By Kevin E. Noonan —

The parties in Interference No. 106,133, namely Senior Party Sigma-Aldrich and Junior Party the Broad Institute, Harvard University, and MIT (collectively, "Broad"), filed their respective lists of proposed preliminary motions four days prior to their August 3rd teleconference with the Board to present their arguments for the Board to grant leave to file any of them.

Junior Party Broad proposed Substantive Preliminary Motion No. 1, to change the Count under 37 C.F.R. §§ 41.121(a)(1)(i) and 41.208(a)(2).*  The justification here as in earlier interferences (Nos. 106,115 and 106,126) is to provide "a count broad enough to cover Broad's best proofs, which are directed to CRISPR-Cas9 systems using dual-molecule RNA but not including a donor polynucleotide sequence."  Proposed substitute Count 2 is:

A CRISPR-Cas9 system, for use in a eukaryotic cell, comprising:
    a) a Cas9 or a nucleic acid encoding the Cas9 and
    b) an RNA or a nucleic acid encoding the RNA, wherein the RNA is a dual RNA comprising a CRISPR RNA (crRNA) and a trans activating crRNA (tracrRNA) or wherein the RNA is a chimeric RNA comprising a crRNA fused to a tracrRNA,
wherein the crRNA directs the Cas9 to a target sequence in a eukaryotic cell, whereby a site-specific, double-strand break is introduced, or the target sequence is edited.

Once again, Broad's argument involves the purported "fairness" that this Count provides compared with the Count as declared, which Broad asserts "does not appropriately capture the common subject matter," i.e., "use of CRISPR-Cas9 systems in eukaryotic cells."  Broad's "best proofs," they argue, "include dual-molecule RNA systems without a donor polynucleotide" (this latter feature recited in Sigma-Aldrich's alternative to Count 1).  In addition, Broad argues that Sigma-Aldrich's invention is likewise not limited to single-molecule RNA embodiments of CRISPR (for clarity, these embodiments comprise a fusion of the crRNA species, specific for the target, and tracrRNA which interacts with Cas9 in forming the CRISPR complex).  Moreover, Broad cites portions of Sigma-Aldrich's prosecution history to support its motion, reminding the Board that Sigma-Aldrich asserted to the Examiner that the party "reserves the right to file patentably distinct CRISPR cleavage-only claims at a later date in one or more continuing applications."  According to Broad, Sigma-Aldrich sought to provoke an interference directed to "methods of integrating a donor polynucleotide sequence into the chromosomal sequence of a eukaryotic cell," and understandably reminds the Board that the only CRISPR interference that has reached a conclusion, No. 106,048 (which Broad "won" by having the Board find no interference-in-fact), had a scope that encompassed both single molecule and dual molecule RNA CRISPR embodiments.  And the "best proofs" Broad refers to are its achievement (disputed by Junior Party CVC in Interference No. 106,115) of dual molecule CRISPR embodiments in eukaryotic cells in 2011.

Broad also proposes an alternative Count 3 under 37 C.F.R. §§ 41.121(a)(1)(i) and 41.208(a)(2), intended to limit the scope of the interference to the extent that would support a motion by Broad to declare most of its claims to not correspond to the substituted Count.  Proposed Count 3 recites in the alternative claim 52 of Broad involved application 16/177,403:

A method comprising: introducing into, or expressing in, a eukaryotic cell having a DNA molecule,
    (I)    a Cas9 protein or one or more nucleotide sequences encoding the Cas9 protein;
    (II)   an RNA or one or more nucleotide sequences encoding the RNA, the RNA comprising: (a) a first RNA comprising a first ribonucleotide sequence and a second ribonucleotide sequence, and (b) a second RNA; and
    (III) a template polynucleotide;
wherein the second RNA forms an RNA duplex with the second ribonucleotide sequence, and wherein, in the eukaryotic cell, the first ribonucleotide sequence directs the Cas9 protein to a target sequence of the DNA molecule, whereby the Cas9 cleaves both strands of the DNA molecule and the cleavage is repaired by integration of the template polynucleotide into the DNA molecule in the eukaryotic cell.

