiver does not mean it is unfair that UC cannot rely on its non-eukaryotic in vitro proofs to
show priority. It means those proofs are irrelevant to the relevant question of which party first
invented eukaryotic CRISPR. UCs deliberate decision to waive its rights certainly does not
justify prejudicing Junior Party by substituting a count that excludes Junior Partys best proofs.
Third, UC has failed to carry its burden of demonstrating that Count 1 does not define a
separately patentable invention and therefore failed to rebut the presumption that Count 1 defines
separately patentable subject matter. In fact, UCs argument in this motion that its single-
10
molecule guide RNA claims are non-obvious because of the uncertain effect that modifying the
11
ends of RNA strands might have on protein binding merely highlights the non-obviousness of a
12
functioning CRISPR system in eukaryotes, where there are many more uncertainties and choices.
13
Fourth, proposed Count 2 fails to properly define the interfering subject matter. Only a
14
fraction of Junior Partys claims require a single-molecule guide RNA that is covalently linked.
15
UCs claim construction argument to the contrary is meritless. The term guide RNA as used in
16
the art, and as used in Junior Partys specifications includes both single-molecule covalently-
17
linked guide RNA and two-molecule guide RNA. More than 80% of Junior Partys claims are
18
generic to guide RNA and therefore are not limited to single-molecule guide RNA. Proposed
19
Count 2 therefore is directed to a small subset of the subject matter claimed by Junior Partys
20
involved claims and would therefore be a poor definition of the interfering subject matter.
21
Fifth, using the standard for obviousness adopted by UC and its experts when addressing
22
the eukaryotic invention of Count 1i.e., whether a method was worth a try the subject
23
matter of proposed Count 2 is certainly obvious. As shown below, after the relevant 2011
publicationswhich are 102(b) prior art to both parties earliest filing datesit was obvious to
confirm the role of tracrRNA and create a covalently linked single guide RNA in vitro.
In any event, any count the Board adopts should be broad enough to encompass Junior
Partys early work on CRISPR in eukaryotic cells using two-molecule guide RNA.
II.
STATEMENT OF PRECISE RELIEF REQUESTED

Junior Party Broad requests that the Board deny UCs Motion 3 and maintain Count 1 as
the count for this interference because proposed Count 2by designexcludes Junior Partys
earliest proofs and because Count 1 is properly limited to the key patentable subject matter
using CRISPR in a eukaryotic cell. Alternatively, any new count should permit Junior Party to
10
prove priority using its earliest proofs, which used two-molecule guide RNA.
11
Moreover, the Board need not reach UCs Motion 3, because the Board should grant
12
Junior Partys Motion 2 on the threshold issue that no interference-in-fact exists between UCs
13
involved claims and the Broads involved claims. As UC admits at page 1, line 19 page 2, line
14
3: All of Junior Partys claims have a eukaryotic limitation. None of UCs claims do. If the
15
method in eukaryotic cells is separately patentable, there is no interference-in-fact.
16
III.
17
DESCRIPTION OF APPENDICES
Appendix 1 is a list of Exhibits cited in this motion. Appendix 2, section A, is a listing of
18
UCs statement of facts which are admitted, denied or which cannot be admitted or denied, and
19
section B is Broads statement of facts in support of the opposition.
20
IV.
REASONS WHY THIS MOTION SHOULD BE DENIED
21
A.
22
This interference concerns methods of using CRISPR to cleave or edit target DNA or
23
The Subject Matter of Count 1 and Proposed Count 2
modulate its transcription. Fact 79; Ex. 2001, Simons 1st Dec 4.2. CRISPR occurs naturally in
prokaryotic cells and is programmed in nature to target specific phage or plasmid DNA targets.
Fact 80; Ex. 2001, Simons 1st Dec 2.1.
There are two alleged inventions at issue in UCs motion to change the Count. The first
invention relates to Type II CRISPR/Cas (hereinafter CRISPR) systems adapted for use in
eukaryotic cells. All of the Junior Partys involved claims are limited to this invention, but none
of UCs involved claims are limited to a eukaryotic cell environment. UC Motion at 1. Junior
Party obtained its claims by arguing that the limitation to eukaryotic methods and systems made
them patentable over prior art CRISPR methods in other environments. Fact 81; see, e.g., Ex.
2424. This fact was publicly known from Junior Partys ex parte prosecution files. Ex. 2009,
10
Simons 3d Dec. 12.512.7. Moreover, UCs involved application is related to eukaryotic
11
CRISPR methods. Fact 82; Ex. 1001. Almost all of UCs examples and many claims that UC
12
submitted (and then canceled) require a eukaryotic environment. Fact 93; See, generally, Ex.
13
1001 at 562-662; see also Ex. 2414.
14
The second alleged invention at issue is the use of CRISPR systems in any environment,
15
including a test tube outside of any cell, where the two RNA components that guide the Cas9
16
complex to the target DNA are covalently linked. This kind of guide RNA is sometimes called
17
single guide RNA or chimeric guide RNA. Fact 83; Ex. 2009, Simons 3d Dec. 12.20. Most
18
of Junior Partys claims also cover guide RNA consisting of two separate moleculeswhat is
19
called dual guide by UCs experts and attorneys. Fact 84; Paper 45 at 19:6-15; Ex. 1022 at
20
374, 425; Ex. 2009, Simons 3d Dec. 12.2712.31.
21
The two counts at issueCount 1 and UCs proposed Count 2are directed to these two
22
inventions. Count 1 is directed to the eukaryotic first invention. It requires three components for
23
the CRISPR system that complex together: (1) a Cas9 protein, (2) a targeter RNA or guide
sequence that hybridizes to the target DNA and (3) an activator RNA or tracrRNA that
hybridizes with the targeter RNA to form a double-stranded duplex. The two RNA components
can be separate RNA molecules. In that case, the RNA components are called dual guide
RNA or two-molecule guide RNA. Paper 45 at 19:6-15; Ex. 1022 at 374, 425; Ex. 2009,
Simons 3d Dec. 12.20. The two RNA components could also be part of a single RNA
molecule that folds to hybridize forming a well-known hairpin RNA structure. In that situation
the RNA components are called single guide RNA or single-molecule guide RNA. (Id.)
Proposed Count 2 is directed to the alleged single molecule guide RNA invention. Count
2 requires the same three components as Count 1the Cas9 and the two RNA componentsbut
10
is limited to a covalently-linked single guide RNA. It recites no limitation on environment and
11
would cover CRISPR methods performed in any cell or even in a test tube.
12
B.
Proposed Count 2 unfairly excludes Junior Partys best proofs
13
Proposed Count 2 should be rejected as unfair to Junior Party because Count 2 excludes
14
Junior Partys best proofs. Junior Partys best proofs used two-molecule guide RNA, not the
15
single molecule guide RNA required by Count 2. Ex. 2009, Simons 3d Dec. 12.412.7.
16
Unlike many interferences where each party must propose counts without knowledge of
17
the dates and content of the other partys early work, here, UC has long known of the nature of
18
Junior Partys earliest proofs. Fact 85; see Paper No. 27 at 30:12-31:12. In Junior Partys
19
publication in Cong et al. (Ex. 1055 at 819-820), the Junior Party inventors indicate that their
20
work on non-covalently linked guide RNA preceded their work on single-molecule guide RNA.
21
Fact 86; Ex. 1055 at 819-820. This work is also included in Junior Partys first provisional
22
application. Moreover, in ex parte prosecution, Junior Party submitted numerous declarations
23
and provided laboratory work from 2011 and 2012 that was not performed using covalently
linked single guide RNA. Fact 87; Ex. 2009, Simons 3d Dec. 12.5. That work, which is
referenced in Junior Partys Priority Statement, Paper No. 53, is excluded from the scope of
proposed Count 2. Id.
For example, early 2011 work submitted to the PTO in January 2014 shows the full
nucleotide sequence for a eukaryotic vector CRISPR expression system that was used in the
early 2011 work. (Ex. 2412 at pages Z-5 to Z-23; Simons 3d Dec. 12.5) This sequence shows
the engineered guide RNA that was used in this experiment at page Z-24. This guide RNA is not
a single molecule guide RNA. ( Ex. 2009, Simons 3d Dec. 12.5.)
Another example of Junior Partys early work is shown in the NIH grant application also
10
submitted to the PTO. (Fact 88; Ex. 2411). This NIH application, dated January 12, 2012,
11
shows the design of an entire mammalian CRISPR expression system, shown below:
12
13
Fact 89; Ex. 2411 at 16, Figure 4B. The above figure shows a eukaryotic expression system with
14
separate tracrRNA and guide sequences. Ex. 2009, Simons 3d Dec. 12.6. This system would
15
result in the Cas9 and RNaseIII proteins (each included above) processing the precursor crRNA
16
with a resulting two molecule tracrRNA:crRNA duplex. Id. This system does not include the
17
covalently-linked single molecule guide RNA. Id.
18
19
Each of these examples of Junior Partys early CRISPR work would be excluded by UCs
proposed Count 2. UC is well aware of that fact. In its List of Proposed Motions, it cited to
Junior Partys submission to the PTO of the early 2011 work. Consequently, UC proposes Count
2 specifically with the intention of excluding Junior Partys best proofs.
C.
Count 1 is not unfair to Senior Party
UC argues at page 4, lines 18-19 that Count 1 is unfair because it excludes UCs best
proofs. The response is the unfairness alleged by UC is not unfairness at all but simply a
consequence of UCs own deliberate actions in setting up and participating in this interference.
UC could have avoided all alleged unfairness by simply copying one of Junior Partys
claims and seeking an interference to decide who first invented eukaryotic CRISPR. Apparently,
UC knew it would fail to prevail in a priority contest using that straightforward approach.
10
Therefore, UC has attempted to game the system by having an interference involving all of
11
Junior Partys claims, but attempting to write eukaryotic out of the count. UC is now reaping
12
what it has sown. But this is not unfair for several reasons.
13
First, UCs fairness argument assumes that its non-eukaryotic in vitro work is properly
14
part of the interfering subject matter. However, UC has led the PTO to believe that UC, like
15
Junior Party, invented eukaryotic CRISPR methods. Indeed, most of UCs involved
16
specification examples are in a eukaryotic environment. Fact 90. In fact, UC previously filed,
17
but then unilaterally abandoned, CRISPR claims requiring a eukaryotic environment. Fact 91;
18
see, e.g., Ex. 2414. While such tactics are permissible and can serve valid purposes, UC is
19
arguing that Count 1 is unfair because [a]ll of Junior Partys claims have a eukaryotic
20
limitation, but [n]one of Senior Partys claims do. Paper 56, page 2, lines 1-2. This
21
difference in claim scope is not because Senior Party has not disclosed or claimed eukaryotic
22
subject matter but because Senior Party has canceled its eukaryotic claims in an attempt to
23
suggest, erroneously, that the eukaryotic invention is not a separate invention.
The Board properly drafted Count 1 to require eukaryotic methods. All of Junior Partys
involved claims requires a eukaryotic environment. Fact 92; Ex. 1007-1019. Junior Party
obtained its patents by relying on this environment as the basis for non-obviousness. And UC
has signaled to the PTO that it, too, invented this subject matter. It is thus not unfair that Count 1
requires a eukaryotic environment; it is a consequence of UCs deliberate, calculated strategy. It
is therefore fair that UC cannot rely on in vitro work to prove priority on this key invention.
Indeed, UC has repeatedly argued (1) that its in vitro tests were the triggering event for
successful adaption of CRISPR for eukaryotes and (2) that one would have been immediately
motivated and able to apply the CRISPR system to eukaryotic cells using routine methods after
10
those tests. Thus, with first access to its own in vitro test results, UC supposedly should have
11
succeeded in the eukaryotic system shortly after its in vitro work and should have eukaryotic
12
proofs ahead of all other groups. The problem for UC, however, is that Senior Partys eukaryotic
13
efforts stalled for many months and they only disclosed that they achieved alleged success after
14
receipt of unpublished data from another group. Thus, the entire premise of UCs position in this
15
interference is flawed.
16
UC also suggests that because its involved claims include within their scope other,
17
allegedly patentable embodiments of CRISPR methods that were not done in eukaryotic cells, it
18
is unfair to UC if it cannot rely on this work in this interference. The response is that the
19
appropriate remedy for this potential unfairness, which UC has waived, would have been for UC
20
to seek to have these claims designated as not corresponding to the count. However, again
21
because of the strategic choices UC has made in this interference, it cannot now pursue that
22
option. Apparently, UC appreciated that if it filed a motion de-designating those claims, it would
23
only prove the correctness of Junior Partys position that there is no interference-in-fact, so
instead UC has deliberately waived its opportunity to seek to de-designate its involved claims.
As a result of this tactical choice, claims are now involved in the interference even though they
are allegedly directed to subject matter not corresponding to Count 1. See Paper No. 27 at 13:1-
18. But that is not unfairness; that is simply a consequence of UCs choice.
D.
Count 1 is not deficient
At page 16, lines 11-23, UC argues that Count 1 is improper because the guide sequence
does not hybridize to the activator-RNA. The response is that Count 1 does not require that the
guide sequence hybridize with the activator. Fact 93; Ex. 2005, Greider Dep. at 30:7-10. Count
1 specifies only that the activator hybridizes with some part of the targeter-RNA, which
10
includes the guide sequence but also includes other sequences, such as the tracrmate sequence.
11
Fact 94; Ex. 2009, Simons 3d Dec. 12.812.9. But the Board chose language for Count 1 that
12
did not include the activator-RNA hybridizing with the guide sequence. Since there is no
13
dispute that the targeter-RNA includes the tracrmate sequence that hybridizes with the
14
activator-RNA, Count 1 is proper. See Ex. 2005, Greider Dep. at 26:20-27:4, 209:6-17. Even if
15
the term guide sequence were improper, it could simply be deleted to remove any confusion.
16
17
E.
Because Eukaryotic CRISPR Methods are Separately Patentable, UCs