Or, as in this interference as declared, claim 31 of U.S. Application No 15/456,204.  Broad justifies this Proposed Count 3 by asserting that:

Sigma limited its claims to only those requiring use of a donor polynucleotide, arguing that this specific limitation rendered its claims non-obvious over Jinek 2012 and Kim P1.  Having so limited its claims to only those requiring a donor polynucleotide in order to secure allowance, Sigma should not now be permitted to attempt to claim for itself broader subject matter ([i.e.,]use of CRISPR-Cas9 in eukaryotic cells more generally without a template, the subject matter of Broad's half of Count 1).

Broad helpfully recites the claims in Broad's involved application and patents that would remain in the interference should the Board substitute Proposed Count 3 in this interference:  "U. S. Patent No. 8,871,445, claim 13; U.S. Patent No. 8,932,814, claims 2, and 14-15; U.S. Patent No. 8,889,356, claims 2 and 14; U.S. Patent No. 9,840,713, claim 14; and application 14/704,551, claims 14-15" (as well as claims 52-56 of U.S. Application No. 16/177,403 should the Board grant a series of contingent motions, vide infra).

Again, pursuant to 37 C.F.R. §§ 41.121(a)(1)(i) and 41.208(a)(2), Broad proposes a series of Contingent Preliminary Motions dependent upon the Board granting its Substantive Motion No. 1 for either of the Proposed Substitute Counts.  Under circumstances where the Board grants Broad's Motion No. 1 to substitute Proposed Count 2, Broad asks the Board to grant leave to add to the interference claims 1 and 40-41 of Application No. 15/160,710; and claims 74 and 94-95 of U.S. Application No. 15/430,260.  Under circumstances where the Board grants Broad's Motion No. 1 to substitute Proposed Count 3, Broad asks the Board to grant leave to add to the interference claims 52-56 of U.S Application No. 16/177,403.

In a second Contingent Preliminary Motion Broad asks the Board for leave to designate claims as not corresponding to the substituted Count under 37 C.F.R. §§ 41.121(a)(1)(iii) and 41.208(a)(2), based on such claims reciting a Staphylococcus aureus Cas9 species not disclosed in Sigma-Aldrich's application, including all involved claims of Broad U.S. Patent Nos. 8,865,406 and 8,895,308, as well as claims 1, 16-21, and 30-40 of U.S. Application No. 15/330,876.  Under the same Rules, Broad asks the Board to de-designate all involved claims of its U.S. Patent No. 8,889,418 based on limitations in those claims that the Cas9 comprising the claimed CRISPR complex is chimeric, i.e., comprised of first and second protein fragments from different Cas9 proteins.  Also contained in this proposed Contingent Preliminary Motion is Broad's request that the Board de-designate all involved claims of its U.S. Patent Nos 8,871,445 and 8,932,814, as well as claim 7 of U.S. Patent No. 8,993,233 and claims 9-11 of U.S. Application No. 14/704,551 and claim 34 of U.S. Application No. 15/330,876.  The basis for this request is that these claims recite Cas9 species with improved nuclear localization by incorporation of more than one nuclear localization signal.  Broad further asks the Board for leave to file a Contingent Preliminary Motion to de-designate all involved claims of U.S. Patent Nos. 8,993,233 and 8,999,641 and claims 18-19, 25, 29-30 and 36 of U.S. Patent No. 9,840,713 and claim 21 of U.S. Application No. 15/330,876 on the basis that these claims do not recite Cas9 species fused to "specified protein domains or [that] includes one or more heterologous domains or includes a functional domain."  Finally, Broad asks the Board for leave to file a Contingent Preliminary Motion to de-designate all involved claims of U.S. Patent Nos 8,865,406; 8,889,356; 8,889,418; 8,932,814; 8,945,839; 8,993,233; and 8,999,641, as well as claims 1-3, 5-20, 12-17, and 19-20 of U.S. Patent No. 8,697,359; claims 1-4 and 6-19 of U.S. Patent No. 8,771,945; claims 1-12 and 14-30 of U.S. Patent No. 8,871,445; claims 1-9, 11-14, 16-25, and 27-28 of U.S. Patent No. 8,895,308; claims 1, 3-4 and 6-30 of U.S. Patent No. 8,906,616; claims 1-7, 10-13, 15, 17-26, and 28-41 of U.S. Patent No. 9,840,713, and claims 2, 4-13, and 16-18 of U.S. Application No. 14/704,551.  As Broad summed up, if the Board granted these motions:

[C]laims 4, 11, and 18 of U.S. Patent No. 8,697,359; claim 5 of U.S. Patent No. 8,771,945; claims 1-20 (all involved claims) of U.S. Patent No. 8,795,965; claim 13 of U.S. Patent No. 8,871,445; claims 10, 15 and 26 of U.S. Patent No. 8,895,308; claims 2 and 5 of U.S. Patent No. 8,906,616; claims 8-9, 14, 16, and 27 of U.S. Patent No. 9,840,713, claims 14 and 15 of application 14/704,551 and claims 1, 16-21, and 30-40 (all involved claims) of application 15/330,876 would remain designated as corresponding to Count 1 (although some of those claims are subject to other grounds for being designated as not corresponding to the Count) as those are the only involved claims that require chimeric RNA where the RNA components are fused or covalently linked through intervening nucleotides in the CRISPR-Cas9 complex and/or inclusion of a donor polynucleotide for HDR after DSB [i.e., these would be the only Broad claims involved in this Interference].

Broad also asked the Board for leave to file two additional substantive motions.  Broad Substantive Preliminary Motion No. 2 seeks judgment of unpatentability under 37 C.F.R. §§ 41.121(a)(1)(iii) on the basis that Sigma-Aldrich's involved application (Application No. 15/456,204) is not entitled to priority benefit to its first provisional application, U.S. Application No. 61/734,256, for failing to provide an adequate written description and for failing to provide a constructive reduction to practice of the claimed subject matter.  In addition, Broad argues that without such benefit prior art including Broad's Cong et al. paper (Science 339: 819-23, January 3, 2013), Mali et al., Science 339: 823-26, January 3, 2013, and U.S. Publication No. 2014/0342457, claiming priority to U.S. Application No. 61/738,355, filed December 17, 2012, are invalidating prior are under § 102 and/or § 103.

Broad's final proposed Substantive Preliminary Motion No. 3 is brought under 37 C.F.R. § 41.121(a)(3) and asks the Board to enter an Order requiring Sigma-Aldrich to keep Broad and the Board abreast of any issuance or notice of allowance for any related, pending applications.

And of course, Broad filed a motion under 37 C.F.R. § 41.208(a)(4) seeking judgment based on priority.

For its part, Sigma-Aldrich filed its list of three proposed Substantive Preliminary Motions.  In proposed Substantive Preliminary Motion No. 1, under 37 C.F.R. § 41.121(a)(1), Sigma-Aldrich asks the Board to deny Broad standing in this interference, based on failing to satisfy the requirements under the Leahy-Smith America Invents Act to fall under prior "first to invent" regime under the 1952 Patent Act.  Sigma-Aldrich asks the Board to consider this a threshold motion under 37 C.F.R. § 41.201.  Sigma-Aldrich contends that "[e]ach of Broad's involved patents and applications is subject to the first inventor-to-file ("FITF") law, regulations, rules, and procedures, as enacted and promulgated as a consequence of the AIA" because "each of Broad's involved patents and applications contains claims to subject matter that (a) contains (or at one time contained) a claim to a claimed invention having an effective filing date after March 16, 2013; and/or (b) claims (or at one time claimed) the benefit of an earlier filing date based upon an earlier application that contained such a claim," citing M.P.E.P. § 2159.02.  (CVC asked the Board for leave to file a similar Preliminary Motion in Interference No. 106,048).  Rather than burdening the text of the motion, Sigma-Aldrich provides its detailed support for this Motion in an appendix, providing in its argument a list of five claim limitations it contends were not supported by pre-AIA disclosures.  Sigma-Aldrich contends that "while an applicant is permitted to rely upon the filing date of an earlier-filed patent application, an applicant is not permitted to submit evidence of earlier invention, e.g., evidence of earlier conception and reduction to practice" under the AIA, and thus Broad lacks standing to submit any evidence of invention earlier than its first priority date, December 12, 2012, for U.S. Application No. 61/736,527 (also known as "Broad P1" in this and related CRISPR interferences).