Motion 3 Should be Denied.
18
UC failed to carry its burden of demonstrating that Count 1 is not separately patentable,
19
and because of that failure UCs motion should be denied. Specifically, on page 12 of UCs
20
Motion 3, at lines 9-12, UC argues that the limitation in Count 1 to eukaryotic CRISPR methods
21
is not separately patentable over proposed Count 2 UC also argues on pages 9-12 of its motion
22
that published in vitro CRISPR methods using single guide RNA renders obvious the subject
23
matter of CRISPR methods in a eukaryotic environment. The response is that UCs argument is
24
meritless because the in vitro tests would not have rendered that subject matter obvious.
9
An important, over-arching fact is that UC contends its own single-molecule guide RNA
claims recite non-obvious subject matter because of an alleged uncertainty and unpredictability
in the prior art. UCs argument, in fact, highlights the non-obviousness of using CRISPR in a
eukaryotic system, where there were many more complex uncertainties and a spectrum of
possible choices required to achieve success in the unpredictable eukaryotic environment.
Specifically, the difference between proposed Count 2s single molecule guide RNA and
the prior art double molecule guide RNA is the addition of a covalent linker between the
tracrRNA and the crRNA. UC argues that whether this linker would work was uncertain because
in other systems involving RNA bound to proteins, modifying the ends of the RNA could affect
10
the protein binding. However, it would be simple to test whether this one concernwhether a
11
tetraloop would or would not interfere with protein bindingwas an impediment to CRISPR
12
function. Fact 95; Ex. 2009, Simons 3rd Dec 12.49.
13
14
15
Nevertheless, UC argues, at page 13, line 23 to page 15, line 6, that this uncertainty
demonstrates the non-obviousness of its single molecule guide RNA claims.
As demonstrated below, eukaryotic CRISPR systems presented a skilled person with a
16
host of uncertainties that could not be addressed with a simple test. Ex. 2009, Simons 3d Dec.
17
11.3011.32. Consequently, using UCs approach to non-obviousness, UC has failed to carry its
18
burden of showing that a claim directed to the use of CRISPR-Cas system in eukaryotic cells
19
would not be patentable either over proposed Count 2 or the prior art.
20
21
22
1.
Senior Party fails to prove that CRISPR in Eukaryotic Cells Would

have been obvious over the publication of Single Guide RNA CRISPR
UC argues on page 9, lines 4-7 that immediately after UCs inventors published the
23
Jinek 2012, it would have been obvious to apply the CRISPR Type II system in eukaryotic cells.
24
However, UC, which on this motion bears the burden of proof, has failed to carry that burden, at
10
least because a person of ordinary skill in the art would not have had a reasonable expectation
that the CRISPR Type II system would work to cleave DNA in a eukaryotic environment. Ex.
2001, Simons 1st Dec. 6.16.72; Ex. 2009, Simons 3d Dec. 12.13.
UC relies on statements that CRISPR might be repurposed for genome engineering,
could theoretically cleave eukaryotic DNA and was clearly well worth a try. (UC Mot. 3 at
9:16-23.) However, one of these articles was published October 2013, after Junior Partys
inventors publication of eukaryotic CRISPR methods, and not immediately after Jinek 2012
was published. (Ex. 1473.) This article therefore cannot demonstrate that prior to publication of
Junior Partys invention, it would have been obvious to use CRISPR in a eukaryotic cell.
10
The other statements show that skilled artisans did not have a reasonable expectation that
11
CRISPR would function in a eukaryotic cell. The statements merely repeated the hopes that had
12
been expressed for years about what might be possible with CRISPR. For example, as early as
13
February 2008, other alleged inventors disclosed that it was contemplated that the CRISPR
14
system be transferred into eukaryotic cells utilizing any suitable method known in the art,
15
including, but not limited to transformation via plasmids. (Fact 96; Ex. 1435 at 101:22-23.)
16
However, those inventors did not publish any results showing any CRISPR system in eukaryotic
17
cells before the Junior Partys early 2013 publication. (Fact 97; Ex. 2009, Simons 3d Dec.
18
12.14).
19
Similarly, in 2009, another group of alleged inventors filed a patent application claiming
20
a method of using CRISPR in a eukaryotic cell. (Fact 98; Ex. 1161 at 11). They disclosed a
21
representative of each type of CRISPR as a model system: E. coli (Type I), S. thermophilus
22
(Type II) and S. epidermis (Type III). Fact 99; Ex. 1161 at 8 0054; Ex. 2009, Simons 3d Dec.
23
12.14). However, they never published working eukaryotic CRISPR methods. Fact 100; Simons
11
3d Dec. 12.14. After the PTO rejected the application for lack of enablement, they let it go
abandoned. (Fact 101; Ex. 2413; Ex. 2009, Simons 3d Dec. 12.14.) Even though this group
expressed the hope that CRISPR might work in eukaryotes and were so motivated to find a
solution that they filed a patent application with a detailed research plan, they only made
CRISPR succeed in eukaryotes after Junior Party published its method. (Ex. 2009, Simons 3d
Dec. 12.14).
These expressions of hope did not become any more confident after the publication of
Jinek 2012. Given all the false alarms over the years, the expressions of hope following Jinek
2012 were laced with doubt and caution. For example, the Carroll article, cited by UC, which
10
states that eukaryotic CRISPR was clearly well worth a try also cautioned that because
11
CRISPR originated in prokaryotic, not eukaryotic systems, there is no guarantee that Cas9 will
12
work effectively on a chromatin target or that the required DNA-RNA hybrid can be stabilized in
13
that context. (Fact 102; Ex. 1152 at 1660.) Dr. Carroll warned that a key CRISPR component
14
might be disassembled by endogenous eukaryotic enzymes, and warned that eukaryotic DNA
15
processing systems might cause a potential side effect of extraneous DNA cuts. (Fact 103; Ex.
16
1152 at 1660.) He cautioned that gene editing through base pairing [the technique under which
17
he classified CRISPR] has been attempted many times. (Fact 104; Ex. 1152 at 1660.) He
18
referred to some prior attempts and described them as having efficiencies that were
19
discouragingly low, having limited range and less efficiency than other techniques. (Fact
20
105; Ex. 1152 at 1660.) He summed up with, Whether the CRISPR system will provide the
21
next-next generation of targetable cleavage reagents remains to be seen, but it is clearly well
22
worth a try. Stay tuned. (Fact 106; Ex. 1152 at 1660.) This statement does not suggest, as UC
12
erroneously argues, any change in the skilled persons expectations of success. Ex. 2009,
Simons 3d Dec. 12.15.
Dr. Carrolls article did not include any statement that there was a reasonable likelihood
of success. Nor did Dr. Carroll disclose a solution. Fact 107-108; Ex. 2009, Simons 3d Dec.
12.16. Instead, he repeated the refrain appearing in the art as early as 2008 that it was worth
trying to make CRISPR work in it work in eukaryotes. See id.
UC contends that before May 2012, the roles of each component of the CRISPR system
were unknown and that the identification of the necessary and sufficient components first
made CRISPR in eukaryotes possible. (See, e.g., Ex. 1022 at 431.) However, UC fails to
10
explain how knowledge of the function of tracrRNA and Cas9 in the cleavage process was
11
necessary to understand whether CRISPR would work in a eukaryotic cell. It was already known
12
that all three componentstracrRNA, crRNA and Cas9were necessary for the combination of
13
the maturation and the cleavage steps. Fact 109; Ex. 2009, Simons 3d Dec. 12.43; see also Ex.
14
2010, Breaker Dec. 1.11-1.26. It was known in the prior art that no other cas protein was
15
necessary for bacterial immunity. Fact 110; Ex. 2009, Simons 3rd Dec 12.37. Therefore, the
16
only issue left to experimentally resolve after Deltcheva was whether only a subset of these three
17
components were necessary for cleavage. Further explicating the precise roles for tracrRNA and
18
Cas9 in cleavage simply confirmed that all three were necessary for each of these steps, not just
19
the maturation step.
20
Further, at best, alleged predicted application[s] of CRISPR in eukaryotes pointed out
21
by UC (UC Mot. 3 at 9:13-24) suggest trying the chimeric constructs Jinek 2012 disclosed. But
22
there were several outright failures, and very poor results were obtained by others, even those
13
who used unconventional techniques, including for delivery and/or adaptations thus testing
something that is not Chimera A. Ex. 2009, Simons 3rd Dec. 11.12211.134.
UC also argues, on page 10, line 12-14 that [p]ersons of ordinary skill in the art would
have had a reasonable expectation of success because the techniques to practice CRISPR in
eukaryotic cells were well-known and routinely used in the prior art. See also Ex. 2008,
Carrol Dep. at 352:13-353:4. UCs arguments are flawed. The existence of these routine
techniques did not cause inventors who filed patent applications in 2008 and 2009, discussed
above, to obtain a workable eukaryotic CRISPR system.
UC argues on page 11, lines 10-15 that analogous methods of manipulating DNA in
10
eukaryotic cells using prokaryotic proteins had been demonstrated many times. But there were
11
just as many, if not more, instances of failures including in the most closely analogous area of
12
Group II introns, which like CRISPR, involved RNA and protein and have not been readily
13
adapted for use and function in eukaryotic cells. (Fact 111; Ex. 2010, Breaker Dec 1.50.)
14
Accordingly, UCs motion should be denied for the additional, independent reason that it
15
has failed to carry its burden of demonstrating the unpatentability of adapting a CRISPR-Cas
16
system for use and function in eukaryotic cells.
17
F.
Proposed Count 2 does not properly define the interfering subject matter
18
UCs Motion 3 should also be denied because proposed Count 2 fails to properly define
19
the interfering subject matter. As UC admits, Junior Partys claims are all limited to eukaryotic
20
cells. Only 55 of Junior Partys approximately 400 involved claimsless than 15%require
21
single molecule guide RNA. Fact 164; Ex. 2009, Simons 3d Dec. 12.21. The rest cover
22
CRISPR methods using dual guide RNA. Fact 130; Ex. 1007-1019; Ex. 2009, Simons 3d Dec.
23
12.2123.
14
In its motion, UC takes a contrary position, asserting that all of Junior Partys claims
require single-molecule guide RNA. On page 22, lines 10-11, UC argues [p]ersons of ordinary
skill in the art would have understood Junior Partys use of guide RNA in the claims of its
involved patents and application to mean single-molecule DNA-targeting RNA. However, UC
is incorrect, the term guide RNA includes both two-molecule and single-molecule guide RNA.
Fact 112; Ex. 2009, Simons 3d Dec. 12.1712.26.
In construing claim language in an interference, the PTO uses the broadest reasonable
claim interpretation, looking at the ordinary meaning of a claim term, in light of the
specification, from the perspective of one skilled in the relevant art. Strelchenko v. Univ. Mass.,
10
2003 WL 1386644, *13 (BPAI 2003)(claim terms take on their ordinary and accustomed
11
meanings unless the patentee demonstrated an intent to deviate from the ordinary and
12
accustomed meaning of a claim term by redefining the term or by characterizing the invention in
13
the intrinsic record using words or expressions of manifest exclusion or restriction, representing
14
a clear disavowal of claim scope.)
15
Junior Partys patents and application use the term guide RNA to refer to the RNA that
16
guides the Cas9:RNA complex to its DNA target. Fact 113; Ex. 2009, Simons 3d Dec. 12.18
17
12.20. This meaning of guide RNA is also the one that has been used in the RNA interference
18
art, including the CRISPR art, for many years.
19
20
21
1.
Guide RNA is used in the intrinsic evidence to include both twomolecule and single-molecule guide RNA
The intrinsic evidence for Junior Partys patents shows the use of guide RNA to mean
22
the RNA that guides the Cas9 protein to the target site, whether that RNA is one or two
23
molecules. For example 359 Patent (Ex. 1007) claim 1 requires a guide RNA, with no
24
limitation on the number of molecules it contains. Fact 114; Ex. 1007 Claim 1. However,
15
dependent claim 4 adds a single limitation to the CRISPR method of claim 1: wherein the guide
RNAs comprise a guide sequence fused to a trans-activating cr (tracr) sequence. Fact 115; Ex.
1007 claim 4. For claim 4 to have meaning, the guide RNAs of claim 1 are not fused and
therefore include two-molecule guide RNA. Thus, a skilled person would understand guide
RNA in Junior Partys patents to have the same meaning it has in the artthe RNA molecules
that guide Cas9 to its target. Ex. 2009, Simons 3d Dec. 12.24.
Similarly, Example 6 of the 356 patent (Ex. 1010) uses the term guide RNA to
encompass both single guide RNA and dual guide RNA. Fact 116; Ex. 1010 col. 105 lines 3-8.
The title of the example is Optimization of the Guide RNA for [S. pyogenes] Cas9. Ex. 1010,
10
col. 105 lines 34. It describes optimizations in the tracrRNA and direct repeat sequences on
11
the one hand and chimeric guide RNA on the other. Id., col. 105 lines 68. Thus, while two
12
different optimizations are discussed, one on two-molecule guide RNA and another on single-
13
molecule guide RNA, the title refers generically to Optimizations of the Guide RNA
14
forCas9. Id., col. 105 lines 34.
15
Second, the 359 patent states that in some embodiments the tracr sequence and the
16
tracr mate sequence are contained within a single transcript. Fact 117; Ex. 1007, 359 patent,
17
Col. 21, lines 41-45. That means that in other embodiments, they will not be in a single
18
transcript, requiring a two-molecule guide RNA in those embodiments. Indeed, Example 1 of
19
the patent, which is included in the examples that are given for purposes of illustrating various
20
embodiments of the invention, includes several embodiments that use two-molecule guide
21
RNA. Fact 118; Ex. 1007, 359 patent, col 43 lines 4748; Ex. 2009, Simons 3d Dec. 12.25.
22
23
Third, column 38 of the 308 patent (Ex. 1015) at lines 33-43 suggests introducing Cas9
and the RNA components of the guide RNA as either DNA or RNA. The first sentence
16
describes two alternativesusing chimeric guide RNA or a combination of tracrRNA and
crRNA. For the rest of the paragraph, the patent refers generically to both alternatives as guide
RNA.
4
5
6
7
8
Thus, in the intrinsic evidence guide RNA includes both one and two molecule RNA.
Ex. 2009, Simons 3d Dec. 12.24-12.25.
2.
The ordinary meaning of guide RNA in the art includes two-molecule

constructs
Consistent with the intrinsic evidence from Junior Partys patents, UC in its publications,
UCs attorneys in this interference, and prior art authors have all used the term guide RNA to
10
mean whatever RNA guides the interference complex to the target. Fact 119; Ex. 2009, Simons
11
3d Dec. 12.2712.31.
12
The UC inventors wrote in Jinek 2012, In this ternary complex, the dual
13
tracrRNA:crRNA structure acts as guide RNA that directs the endonuclease Cas9 to the cognate
14
target DNA. Fact 120; Ex. 1155, Fig. S1 caption. The ternary complex refers to the three
15
part complex consisting of (1) Cas9, (2) a mature crRNA molecule and (3) a tracrRNA molecule.
16
Fact 121; Ex. 2009, Simons 3d Dec. 12.27. Thus, the dual tracrRNA:crRNA structure is a
17
two component complex, not a single component complex. Fact 122; Ex. 2009, Simons 3d Dec.
18
12.27. Otherwise, UC would not have called the complex with the protein a ternary one.
19
Thus, in Jinek 2012, UC used the term guide RNA to refer to a dual guide complex consisting
20
of separate molecules of tracrRNA and crRNA. Fact 123; Ex. 2009, Simons 3d Dec. 12.27.
21
Similarly, UCs 859 application defines DNA-targeting RNA as being synonymous with
22
guide RNA and as including two molecule guide RNA. Fact 124; Ex. 1001 at 130; Ex. 2005,
23
Greider Dep. at 291:20-292:21; Ex. 2009, Simons 3d Dec. 12.28.
17
UCs representations to the Board and its experts also use guide RNA to include both
dual and single guide species. UCs experts refer to the use of a composition that includes
purified recombinant S. pyogenes Cas9 protein and either a single-guide or dual-guide DNA
targeting RNA, i.e., the complex of Count 1 and Proposed Count 2 (single-guide DNA-targeting
RNA complex.) Fact 125; Ex. 1022 374; Ex. 1024 365, emphasis added; Ex. 2009, Simons
3d Dec. 12.30. And UCs counsel represented to the Board that UC planned to propose a count
that was generic as to guide RNA, meaning that it covers both the dual guide and the single
guide embodiments. Fact 126; Paper 45, May 6, 2016 Conf. Call Tr. 19:8-11; see also Tr.
22:12-23:7; Ex. 2009, Simons 3d Dec. 12.31.
10
The term guide RNA has long been used in the prior art to mean whatever RNA was
11
understood to be required for guiding the RNA to the target. For example, one paper explained
12
that crRNA serves as a guide (hence the term guide RNA has also been used) to allow for
13
specific base paring between crRNA and the corresponding protospacer on the foreign
14
DNA. (Fact 127; Ex. 1204: Bhaya et al. 2011 at 286. The same paper explained, CRISPR
15
RNA (crRNA): small noncoding RNA (also known as guide RNA) Based on their
16
function, these small RNAs have also been referred to guide RNAs. Fact 128; Ex. 1204 at
17
276 (side bar citation omitted). Many other papers used the term in the same way. Fact 129; Ex.
18
1215, Carte at 3490 (refers to guide RNAs in its title and states, The primary products of the
19
CRISPR loci appear to be short RNAs that contain the invader targeting sequences, and are
20
termed guide RNAs .); Ex. 1257, Hale et al., at 2577 (CRISPR RNA-protein complexes:
21
The common primary and secondary psiRNAs species are likely candidates for the guide RNA
22
component of the effector complex.); Ex. 2277, Jore et al. 2011, at 529 (The guide RNA-
23
loaded Cmr complex.) Ex. 2009, Simons 3d Dec. 12.32.
18
1
2
3
4
Thus, guide RNA is used in the prior art and in UCs own statements to include twomolecule guide RNA.
3.
Senior Partys Arguments to the contrary are meritless
Against the contrary evidence, UC argues that the Junior Partys specifications have
specially defined the term guide RNA to limit its meaning to single molecule guide RNA. The
paragraph cited by UC states that [i]n aspects of the invention, certain terms are used
interchangeably. Specifically, this paragraph states that in these aspects of the invention, the
terms guide RNA along with single guide RNA and chimeric RNA are used
interchangeably and refer to the polynucleotide sequence comprising the guide sequence, the
10
11
tracr sequence and the tracr mate sequence.

However, this paragraph is not a definition. Fact 131; Ex. 2009, Simons 3rd Dec 12.19.
12
It is limited to certain aspects of the invention, implying that in other aspects, the term is used
13
in a different way. Furthermore, UCs interpretation of this paragraph is inconsistent with the
14
claim language and the portions of the specifications cited above and its usage in the art.
15
UC points to no clear disavowal that narrows Junior Partys use of the term. In fact,
16
the clear intent of the paragraph UC relies on is to broaden the scope of the disclosure, not
17
narrow it. It is improper to narrow the scope of a well-known term based on an at-best
18
ambiguous statement in a specification that fails to indicate a clear intent to disavow the broader
19
meaning. Openwave Sys., Inc. v. Apple Inc., 808 F.3d 509, 513 (Fed. Cir. 2015).
20
Consequently, UCs claim construction argument is erroneous and more than 330
21
involved claims of the Junior Party include subject matter outside the scope of proposed Count 2.
22
That count therefore fails to properly define the interfering subject matter.
19
G.
On page 13, line 9 through page 16, line 4, it is argued by UC that the single molecule
guide RNA of proposed Count 2 would have been patentable in 2012 since it would not have
been obvious to form a functional RNA molecule that linked the targeter-RNA and the activator-
RNA. Junior Partys response 1 is that, even if there is an interference-in-fact, Proposed Count
2s subject matter is unpatentable because it would have been obvious to combine the targeter-
RNA and activator-RNA into a single molecule. Ex. 2009, Simons 3d Dec. 12.4612.50.
UC contends that eukaryotic methods are obvious over in vitro CRISPR methods because
8
9
The subject matter of Proposed Count 2 is unpatentable over the prior art
they were allegedly well worth a try. (Paper 56 at 9:18-21.) If that obviousness test is
10
erroneousas Junior Party assertsthere certainly is no interference-in-fact and this motion is
11
moot. If on the other hand UCs obviousness test is correct, then it should be applied in
12
considering the patentability of the subject matter of proposed Count 2 as well. Using UCs
13
obviousness test, prior art teaches that CRISPR single-molecule guide RNA was clearly well
14
worth a try and therefore the subject matter of proposed Count 2 would be unpatentable under
15
that test. Ex. 2009, Simons 3d Dec. 12.4612.50.
16
Specifically, the Deltcheva article, published in March 2011, disclosed that Cas9 and the
17
precursors to crRNA and tracrRNA complexed together as part of the maturation process of the
18
crRNA and the tracrRNA. Fact 132; Ex. 1032 at 603-605; Ex. 2009, Simons 3d Dec. 12.35.
19
Deltcheva showed that tracrRNA was involved in the maturation of crRNA, i.e., the processing
20
of the long pre-crRNA (repeat-spacer-repeat-spacer-repeat-etc. (possibly hundreds of repeat-
Junior Party recognizes that a count must be limited to subject matter that is patentable over the
prior art although not necessarily patentable to either party.
20
spacer units)) to the crRNA (a single repeat-spacer unit.) Fact 133; Ex. 1032 at 603. Deltcheva
showed that tracrRNA formed a complex with both crRNA and Cas9 during this process, and
described the third step of the CRISPR system as (3) interference with invading cognate foreign
genomes by mechanisms that are yet to be fully understood. Fact 134; Ex. 1032 at 602.
Deltcheva also states that [Cas9] may also be involved in the silencing of invading sequences.
Fact 135; Ex. 1032 at 605 (Fig 4. caption). This echoes the Garneau 2010 publication, which
states that the endonuclease activity [of S. thermophilus CRISPR] seems to require [Cas9].
Fact 136-137; Ex. 1153 at 70; Ex. 2009, Simons 3d Dec. 12.36.)
Furthermore, the prior art discloses that crRNA was involved in the interference step.
10
(Fact 138; Ex. 1033 at 9275, 9280; Ex. 2009, Simons 3d Dec. 12.38.) Deltcheva also showed
11
that the precursors for the tracrRNA:crRNA duplex and Cas9 are complexed together just before
12
the formation of the mature crRNA. Fact 139; Ex. 1032 at 605; Ex. 2009, Simons 3d Dec.
13
12.35. She also showed that the tracrRNA and crRNA form a hybridized duplex resulting from a
14
significant degree of Watson-Crick base pairing. Fact 140; Ex. 1032, Deltcheva at 603); shown
15
below is the mature crRNA:tracrRNA predicted by figure 1b from Deltcheva showing this high
16
degree of base pairing between the tracrRNA and the crRNA:
17
18
(Ex. 1032 at 603.) A person of ordinary skill in the art would know from this extent of base
19
pairing that it was very unlikely that the tracrRNA:crRNA duplex disclosed in Deltcheva would
20
disassociate. Ex. 2009, Simons 3d Dec. 12.40; Ex. 2010, Breaker Dec. 1.101.12. Since the
21
1970s, techniques had been developed to study the thermodynamics of the disassociation of
22
double stranded RNA (Fact 141; Ex. 2009, Simons 3d Dec. 12.41). As discussed in the
21
Declaration of Dr. Breaker, those well-known methods would have indicated to a person of
ordinary skill in the art that it was highly likely that the pre-crRNA:tracrRNA duplex did not
disassociate and remained hybridized after the mature crRNA was formed. Fact 142-145; Ex.
2010, Breaker Dec. 1.91.29; Ex. 2009, Simons 3d Dec. 12.41-12.42. Therefore the skilled
person would have thought it highly likely that the Cas9:crRNA:tracrRNA complex was
involved in cleaving of the target DNA. Ex. 2010, Breaker Dec. 1.27; Ex. 2009; Simons 3d
Dec. 12.43-12.44.
This belief combined with a lack of direct proof suggested by Deltcheva and
Sapranauskas would have only heightened the motivation for conducting simple confirmatory
10
testing to put the question to rest. Ex. 2009, Simons 3d Dec. 12.44. The simplest and easiest
11
experiment to answer this question was to combine Cas9, mature crRNA and tracrRNA in a test
12
tube with a DNA target to see whether cleavage occurs. Id. There were only a few possibilities
13
necessary to confirm this result:

Experiment Cas9
tracrRNA
mature crRNA
Yes
Yes
Yes
No
Yes
Yes
Yes
No
Yes
Yes
Yes
No
14
15
Id. Performing those obvious experiments would necessarily resolve whether tracrRNA is
16
necessary for the CRISPR interference step. Id.
17
Furthermore, the use of a covalent linker would have been obvious. Ex. 2009, Simons 3d
18
Dec. 12.4612.50; Ex. 2010, Breaker Dec. 1.301.40. In particular, to ensure that the
19
duplex is formed properly, a skilled person would know that they could use a covalent linker to
22
ensure that the base pairings shown in Deltcheva would combine properly in the test tube. (See
Ex. 2008, Carroll Dep. at 356:7-357:3.) To ensure double stranded RNA properly forms in vitro
it has been routine since the 1990s to connect the two strands by covalent linkers of four
nucleotidescalled tetraloops. Fact 146; Ex. 2009, Simons 3d Dec. 12.46; Ex. 2010,
Breaker Dec. 1.38. Tetraloops avoided the uncertainties in preparing double stranded RNA in
vitro by ensuring the desired folding of RNA. (Fact 147; Ex. 2280 at 3063; Ex. 2009, Simons
3d Dec. 12.46; Ex. 2010, Breaker Dec. 1.38.) A common example of a well-known tetraloop
used for this purpose was the sequence GAAA, which was used in Jinek 2012. Fact 148; Ex.
2010, Breaker Dec. 1.301.33.
10
Another obvious reason to use a tetraloop linker is to facilitate the formation of a crystal
11
structure of Cas9 in complex with the tracrRNA:crRNA duplex. Formation of this crystal
12
structure would be required as part of the normal next step in characterizing Cas9 by its crystal
13
structures. Ex. 2009, Simons 3d Dec. 12.4712.48; Ex. 2010, Breaker Dec. 1.351.37.
14
RNA, especially double stranded RNA, is notoriously badly behaved in crystal structures,
15
frequently resulting in neighboring molecules packing subtly out of register. Fact 149; Ex.
16
2272 at 625; Ex. 2009, Simons 3d Dec. 12.49. However, it was disclosed in the 1990s (by one
17
of UCs inventors) that tetraloopsespecially the GAAA tetraloop disclosed in Jinek 2012are
18
useful for restoring the proper well-registered array of crystals. Fact 150; Ex. 2272 at 625; Ex.
19
2009, Simons 3d Dec. 12.49; Ex. 2010, Breaker Dec. 1.39. Additionally, some of UCs
20
inventors had also already shown that Csy4, which like Cas9 was known to process pre-crRNA
21
to tracrRNA in a different CRISPR system, bound RNA most effectively when a GNRA-
22
tetraloop structure (which include GAAA) was used. Fact 151; Ex. 1379 at 665; see also Ex.
23
1262 at 1357; Ex. 2010, Breaker Dec. 1.37.) However, for these tetraloops to be useful, they
23
must not affect the biochemical activity of the protein:RNA complex. Ex. 1379 at 621; Ex.
2009, Simons 3d Dec. 12.49. Therefore, a person of ordinary skill in the art would be
motivated to conduct in vitro testing on a tetraloop construct to confirm it did not affect the
activity of the Cas9:RNA complex. Ex. 2009, Simons 3d Dec. 12.49.
Accordingly, it would have been obvious to test whether Cas9 and covalently linked
crRNAtracrRNA single guide RNA would successfully cleave a DNA target. In addition, a
person of ordinary skill in the art would have had a reasonable expectation of success that the
covalently linked single molecule would work in a cell-free experiment, at least applying the
same standard for reasonable expectation and success used by UCs experts. Ex. 2006, Greider
10
Dep. at 386:3-15 (testifying that standard used for reasonable expectation of success was,
11
[e]xperimentally whether this set of experiments you could carry out if you were of ordinary
12
skill in the art with what was known in the art.).
13
H.
Any Count Should Allow Junior Party to Present Its Earliest Proofs
14
If the Board denies Broads Motion for No Interference-in-Fact, and further disagrees
15
that Proposed Count 2 is not patentable over the prior art, any count should permit Junior Party
16
to present its earliest proofs and thus should include two-molecule guide RNA within its scope.
17
To the extent the Board adopts proposed Count 2 or any other Count that does not require
18
a eukaryotic environment, then for the reasons set forth above in section IV.E., all of Broads
19
claims reciting eukaryotic limitations should be designated as not corresponding to the count and
20
other pending Broad claims more directly drawn to the subject matter of Count 2 should be
21
added to this interference and designated as corresponding to such a count.
22
23
If, despite all the arguments herein (and in Broads Motion 2 for No Interference In Fact),
the Board determines both that this interference should go forward and that it should not go
24
forward with Count 1, to address all of the problems, deficiencies and unfairness noted herein
with regard to proposed Count 2, the Board could redeclare the interference with an OR count
using Proposed Count 2 as one part of the count and, as the other part of the count, existing
Count 1 or claim 1 of one or more of the involved Broad patents. But, to be absolutely clear, for
all of the reasons stated herein, Broad considers Count 1 as the count that should be used in the
event that the interference goes forward.
I.
UC argues at 17:1-19:15 that they are entitled to benefit of Count 2. The response is that
UC Is Not Entitled To Benefit of P1, P2 or P3
UC has not provided sufficient evidence that it should be entitled to benefit of P1, P2 or P3 for
10
Count 2. Fact 152; Ex. 2009, Simons 3d Dec. 11.16711.169. P1 provides nothing more than
11
a test tube experiment in which SpCas9 is shown to act on a natural SpCas9 target with 50-fold
12
molar-excess of purified component used. Ex. 2009, Simons 3d Dec. 11.2011.42. A person
13
of skill in the art viewing this experimental design and results using a natural target for that
14
particular Cas9, would not have understood that experiment to describe and enable an
15
engineered CRISPR-Cas system which cleaves, edits or modulates transcription of target DNA
16
as required by Count 2. Id. This conclusion is bolstered for P1 given the lack of a disclosure of
17
a PAM sequence, failures reported for orthologs, and incomplete details of tracr requirements.
18
Id., 11.4311.62. These problems are not resolved with P2, and indeed the evolving versions
19
of Figure 1A and addition of discussion on non-optimal tracr notation - without further details -
20
continue to evidence lack of command of key elements, and persons of skill in the art viewing
21
these further results in P2, and especially once the obviously failures in P3 were provided as
22
positive results, would conclude that inventors were not in possession of species of either count.
23
See id., 11.71-11.95, 11.136-11.165.
25
1
2
3
4
5
6
7
J.
If the Board grants UCs Motion 3, Numerous Junior Party Claims Should
Be De-Designated As Not Obvious Over Proposed Count 2
Even if the Board were to adopt proposed Count 2, there are numerous claims in Broads
patents and applications that should be de-designated from this interference.
a. SaCas9 Claims Would Be Separately Patentable over Count 2 Even If
Eukaryotic CRISPR Methods Were Found To Be Obvious
The claims of the 406 and 308 patents require the use of a Staphylococcus aureus Cas9
(SaCas9) protein or a nucleotide sequence encoding such a protein. Fact 153; Ex. 1014, 406
patent; Ex. 1015, 308 patent; Ex. 2009, Simons 1st Dec. 7.3. These claims are neither
10
anticipated by nor rendered obvious by proposed Count 2, alone or in combination with the prior
11
art. Fact 153; Ex. 2009, Simons 3d Dec. 12.5312.60.
12
UC bears the burden of proof that Broads SaCas9 claims are not patentable over Count
13
2. However, UCs entire argument on why these claims recite subject matter that is obvious over
14
proposed Count 2 is a single conclusory sentence stating that SaCas9 was was known in the
15
art. UC Motion at page 26, lines 16-17. However, the mere fact that a claimed feature was
16
known in the prior art does not by itself establish either anticipation or obviousness. Crown
17
Operations Intl, Ltd. v. Solutia, Inc., 289 F.3d 1367, 1375-76 (Fed. Cir. 2002). Because UC
18
presents no other arguments, UC has failed to carry its burden of showing that the SaCas9 claims
19
should be designated as corresponding to proposed Count 2.
20
While UCs experts give opinions on obviousness of the SaCas9 claims, none of these
21
opinions are even mentioned in UCs motion. This is not a situation where an experts opinion is
22
relied on and explained in a brief and the experts declaration provides a more detailed basis than
23
is set forth in a brief. Here, UCs brief fails to discuss these opinions at all. Therefore, UCs
24
experts opinions on the obviousness of these claims should not be considered.
26
However, even if they are considered, they fail to establish that these claims unpatentable
over proposed Count 2. Neither expert considers anticipation, and with respect to obviousness,
neither expert points to any teaching or suggestion in either proposed Count 2 or the prior art to
use the SaCas9 ortholog with a CRISPR method using single guide RNA.
CRISPR systems using SaCas9 have a surprising combination of high efficacy and small
size, giving Broads claims that require the use of SaCas9 in a eukaryotic system unique and
surprising features that make them non-obvious over Count 2 and the prior art. Fact 154; Ex.
2001, Simons 1st Dec. 7.5-7.9; Ex. 1014, 406 patent, col. 83, l. 25 col. 84, l. 23; Ex. 2009,
Simons 3d Dec. 12.6.
10
UCs experts merely assert that because the sequence for SaCas9 and S. thermophilus
11
Cas9 was known, a skilled person could predict the domain structures of [SaCas9] based on an
12
alignment of protein sequences that included [StCas9] and [SpCas9.] However, knowing the
13
domain structure provides no information about the potential for success or failure of the Cas9
14
protein. Fact 155; Ex. 2001, Simons 1st Dec 7.8. The Broad inventors discovered that,
15
surprisingly, among the hundreds of other known Cas9 varieties, SaCas9 works much better than
16
StCas9 and as good as, if not better than the best prior art Cas9SpCas9. Fact 156; Ex. 2001,
17
Simons 1st Dec 7.8.
18
UCs experts also state that the skilled artisan would have been motivated to study
19
SaCas9 because it had strong homology to the sequence of other Cas9 proteins, citing to S.
20
thermophilus Cas9 (StCas9). Ex. 1022 275; Ex. 1024 266. However, StCas9 was known to
21
be inferior to the S. pyogenes Cas9 (SpCas9), and SaCas9 shares only 17% sequence identity
22
with SpCas9, teaching away from its use. Fact 157; Ex. 2009, Simmons 1st Dec. 7.5.
27
In any event, a comparison of the physical structure between the two orthologs would
have revealed significant structural differences between SaCas9 and SpCas9. Fact 158; Ex.
2001, Simons 7.8; Ex. 2227, Nishimasu 2014; e.g. Ex. 2008, Carroll Dep. at 233:5-234:19. A
skilled artisan would be less inclined to select an ortholog that contains these significant
structural differences. Moreover, the size of the Cas9 would not have been relevant in adapting
the CRISPR-Cas system to eukaryotic cells. Fact 159; Ex. 2001, Simons 1st Dec 7.7. The size
of a Cas9 orthologue would be only one factor considered after the CRISPR-Cas system had
been successfully adapted to eukaryotic cells. Fact 160; Ex. 2001, Simons 1st Dec 7.7-7.9 .
9
10
Consequently, UC has failed to carry its burden of proving the SaCas9 claims are not
patentable over proposed Count 2.
11
12
13
b. One Or More NLS Claims Would Be Separately Patentable over

Proposed Count 2 Even If Eukaryotic Limitation Were Found To Be
Obvious
14
UC also failed to prove that Broad claims requiring the use of one or more or two or
15
more NLSs are not patentable over proposed Count 2. Ex. 1009, 839 patent; Ex. 1015, 308
16
patent. With respect to anticipation, proposed Count 2 does not recite the use of any NLS. Fact
17
161; Paper 32, p. 10; Ex. 2009, Simons 3d Dec. 12.62. With respect to obviousness UC points
18
to no teaching or suggestion in proposed Count 2 or the prior art to use any NLSs in a CRISPR-
19
Cas system. Jinek 2012 did not mention or discuss the use of NLSs and the only two UC
20
applications that pre-date Broads filing do not include any embodiment that uses an NLS. Fact
21
162; see Ex. 1155. Moreover, the only disclosure of an NLS in those two patent applications, is
22
discussing the potential use of a CRISPR-Cas9 system in an organelle, for which there would be
23
no need to use an NLS.
28
A skill person would have had concerns regarding the use of an NLS because they would
have understood that adding amino acids to a protein could alter the proteins folding and affect
its structures and functions. Fact 163; Ex. 2001, Simmons 1st Dec. 7.18. The use of two of
more NLSs is not typical and would not have been predicted. Id. 7.107.27. This is shown in
the post-2012 references that UC relies upon. None of the Cho, Mali or Hwang references used
two or more NLSs.

c. Broad Claims To Specific Tracr Lengths Would Be Separately Patentable
Over Count 2
7
8
9
UC also failed to prove that Broad claims requiring a specific tracr length are not
10
patentable over Count 2. If Count 2 is adopted, then it necessarily follows that Count 2 is
11
patentable because small changes in the RNA sequence would be expected to have a dramatic
12
effect on protein binding and activity. Ex. 1024, Carroll 107; Ex. 1022, Greider 113. Based
13
on UCs own logic, changing the length of the tracrRNA would have a highly unpredictable
14
impact on the binding and activity of Cas9 and therefore Broads claims to specific tracr lengths
15
would be separately patentable.
16
V.
17
18
CONCLUSION
For the reasons set forth herein, UCs Motion 3 should be denied.
Dated: August 12, 2016
Respectfully submitted,
19
20
21
22
23
24
25
26
27
/
Steven R. Trybus
Reg. No. 32,760
Lead Counsel for Broad
Jenner & Block LLP
353 North Clark Street
Chicago, IL 60654
Telephone: (312) 222-9350
Facsimile: (312) 527-0484
strybus@jenner.com
29
APPENDIX 1: LIST OF EXHIBITS

EXHIBIT NUMBER
DESCRIPTION
1001
U.S. Patent Application No. 13/842,859, filed on March 15, 2013.
1007
U.S. Patent No. 8,697,359, issued on April 15, 2014.
1009
U.S. Patent No. 8,945,839, issued on February 3, 2015.
1010
U.S. Patent No. 8,889,356, issued on November 18, 2014.
1014
U.S. Patent No. 8,865,406, issued on October 21, 2014.
1015
U.S. Patent No. 8,895,308, issued on November 25, 2014.
1022
Declaration of Dr. Carol Greider.
1024
Declaration of Dr. Dana Carroll.
1032
Deltcheva et al., CRISPR RNA maturation by trans-encoded

small RNA and host factor RNase III, 471 Nature 602-607 (2011)
with Supplementary Materials.
1033
Sapranauskas et al., The Streptococcus thermophilus CRISPR/Cas

system provides immunity in Escherichia coli, 39 Nucleic Acids
Res. 9275-9282 (2011).
1055
Cong et al., Multiplex Genome Engineering Using CRISPR/Cas

Systems, 339 Science 819-823 (2013) with Supplemental
Material.
1152
Carroll, A CRISPR Approach to Gene Targeting, 20 Molecular

Therapy 1659-1660 (2012).
1153
Garneau et al., The CRISPR/Cas bacterial immune system cleaves

bacteriophage and plasmid DNA, 468 Nature 67-71 (2010).
1155
Jinek et al., A programmable dual-RNA-guided DNA

endonuclease in adaptive bacterial immunity, 337 Science 816821 (2012).
1161
Sontheimer et al., U.S. Patent Publication No. 2010/0076057,

published on March 25, 2010.
A1-1
1204
Cong et al., Multiplex Genome Engineering Using CRISPR/Cas

Systems, 339 Science 819-823 (2013) with Supplemental
Material.
1215
Carte et al., Cas6 is an endoribonuclease that generates guide

RNAs for invader defense in prokaryotes, 22 Genes & Dev. 34893496 (2008).
1257
Hale et al., Prokaryotic silencing (psi)RNAs in Pyrococcus

furiosus, 14 RNA 2572-2579 (2008).
1262
Haurwitz et al., Sequence- and structure-specific RNA processing

by a CRISPR endonuclease, 329 Science 1355-1358 (2010).
1379
Sternberg et al., Mechanism of substrate selection by a highly

specific CRISPR endoribonuclease, 18 RNA 661-672 (2012).
1435
International PCT Publication No. WO 2008/108989 A2,

published on September 12, 2008.
1473
Golic, RNA-Guided Nucleases: A New Era for Engineering the

Genomes of Model and Nonmodel Organisms, 195 Genetics 303308 (2013).
1479
U.S. Provisional Application No. 61/613,373, filed on March 20,

2012.
2001
Declaration of Dr. Paul Simons, executed May 23, 2016.
2005
Deposition Transcript of Dr. Carol Greider, July 20, 2016.
2006
Deposition Transcript of Dr. Carol Greider, July 21, 2016.
2008
Deposition Transcript of Dr. Dana Carroll, July 22, 2016.
2009
Third Declaration of Dr. Paul Simons, executed August 15, 2016.
2010
Declaration of Dr. Ronald Breaker, executed August 15, 2016.
2227
Nishimasu et al., Crystal structure of Cas9 in complex with guide

RNA and target DNA, 156 Cell 935-949 (2014).
2272
Ferr-D-Amar et al., A General Module for RNA

Crystallization, 279 J. Molecular Biology 621-631 (1998).
2280
Molinaro et al., Use of ultrastable UNCG tetraloop hairpins to

fold RNA structures: thermodynamic and spectroscopic
applications, 23 Nucleic Acids Res. 3056-3063 (1995).
2411
SN 14/704,551 Excerpt, NIH grant application.
2412
SN 14/054,414 Excerpt, Cong notebook.
2413
SN 12/565,589 Excerpt.
APPENDIX 2: STATEMENT OF MATERIAL FACTS

UCs Alleged Facts with Broads Responses
1.
Count 1 is limited to contacting in a eukaryotic cell a target DNA with a CRISPR-Cas
system. Redeclaration, Paper No. 32, at 10.

Answer: Admitted.
2.
None of Senior Partys claims are limited to eukaryotes. See Ex. 1022, 90; Ex. 1024,
84; Senior Party Clean Copy of Claims, filed January 25, 2016.
Answer: Admitted.
3.
Senior Party has proffered proofs that are excluded by Count 1, but would be evidence of
an actual reduction to practice of Proposed Count 2. Ex. 1507; Ex. 1022, 166-176; Ex.
1024, 157-167.
Answer: Denied.
4.
Ex. 1507 is a copy of pages from co-inventor Martin Jineks laboratory notebook that are
dated prior to the filing date of Senior Partys First Provisional Application. Ex. 1507.
Answer: Junior Party can neither admit nor deny.
5.
Ex. 1507 is evidence of an actual reduction to practice of Proposed Count 2 that would be
excluded by the eukaryotic cell limitation of Count 1. Ex. 1507; Ex. 1022, 166-176; Ex.
1024, 157-167.
Answer: Denied.
6.
Jinek set out to test chimeric RNA to see whether crRNA and tracrRNA can be fused to
generate a single RNA with which Csn1/Cas9 can be programmed. Ex. 1507, at 84.
A2-1

7.
The experimental details recorded on pages 84-85 of the notebook show how target DNA
was contacted with a CRISPR-Cas system. See Ex. 1022, 173; Ex. 1024, 164.
Answer: Denied.
8.
The system was engineered and non-naturally occurring at least because, as illustrated on
page 86, the chimera A reactions contained crRNA and tracrRNA segments covalently linked to
form one molecule. See Ex. 1022, 173-174; Ex. 1024, 164-165.
Answer: Denied.
9.
In the natural system, the crRNA and tracrRNA are separate RNA molecules. Id.; see
also, e.g., Exs. 1032; 1033; Ex. 1022, 110; Ex. 1024, 103.
Answer: Admitted.
10.
The reaction details on pages 84-85, and the lane labels on page 86, show that Csn1/Cas9
protein was present in the system used in the chimera A reactions. Id.
Answer: Denied.
11.
The results recorded on page 86 of the notebook show that the target DNA was cleaved
when Csn1/Cas9 was complexed with a single-molecule DNA targeting RNA (i.e., chimera A).
See Ex. 1022, 175; Ex. 1024, 166.
Answer: Denied.
12.
On June 28, 2012, approximately one month after Senior Partys First Provisional was
filed, the Jinek Science Paper (Ex. 1155) (Jinek 2012), co-authored by Senior Partys
inventors, was published online, disclosing the necessary and sufficient components for cleavage
A2-2
of target DNA by a Type II CRISPR-Cas system, demonstrating successful DNA cleavage using
the system outside of its natural environment in a prokaryotic cell, and describing use of a single
molecule DNA-targeting RNA. See Ex. 1022, 152-158; Ex. 1024, 143-149.
Answer: Denied.
13.
At the time of, and immediately following, the publication of Jinek 2012, commenters
predicted application of the Type II CRISPR-Cas system to eukaryotic cells. See Ex. 1022,
129-133; Ex. 1024, 122-125.
Answer: Denied.
14.
In the same issue of Science as Jinek 2012, Brouns wrote [b]ased on the 20-nucleotide
guide section of the crRNA, the enzyme could theoretically introduce breaks at unique sites in
any eukaryotic genome. Ex. 1471; Ex. 1022, 132; Ex. 1024, 124.
Answer: Admitted.
15.
Before any reports of the Type II CRISPR-Cas system being applied in eukaryotes had
been published, Dr. Dana Carroll wrote in a peer reviewed article that doing so was clearly well
worth a try, and he discussed methods that could be used to do so. See Ex. 1152; Ex. 1024,
123.
Answer: Denied.
16.
In reference to Jinek 2012, a researcher in the art stated that [i]t was immediately
obvious that [the CRISPR-Cas9] system might be repurposed for genome engineering, similar to
ZFNs and TALENs. See Ex. 1473, at 306; Ex. 1022, 131; Ex. 1024, 124.
Answer: Admitted.
A2-3
17.
Before the Type II CRISPR-Cas system was fully elucidated, it had been suggested that
analogous CRISPR proteins could be used in eukaryotic cells. See Ex. 1161 (Sontheimer), at
0007; Ex. 1022, 133; Ex. 1024, 125.
Answer: Admitted.
18.
Sontheimer demonstrates that at least by September 23, 2009, researchers in the art were
motivated to adapt prokaryotic CRISPR systems to eukaryotic cells, were aware of routinely
used techniques available to do so (including the use of expression vectors, nuclear localization
signals, and codon optimization), and had an expectation of success in doing so. See Ex. 1161, at
0009, 0042, 0054, 0058, 0060; Ex. 1022, 133; Ex. 1024, 125.
Answer: Denied.
19.
Techniques that one might use to practice the method of Count 1, or Proposed Count 2, in
eukaryotic cells were well-known and routinely used in the art prior to Senior Partys First
Provisional. See Ex. 1022, 134, 136-151; Ex. 1024, 126, 128-142.
Answer: Denied.
20.
Methods for introducing a nucleic acid into a eukaryotic cell had been well-known for
over 30 years. See, e.g., Exs. 1040; 1200; 1248; 1233; 1260; 1307; Ex. 1022, 143; Ex. 1024,
134.
Answer: Denied.
21.
It was well-known that a protein or nucleic acid, including prokaryotic polynucleotides,
can be expressed in a eukaryotic cell using an expression vector, including viral vectors. See,
e.g., Exs. 1031; 1039; 1194; 1203; 1218; 1229; 1332; 1337; 1353; Ex. 1022, 136-137; Ex.
1024, 128-129.
A2-4
Answer: Denied.
22.
Well-known viral vectors had been used to express gene editing proteins in eukaryotic
cells. See, e.g., Exs. 1285; 1283; Ex. 1022, 138; Ex. 1024, 130.
Answer: Denied.
23.
It was well-understood that proteins could be targeted to the nucleus, where genomic
DNA is located in eukaryotes, and nuclear localization sequences (NLSs) had been routinely
used for decades. See, e.g., Exs. 1029; 1235; 1236; 1319; Ex. 1022, 140; Ex. 1024, 130.
Answer: Denied.
24.
One of ordinary skill in the art understood how to increase expression of prokaryotic
proteins in eukaryotic cells by codon optimization. See, e.g., Ex. 1030; Ex. 1022, 142; Ex.
1024, 133.
Answer: Denied.
25.
It was routine to combine use of an NLS with codon optimization. See, e.g., Ex. 1217;
Ex. 1022, 142; Ex. 1024, 133.

Answer: Denied.
26.
Neither an NLS nor codon optimization is actually necessary to achieve cleavage of
target DNA in a eukaryotic cell. See Exs. 1058; 1060, Ex. 1022, 141; Ex. 1024, 131.
Answer: Denied.
27.
Researchers had directly injected a pre-assembled prokaryotic protein/RNA complex
(ribonucleoprotein particles) into eukaryotic cells to cause genome modification in those cells.
Ex. 1293, at 12; Ex. 1022, 139; Ex. 1024, 131.
A2-5
Answer: Denied.
28.
Analogous methods of manipulating DNA in eukaryotic cells using prokaryotic proteins
that had been demonstrated included the prokaryotic cre-lox site-specific recombination system,
prokaryotic RecA protein, the C31 recombinase, and bacterial restriction endonucleases. See,
e.g., Exs. 1335; 1336; Ex. 1329, at 3094-95, Fig. 1; Exs. 1327; 1213; 1302; Ex. 1022, 144150; Ex. 1024, 135-141.
Answer: Denied.
29.
In less than a year after Senior Partys disclosure of an in vitro method in Jinek 2012,
researchers completed and published uses of the CRISPR-Cas9 system in multiple types of
eukaryotic cells and organisms and specifically cited the Jinek 2012 paper as a basis of their
work. See Ex. 1022, 163; Ex. 1024, 154; see also Exs. 1055; 1056; 1058; 1059; 1060; 1371,
and 1372.
Answer: Denied.
30.
Count 1 identifies the necessary components of the Type II CRISPR-Cas9 system without
specifying whether the RNA components are comprised in a single molecule. See Ex. 1022,
108; Ex. 1024, 102; Redeclaration, Paper No. 32, at 10.
Answer: Admitted.
31.
All of both parties claims are directed to use of a single-molecule DNA-targeting RNA.
See Ex. 1022, 87-108; Ex. 1024, 80-101.

Answer: Denied.
32.
Proposed Count 2 is directed to a single-molecule DNA-targeting RNA. See Ex. 1022,
110; Ex. 1024, 103.

A2-6
Answer: Admitted.
33.
Given the generic subject matter of Count 1, it would not have been obvious at the time
Senior Partys First Provisional Application was filed that the crRNA and tracrRNA components
could be covalently linked to form a single-molecule DNA-targeting RNA while maintaining a
functioning CRISPR-Cas9 system. See Ex. 1022, 109-124; Ex. 1024, 102-117.
Answer: Denied.
34.
The natural type II CRISPR-Cas system uses two separate RNA molecules, a crRNA
molecule and a tracrRNA molecule, for DNA cleavage. See, e.g., Exs. 1032; 1033; Ex. 1022,
110; Ex. 1024, 103.
Answer: Admitted.
35.
The creation of a single-molecule DNA-targeting RNA requires covalently linking the
targeter-RNA (crRNA) and activator-RNA (tracrRNA). Ex. 1022, 112-113; Ex. 1024,
105-106; see also Ex. 1155, at Fig 5A.
Answer: Denied.
36.
Prior to Senior Partys First Provisional Application and the teachings of Jinek 2012,
persons of ordinary skill in the art would have had good reason to doubt that the DNA-targeting
RNA could be combined into a single molecule and still function with Cas9 to cleave DNA. See
Ex. 1022, 114-122; Ex. 1024, 105-115.
Answer: Denied.
37.
Enzymes that interact with, and functionally rely on, nucleic acids were known to be very
sensitive to structural changes in the nucleic acids. Ex. 1022, 114-117; Ex. 1024, 107-110.
A2-7
Answer: Denied.
38.
A key enzyme in another CRISPR system, Csy4, which, like Cas9, is a nuclease enzyme
that interacts with a crispr-RNA (crRNA) molecule via an RNA duplex region, was known to be
sensitive to even a relatively minor structural change to the RNA duplex region, such that even
small changes in the RNA resulted in a 1,600 to 49,000 fold decrease in RNA binding. See Ex.
1022, 114; Ex. 1024, 107; Ex. 1262, at 1355 and Fig. 2; Ex. 1379 at Figs. 3, 5A.
Answer: Denied.
39.
Argonaute, an RNA binding protein, is extremely sensitive to even small changes in
the ends of a double-stranded RNA duplex that it recognizes, such that even small changes
resulted in a 100 to 10,000 fold decrease in RNA binding and enzymatic activity. See Ex. 1022,
114; Ex. 1024, 107; Ex. 1377, at 196; Ex. 1378, at 318-320.
Answer: Denied.
40.
Telomerase is an enzyme that must bind to RNA having a specific structure, including a
stem and loop, to which the TERT protein is highly sensitive, to carry out its enzymatic activity,
such that mutations that extend the RNA duplex or merely change two residues in the loop
sequence resulted in a non-functional protein-RNA complex. See Ex. 1022, 117; Ex. 1024,
110; Ex. 1376, at 592, 595-597, Fig. 3.
Answer: Denied.
41.
Researchers in the art specifically noted the innovativeness of the single-molecule DNA-
targeting RNA. See, e.g., Ex. 1375 (The most innovative modification was to create a singleguide RNA (sgRNA) that is of the combined functions of crRNA and tracrRNA and is capable of
accurately guiding Cas9 to a predetermined site in the host genome (Jinek et al. 2012).); Ex.
A2-8
1374 (Significant advances for the use of this technique have been promoted by the generation
of a single-guide RNA (sgRNA) that combines the function of the tracrRNA and crRNA in a
chimeric molecule).
Answer: Denied.
42.
As defined by Junior Party, a guide sequence does not include the tracr-mate portion
that is required for hybridization with the activator-RNA (tracrRNA) to form the necessary
protein binding segment. See Ex. 1022, 80-86; Ex. 1024, 73-79.
Answer: Admitted.
43.
The recitation of guide sequence in Count 1 encompasses non-functional systems. See
Ex. 1022, 80-86; Ex. 1024, 73-79.

Answer: Denied.
44.
Proposed Count 2 does not include the guide sequence recitation of Count 1.
Answer: Admitted.
45.
Junior Partys involved applications state that the term guide RNA can be used
interchangeably to refer to the single-molecule DNA-targeting RNA. Id.

Answer: Denied.
46.
Proposed Count 2 includes a guide RNA recitation.
Answer: Admitted.
47.
Each of Senior Partys Provisional Applications describes embodiments within the scope
of Proposed Count 2. See Ex. 1022, 341-454; Ex. 1024, 323-445.
A2-9
Answer: Denied.
48.
Example 1 of Senior Partys First Provisional Application describes and enables a
working example of a method meeting all of the limitations of Proposed Count 2. See Ex. 1022,
449-454; Ex. 1024, 440-445; Ex. 1003, at 248-252, Fig. 3.
Answer: Denied.
49.
Examples, performed in the same, or substantially the same manner, as Example 1 of
Senior Partys First Provisional Application are presented, along with additional data and
description, in each of Senior Partys Second Provisional, Third Provisional, and the 859
Application. See Ex. 1022, 449; Ex. 1024, 440; compare Ex. 1003 at 00248-00252, Figs.
1, 3, 5; Ex. 1004, at 0006, 00312-00318, 00353-00358, Figs. 1, 3, 5, 17;31, 32; Ex. 1005, at
0031, 00234, 00360-00370, 00401-00406, Figs. 1, 3, 5, 13-17, 31, 32; Ex. 1001, at 0035,
0042-0046, 0049, 00504-00524, 00555-00560, Figs, 1, 10-14, 17, 18, 21, 23, 24, 26-31.
Answer: Denied.
50.
Example 1 of the First Provisional discloses an example in which DNA cleavage was
performed. See Ex. 1022, 450; Ex. 1024, 441; Ex. 1003, at 0249.
Answer: Denied.
51.
Sequences of the Cas9 and chimera A single-molecule DNA-targeting RNA are shown in
the figures of the application and the method by which they were made are described. See Ex.
1022, 454; Ex. 1024, 445; Ex. 1003, at 00248, Figs. 2, 12A, 3B.
Answer: Admitted.
A2-10
52.
The single-molecule DNA-targeting chimera A RNAs comprised a targeter-RNA that
hybridizes with the target sequence, and ii) an activator-RNA that are covalently linked as shown
in Figs. 1 and 3B. Ex. 1003, at Figs. 1, 3B.
Answer: Denied.
53.
The system of Example 1 was engineered and non-naturally occurring at least because a
single-molecule DNA-targeting RNA is not found in the naturally occurring system. See Ex.
1022, 452; Ex. 1024, 443; Ex. 1003, at 0012, Figs. 1, 3B, 9.
Answer: Admitted.
54.
Example 1 describes contacting an engineered and non-naturally occurring CRISPR-Cas9
system with a target DNA in that [t]he DNA-targeting RNA/polypeptide complexes were
assembled by incubation in the cleavage buffer and then the assembled complex was added to
target DNA and incubated. See Ex. 1022, 452; Ex. 1024, 443; Ex. 1003, at 249.
Answer: Denied.
55.
Targeting of the target DNA by the complex is illustrated in Fig. 1 of the First
Provisional. See Ex. 1022, 453; Ex. 1024, 444; Ex. 1003, at Fig. 1.
Answer: Denied.
56.
The results of Example 1, shown in Fig. 3A of the First Provisional, demonstrate that
reactions containing the Cas9/Chimera A complex cleaved target DNA. See Ex. 1022, 453;
Ex. 1024, 444; Ex. 1003, at Fig. 3A.
Answer: Denied.
A2-11
57.
Each of Senior Partys Provisionals shares at least one inventor with the 859 Application
and the 859 Application contains the required reference to each of the Senior Partys
Provisionals. Ex. 1003, cover, Ex. 1004, at 264-269 (ADS); Ex. 1005, at 348-353 (ADS); Ex.
1001, at [0001] and 345-352 (ADS).
Answer: Admitted.
58.
Junior Party has not been accorded any benefit. See Redeclaration, Paper No. 32, at 13.
Answer: Admitted.
59.
References that have been cited in the parties applications are listed in Ex. 1380.

60.
Drs. Dana Carroll and Carol Greider have reviewed all the references previously
identified to the USPTO during prosecution of the Involved Patents or during the present
interference dated prior to Senior Partys First Provisional Application, filed May 25, 2012. Ex.
1022, 177-183, 242; Ex. 1023; Ex. 1024, 168-175, 234; Ex. 1025.
Answer: Denied.
61.
None of the references known to Senior Party that are dated prior to May 25, 2012,
together or separately, disclose, nor would have rendered obvious, a CRISPR-Cas9 method using
a single-molecule DNA-targeting RNA as required by Proposed Count 2. Id.
Answer: Denied.
62.
None of the references that have been applied to any involved patent or application or
specifically cited in this proceeding, alone or in combination, disclose or suggest a method of
A2-12
using a single-molecule DNA-targeting RNA in a CRISPR-Cas9 system as required by Proposed

Count 2. See Ex. 1022, 242; Ex. 1024, 234.
Answer: Denied.
63.
All of Junior Partys involved claims should be construed as directed to use of a single-
molecule DNA-targeting RNA. Ex. 1022, 91-107; Ex. 1024, 85-101.

Answer: Denied.
64.
All of Junior Partys involved claims recite a CRISPR-Cas system that includes a Cas9
protein and a guide RNA. See, e.g., Second Replacement Broad Clean Copy of Claims, filed
April 22, 2016.
Answer: Admitted.
65.
Persons of ordinary skill in the art would have understood Junior Partys use of guide
RNA in the claims of its involved patents and application to mean a single-molecule DNAtargeting RNA. Ex. 1022, 91-107; Ex. 1024, 85-101.
Answer: Denied.
66.
The only definition of the term guide RNA in Junior Partys Involved Patents and
Application describes the guide RNA as a single-guide system:

In aspects of the invention the terms chimeric RNA, chimeric guide RNA, guide RNA,
single guide RNA and synthetic guide RNA are used interchangeably and refer to the
polynucleotide sequence comprising the guide sequence, the tracr sequence and the tracr mate
sequence.
See, e.g., Ex. 1007 at col. 12, ll. 6-10; Ex. 1022, 93; Ex. 1024, 87.
A2-13
Answer: Denied.
67.
There is nothing in Junior Partys claims or specifications that is contrary to this
definition. See Ex. 1022, 95-97; Ex. 1024, 89-91.

Answer: Denied.
68.
The term guide RNA is used throughout Junior Partys specifications, including all of
the working examples, only in reference to a single-molecule DNA-targeting RNA. Id.

Answer: Denied.
69.
Junior Party has told the USPTO during prosecution that a guide RNA comprises not
only a guide sequence but also a tracrRNA sequence as well as other necessary sequence(s) for
the guide DNA [sic] to be fully functional in targeting a genomic locus of interest. See
Examiners Interview Summary in U.S. Pat. App. No. 14/463,253, dated Nov. 3, 2015 (Ex.
1511).
Answer: Denied.
70.
Many of Junior Partys involved claims contain limitations that explicitly specify that the
guide RNA is a single-molecule DNA targeting RNA. See Ex. 1022, 100-106; Ex. 1024,
94-100.
Answer: Admitted.
71.
A single-molecule DNA-targeting RNA of Proposed Count 2 would anticipate a
generically-construed guide RNA.

Answer: Denied.
A2-14
72.
Both Senior Partys and Junior Partys involved claims contain limitations that are not
specifically recited in Proposed Count 2, however, each of these additional limitations would
have been obvious to one of ordinary skill in the art at the time these applications were filed,
whether taken alone or in combination. See Ex. 1022, 255; Ex. 1024, 246.
Answer: Denied.
73.
Where some claims of the parties recite systems, and not methods, Proposed Count 2
includes the same elements of the CRISPR-Cas9 system that are recited in those system claims.
See Ex. 1022, 255; Ex. 1024, 246.
Answer: Denied.
74.
None of the limitations in Junior Partys claims that are not explicitly recited in Proposed
Count 2 render any of Junior Partys claims separately patentable from the method recited in
Proposed Count 2. See Ex. 1022, 255-328; Ex. 1024, 246-319.
Answer: Denied.
75.
Proposed Count 2 recites all of the elements of Junior Partys claims except for certain
obvious variations. Ex. 1022, 250-254, Tables 1-13 of Appendices 1 and 2; Ex. 1024, 242245, Tables 1-13 of Appendices 1 and 2.
Answer: Denied.
76.
Drs. Carol Greider and Dana Carroll, who are experts in the field, have considered each
of Junior Partys involved claims and explain, element-by-element, why the claims would have
been obvious in view of Proposed Count 2. Id.; see also Exs. 1023; 1025.
Answer: Denied.
A2-15
77.
All of Senior Partys involved claims are directed to methods of using a single-molecule
DNA-targeting RNA in a Type II CRISPR-Cas system. Ex. 1022, 246-248, Appendices 1 and
2; Ex. 1024, 238-240; Appendices 1 and 2.
Answer: Admitted.
78.
Drs. Carol Greider and Dana Carroll, who are experts in the field, have considered each
of Senior Partys involved claims and explain, element-by-element, why the claims would have
been obvious in view of Proposed Count 2. Id.
Answer: Denied.
A2-16
Broads Additional Facts:

79.
This interference concerns methods of using CRISPR to cleave or edit target DNA or
modulate its transcription. Ex. 2001, Simons 1st Dec 4.2.

80.
CRISPR occurs naturally in prokaryotic cells and is programmed in nature to target
specific phage or plasmid DNA targets. Ex. 2001, Simons 1st Dec 2.1.
81.
Junior Party argued that the limitation to eukaryotic methods and systems made its claims
patentable over prior art CRISPR methods in other environments and then obtained their claims.
See, e.g. Ex. 2424.
82.
UCs application in interference is related to eukaryotic CRISPR methods. Ex. 1001.
83.
Guide RNA where the two RNA components that guide the Cas9 complex to the target
DNA are covalently linked together into a single molecule is sometimes called single guide
RNA or chimeric guide RNA. Ex. 2009, Simons 3rd Dec 12.20.
84.
Guide RNA consisting of two separate molecules is called dual guide by UCs experts
and attorneys. Paper 45 at 19:6-15; Ex. 1022, Greider 374, 425; Ex. 1024, Carroll 365,
416.
85.
UC filed its Motion 3 knowing Junior Partys best proofs used two-molecule guide RNA.
See Paper No. 27 at 30:12-31:12.

86.
Junior Partys publication in Cong et al. shows that Junior Partys earlier work used dual-
molecule RNA systems. Ex. 1055 at 819-820.

87.
In ex parte prosecution, Junior Party submitted numerous declarations describing its
laboratory work in 2011 and 2012 that was performed on dual guide RNA. Ex. 2009, Simons
3rd Dec 12.5.
88.
Junior Partys early work is shown in Junior Party inventors NIH grant application
discussed in Junior Partys 2015 submission to the PTO. Ex. 2411.

A2-17
89.
This NIH application, dated January 12, 2012, shows the design of an entire mammalian
CRISPR expression system, that does not include single molecule guide RNA. Id. at 16 (Figure
4).
90.
Most of UCs involved specifications examples are in a eukaryotic environment. See,
generally, Ex. 1001 at 562-662.

91.
UC previously filed, but canceled, CRISPR claims require a eukaryotic environment. Ex.
2424.
92.
All of Junior Partys involved claims at issue require a eukaryotic environment. Ex.
1007-1019.
93.
Count 1 does not require that the activator-RNA hybridizes to the guide sequence. Ex.
2005, Greider Dep. at 30:7-10.

94.
The activator-RNA hybridizes with some part of the targeter-RNA and the targeter-RNA
includes both the guide sequence and the tracrmate sequence. Ex. 2009, Simons 3d Dec. 12.9.
95.
A person of skill in May 2012 would know that tests can be performed to determine
whether a tetraloop would or would not interfere with protein binding. Ex. 2009, Simons 3rd
Dec 12.49.
96.
In February 2008, a group of inventors disclosed that it was contemplated that the
CRISPR system be transferred into eukaryotic cells utilizing any suitable method known in the
art, including, but not limited to transformation via plasmids. Ex. 1435, 714 Application, p.
101, ll. 22-23.
97.
These inventors did not publish any results showing any CRISPR system in eukaryotic
cells before the Junior Partys inventors early 2013 publication. Ex. 2009, Simons 3d Dec.
12.14.
A2-18
98.
In 2009, another group of inventors filed a patent application claiming a method of using
CRISPR in a eukaryotic cell. Ex. 1161, 589 Application, Claim 1.

99.
These inventors disclosed a representative of each type of CRISPR as model system: E.
coli (Type I), S. thermophilus (Type II) and S. epidermis (Type III). Ex. 1156 at 8 0054; Ex.
2009. Simons 3d Dec. 12.14.
100.
These inventors never published working eukaryotic CRISPR methods. Simons 3d Dec.
12.14.
101.
After receiving enablement rejections from the PTO, Sontheimer et al. abandoned their
patent application. Ex. 2413; Ex. 2009, Simons 3d Dec. 12.14.

102.
Dr. Carroll stated that because CRISPR originated in prokaryotic, not eukaryotic systems,
there is no guarantee that Cas9 will work effectively on a chromatin target or that the required
DNA-RNA hybrid can be stabilized in that context. Ex. 1152, Carroll 2012 at 660.
103.
Dr. Carroll asserted that a key CRISPR component might be disassembled by
endogenous eukaryotic enzymes, warning that eukaryotic DNA processing systems might cause
a potential side effect of extraneous DNA cuts. Id.
104.
Carroll stated, gene editing through base pairing has been attempted many times. Id.
105.
Carroll referred to some prior attempts to obtain a CRISPR system that functions in
eukaryotes and described them as having efficiencies that were discouragingly low, having
limited range and less efficiency than other techniques. Id.
106.
Carroll stated, Whether the CRISPR system will provide the next-next generation of
targetable cleavage reagents remains to be seen, but it is clearly well worth a try. Stay tuned.
Id.
A2-19
107.
There are hundreds of CRISPR loci in the bacterial world, including many different Type
II systems. Ex. 2009, Simons 3d Dec. 12.16.

108.
Most bacteria that have any Type II locus include multiple, different Type II loci in their
genomes. Id.
109.
It was known by May 2012 that tracrRNA, crRNA and Cas9 were necessary for the
combination of the maturation and cleavage steps. Ex. 2009, Simons 3d Dec. 12.43; see also
Ex. 2010, Breaker Dec. 1.11-1.26.
110.
In May 2012 it was known that no other Cas protein was necessary for bacterial
immunity. Ex. 2009, Simons 3rd Dec 12.37.

111.
Group II introns, which are closely analogous to the CRISPR system and which involve
both RNA and protein from bacteria have not been readily adapted for use and function in
eukaryotic cells. Ex. 2010, Breaker Dec 1.50.
112.
The term guide RNA includes both two-molecule and single-molecule guide RNA. Ex.
2009, Simons 3d Dec. 12.1712.26.

113.
Junior Partys patents and application use the term guide RNA to refer to the RNA that
guides the Cas9:RNA complex to its DNA target. Ex. 2009, Simons 3d Dec. 12.1812.20.
114.
The 359 Patent claim 1 requires a nucleotide sequence that encodes a guide RNA,
with no limitation on the number of molecules it contains. Ex. 1007 Claim 1.

115.
Dependent claim 4 of the 359 patent adds a single limitation wherein the guide RNAs
comprise a guide sequence fused to a trans-activating cr (tracr) sequence. Ex. 1007 Claim 4.
116.
Example 6 of the 356 patent uses the term guide RNA to encompass both single guide
RNA and dual guide RNA. Ex. 1010 col. 105 lines 3-8.
A2-20
117.
The 359 patent expressly states that in some embodiments the tracr sequence and the
tracr mate sequence are contained within a single transcript. Ex. 1007, 359 patent, col. 21, l.
41-45.
118.
Example 1 of the 359 patent includes several embodiments that use two-molecule guide
RNA. Id. at col. 43-50.

119.
UC in its publications, UCs attorneys in this interference, and prior art authors have all
used the term guide RNA to mean whatever RNA guides the interference complex to the
target. Ex. 2009, Simons 3d Dec. 12.2712.31.
120.
In Jinek 2012 the UC inventors wrote, In this ternary complex, the dual
tracrRNA:crRNA structure acts as guide RNA that directs the endonuclease Cas9 to the cognate
target DNA. Ex. 1155, Jinek 2012, Figure S1 caption.
121.
The ternary complex in Jinek 2012 refers to the three part complex consisting of (1)
Cas9, (2) a mature crRNA molecule and (3) a tracrRNA molecule. Ex. 2009, Simons 3d Dec.
12.27.
122.
The dual tracrRNA:crRNA structure of Jinek 2012 is a two component complex. Id.
123.
In Jinek 2012, UC used the term guide RNA to refer to a dual guide complex
consisting of separate strands of tracrRNA and crRNA. Ex. 2009, Simons 3d Dec. 12.27.
124.
UCs 859 application defines the term DNA-targeting RNA as being synonymous
with guide RNA and as including two molecule guide RNA. Ex. 1001, 859 application at 130;
see also Ex. 2005, Greider Dep. at p. 291, l. 20 p. 292, l. 21.
125.
UCs experts refer to the use of a composition that includes purified recombinant S.
pyogenes Cas9 protein and either a single-guide or dual-guide DNA targeting RNA, i.e., the
A2-21
complex of Count 1 and Proposed Count 2 (single-guide DNA-targeting RNA complex.) Ex.
1022, Greider 374; Ex. 1024, Carroll 365 (emphasis added).
126.
UCs counsel represented to the Board that UC planned to propose a count that was
generic as to guide RNA, meaning that it covers both the dual guide and the single guide
embodiments. Paper 45, May 6, 2016 Conf. Call Tr. 19:8-11; Tr. p. 22, l. 12 p. 23, l. 7.
127.
A 2011 paper explained, [t]he crRNA serves as a guide (hence the term guide RNA has
also been used) to allow for specific base paring between the exposed crRNA within the
ribonucleoprotein interference complex and the corresponding protospacer on the foreign DNA.
Ex. 1204, Bhaya at 286.
128.
The same paper explained, CRISPR RNA (crRNA): small noncoding RNA ... (also
known as psiRNAs or guide RNA) Based on their function, these small RNAs have also
been referred to as ... guide RNAs. Ex. 1204 at 276 (side bar citation omitted).
129.
Many other papers used the term guide RNA in the same way. Ex. 1215, Carte et al. at
3490; Ex. 1257, Hale et al., at 2577; Ex. 2227, Jore at 529.
130.
The rest of Junior Partys claims cover CRISPR methods that use dual guide RNA. Ex.
1007-1019.
131.
Junior Partys statement in its 359 Patent that [i]n aspects of the invention, the terms
guide RNA along with single guide RNA and chimeric RNA are used interchangeably and
refer to the polynucleotide sequence comprising the guide sequence, the tracr sequence and the
tracr mate sequence is not a definition. Ex. 2009, Simons 3rd Dec 12.19.
132.
The Deltcheva article, published in March 2011, disclosed that Cas9 and the precursors to
crRNA and tracrRNA complexed together as part of the maturation process of the crRNA and
the tracrRNA. Ex. 1032, Deltcheva at 603-605.
A2-22
133.
Deltcheva showed that tracrRNA was involved in the maturation of crRNA, i.e., the
processing of the long pre-crRNA (repeat-spacer-repeat-spacer-repeat-etc. (possibly hundreds of

repeat-spacer units)) to the crRNA (a single repeat-spacer unit.) Ex. 1032, Deltcheva at 603.
134.
Deltcheva showed that tracrRNA formed a complex with both crRNA and Cas9 during
this process, and described the third step of the CRISPR system as (3) interference with
invading cognate foreign genomes by mechanisms that are yet to be fully understood. Ex.
1032, Deltcheva at 602.
135.
Deltcheva also states that [Cas9] may also be involved in the silencing of invading
sequences. Ex. 1032, Deltcheva at 605 (Fig 4. caption).

136.
The Garneau 2010 publication, cited by Deltcheva, states that the endonuclease activity
[of S. thermophilus CRISPR] seems to require [Cas9]. Ex. 1153, Garneau at 70.
137.
It was known by 2012 that Cas9 was the only Cas protein necessary for cleavage. Ex.
2009, Ex. 2009, Simons 3rd Dec 12.37.

138.
It was known by May 2012 that crRNA was involved in the interference step. . See Ex.
1033, Sapranauskas at 9275.

139.
Deltcheva showed that the precursors for the tracrRNA:crRNA duplex and Cas9 are
complexed together just before the formation of the mature crRNA. Ex. 1032, Deltcheva at 605.
140.
Deltcheva showed that the tracrRNA and crRNA form a hybridized duplex resulting from
a significant degree of Watson-Crick base pairing. Ex. 1032, Deltcheva at 603.

141.
Since the 1970s, techniques had been developed on the thermodynamics of disassociation
of double stranded RNA. Ex. 2009, Simons 3d Dec. 12.41.
A2-23
142.
Before May 2012, the widely-used algorithm mfold was available to provide an estimate
of the free energy of dissociation, G, for any RNA duplex. Ex. 2010, Breaker Dec. 1.15
1.16.
143.
The mfold algorithm predicts a G value of -20.4 kcal/mole for an RNA duplex having
the base pairing shown in Deltcheva Figure 1. Id at 1.18.

144.
A G value of 20.4 kcal/mole corresponds to a kinetic rate constant for dissociation that
is so small that no appreciable separation would be predicted to occur under biologically relevant
conditions. Ex. 2010, Breaker Dec. 1.171.18.
145.
Based on the number of base pairs disclosed in the Deltcheva duplex, its melting
temperature would be much greater than 37C. Ex. 2010, Breaker Dec. 1.211.22; Ex. 1032
at 608.
146.
To ensure double stranded RNA properly forms in vitro it has been routine since the
1990s to connect the two strands by covalent linkers of four nucleotidescalled tetraloops.
Ex. 2010, Breaker Dec. 1.38.
147.
Tetraloops ensure the desired folding of RNA. Ex. 2280, Molinaro at 3063.
148.
A common example of a well-known tetraloop used for this purpose was the sequence
GAAA, which was used in Jinek 2012. Ex. 2010, Breaker Dec. 1.301.33.
149.
RNA, especially double-stranded RNA, is notoriously badly behaved in crystal
structures, frequently resulting in neighboring molecules packing subtly out of register. Ex.
2272, Ferr-DAmer at 625.
150.
It was disclosed in the 1990s that tetraloopsespecially the GAAA tetraloopare
useful for restoring the proper well-registered array of crystals. Ex. 2272, Ferr-DAmer at
625; Ex. 2010, Breaker Dec. 1.39
A2-24
151.
Csy4, which like Cas9 was known to process pre-crRNA to tracrRNA in a different
CRISPR system, bound RNA most effectively when a GNRA-tetraloop structure (which include
GAAA) was used. Ex. 1379 at 665; see also Ex. 1262 at 1357.
152.
UC is not entitled to benefit of P1, P2 or P3 for Count 2. Ex. 2009, Simons 3d Dec.
11.16711.169.
153.
The claims of the 406 and 308 patents require the use of a Staphylococcus aureus Cas9
(SaCas9) protein or a nucleotide sequence encoding such a protein, and are not anticipated or
rendered obvious by the prior art. Ex. 1014, 406 patent; Ex. 1015, 308 patent; Ex. 2009,
Simons 3d Dec. 12.5312.60.
154.
CRISPR systems using SaCas9 have a surprising combination of high efficacy in
eukaryotes and small size. Ex. 2001, Simons 1st Dec. 7.6, 1 7.9; Ex. 1014.
155.
Knowing the domain structure provides no information about the potential for success or
failure of the Cas9 protein. Ex. 2001, Simons 1st Dec 7.8.
156.
The Broad inventors discovered that, among the hundreds of other known Cas9 varieties,
SaCas9 works much better than StCas9 and as good as, if not better than the best prior art
Cas9SpCas9. Ex. 2001, Simons 1st Dec 7.8.
157.
StCas9 was known to be inferior to the S. pyogenes Cas9 (SpCas9) in terms of cleavage
efficience, and SaCas9 shares only 17% sequence identity with SpCas9, teaching away from its
use. Ex. 2009, Simons.3d Dec 12.60.
158.
There are significant structural differences between SaCas9 and SpCas9. Ex. 2227;
Nishimasu 2014; see e.g. Ex. 2008, Carroll Dep. at 233:5-234.

159.
The size of the Cas9 would not have been relevant in adapting the CRISPR-Cas system to
eukaryotic cells. Ex. 2001, Simons 1st Dec 7.7.
A2-25
160.
The size of the Cas9 orthologue would be only one factor among many considered after
the CRISPR-Cas system had been successfully adapted to eukaryotic cells. Ex. 2001, Simons 1st
Dec 7.7-7.9.
161.
Count 2 does not recite the use of any NLS. Paper 32, p. 10
162.
Jinek 2012 did not disclose the use of NLSs and the only two UC applications which pre-
date Broads filing do not include any embodiment which uses an NLS. JINEK 2012
163.
A person of ordinary skill in the art would have understood that adding amino acids to a
protein could alter the proteins folding and affect its structures and functions. Ex. 2001,
Simmons 7.18.
164.
Only 55 of Junior Partys approximately 400 involved claimsless than 15% of them
require single molecule guide RNA. Ex. 2009, Simons 3d Dec. 12.21.
A2-26
CERTIFICATE OF FILING AND SERVICE

I hereby certify that on the 15th day of August, 2016, a true and complete copy of the
foregoing BROAD et al. OPPOSITION 3 (to oppose UCs motion to substitute Count 1 with
proposed Count 2) 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.
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
Date: August 15, 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
353 North Clark Street
Chicago, IL 60654
Telephone: (312) 222-9350
Facsimile: (312) 527-0484
strybus@jenner.com

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Broad Opp. No. 4

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Filed on behalf of: Junior Party, Broad

Paper No. ____

UNITED STATES PATENT AND TRADEMARK OFFICE

Patent Interference No. 106,048 (DK)

BROAD et al. OPPOSITION 3

INTRODUCTION and SUMMARY ...................................................................................1

STATEMENT OF PRECISE RELIEF REQUESTED ........................................................3

DESCRIPTION OF APPENDICES ....................................................................................3

REASONS WHY THIS MOTION SHOULD BE DENIED ...............................................3

The Subject Matter of Count 1 and Proposed Count 2 ............................................3

Proposed Count 2 is unfair to Junior Party because it excludes Junior

Count 1 is not unfair to Senior Party .......................................................................7

Count 1 is not deficient ............................................................................................9

Because Eukaryotic CRISPR Methods are Separately Patentable, UCs

Senior Party fails to prove that CRISPR in Eukaryotic Cells Would

Senior Partys Arguments to the contrary are meritless ............................19

UC Is Not Entitled To Benefit of P1, P2 or P3 ......................................................25

BROAD et al. OPPOSITION 3

BROAD et al. OPPOSITION 3

INTRODUCTION and SUMMARY

has repeatedly cited to it in this interference. Consequently, in proposing Count 2, UC intends to

that eukaryotic CRISPR is separately patentable over the prior art.

BROAD et al. OPPOSITION 3

BROAD et al. OPPOSITION 3

STATEMENT OF PRECISE RELIEF REQUESTED

method in eukaryotic cells is separately patentable, there is no interference-in-fact.

section B is Broads statement of facts in support of the opposition.

REASONS WHY THIS MOTION SHOULD BE DENIED

The Subject Matter of Count 1 and Proposed Count 2

BROAD et al. OPPOSITION 3

Fact 80; Ex. 2001, Simons 1st Dec 2.1.

Simons 3d Dec. 12.512.7. Moreover, UCs involved application is related to eukaryotic

1001 at 562-662; see also Ex. 2414.

374, 425; Ex. 2009, Simons 3d Dec. 12.2712.31.

BROAD et al. OPPOSITION 3

is limited to a covalently-linked single guide RNA. It recites no limitation on environment and

Proposed Count 2 unfairly excludes Junior Partys best proofs

application. Moreover, in ex parte prosecution, Junior Party submitted numerous declarations

BROAD et al. OPPOSITION 3

proposed Count 2. Id.

a single molecule guide RNA. ( Ex. 2009, Simons 3d Dec. 12.5.)

covalently-linked single molecule guide RNA. Id.

BROAD et al. OPPOSITION 3

2 specifically with the intention of excluding Junior Partys best proofs.

Count 1 is not unfair to Senior Party

suggest, erroneously, that the eukaryotic invention is not a separate invention.

BROAD et al. OPPOSITION 3

requires a eukaryotic environment; it is a consequence of UCs deliberate, calculated strategy. It

BROAD et al. OPPOSITION 3

Count 1 is not deficient

Because Eukaryotic CRISPR Methods are Separately Patentable, UCs

BROAD et al. OPPOSITION 3

possible choices required to achieve success in the unpredictable eukaryotic environment.

function. Fact 95; Ex. 2009, Simons 3rd Dec 12.49.

Senior Party fails to prove that CRISPR in Eukaryotic Cells Would

BROAD et al. OPPOSITION 3

UC relies on statements that CRISPR might be repurposed for genome engineering,

BROAD et al. OPPOSITION 3

BROAD et al. OPPOSITION 3

Simons 3d Dec. 12.15.

trying to make CRISPR work in it work in eukaryotes. See id.

the maturation step.

Further, at best, alleged predicted application[s] of CRISPR in eukaryotes pointed out

BROAD et al. OPPOSITION 3