Sigma-Aldrich's Substantive Preliminary Motion No. 2 under 37 C.F.R. § 41.121(a)(1) asks the Board to deny Broad benefit of priority to seven provisional applications in addition to P1 filed between December 12, 2012 and March 15, 2013 (P2: Application No. 61/748,427, filed Jan. 2, 2013; P3: Application No. 61/758,468, filed January 30, 2013; P4: Application No. 61/768,595, filed February 25, 2013; P5: Application No. 61/769,046, filed February 25, 2013; P6: Application No. 61/791,409, filed March 15, 2013; and P7: Application No. 61/802,174, filed March 15, 2013).  (Sigma-Aldrich notes in a footnote that these provisional applications were all filed before the effective date of the AIA, and that while Broad has 14 other related provisional applications, the complexities of their interrelatedness preclude considering the deficiencies in their disclosures in this single Motion.)  The basis for this Motion is that in these applications Broad did not demonstrate a constructive reduction to practice of an invention according to the Count, wherein is recited "a method of using CRISPR-Cas9 in a eukaryotic cell to successfully cleave a target DNA and thereafter to successfully either integrate a donor DNA sequence into that cleaved target DNA, or alter the expression of the gene product of that cleaved target DNA."

Sigma-Aldrich's Substantive Preliminary Motion No. 3 under 37 C.F.R. § 41.121(a)(3) seeks to remove Broad's allowed Application No. 15/330,876 from the interference, because "[a]ll of the claims in the '876 application are directed solely to, inter alia, a composition of CRISPR-Cas9 in a eukaryotic cell to simply cleave a target DNA molecule" and "[n]one of the claims in the '876 application recite further that the composition subsequently integrates a donor DNA sequence into the target DNA molecule, nor do they recite further that the composition alters the expression of the gene product of the cleaved target DNA molecule."  Accordingly, because "none of Broad's claims in the '876 application is substantially the same as (i.e., patentably indistinct from) Sigma's claims in the present interference . . . none of the claims in the '876 application interferes with any of the claims of Sigma's involved Application 15/456,204."

Sigma-Aldrich also seeks a Protective Order such as the one entered in other CRISPR interferences, and finally filed a motion under 37 C.F.R. § 41.208(a)(4) seeking judgment based on priority.

In addition, Sigma-Aldrich asks the Board to address some "miscellaneous administrative issues" such as deadlines for filing and service in this interference and asks the Board to waive the requirement for a separate Statement of Material Fact or not have these pages be included in the page limit.

Future posts will discuss the parties arguments at the August 3rd teleconference and the Board's determinations regarding which Preliminary Motions the parties will be permitted to file.

* Readers familiar with the other CRISPR interference will recognize this motion.

By Kevin E. Noonan —

On June 21st,* the Patent Trial and Appeal Board declared two new interferences involving CRISPR technology.  The first, Interference No. 106,132, named Sigma-Aldrich as Senior Party and the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") as Junior Party, while the second, Interference No. 106,133 named Sigma-Aldrich as Senior Party and the Broad Institute, Harvard University, and MIT (collectively, "Broad") as Junior Party.

Each Interference names Sigma-Aldrich U.S. Application No. 15/456,204 as the involved application.  In the '133 Interference, the following Broad patents are involved:

• U.S. Patent No. 8,697,359 – claims 1-20
• U.S. Patent No. 8,771,945 – claims 1-29
• U.S. Patent No. 8,795,965 – claims 1-30
• U.S. Patent No. 8,865,406 – claims 1-30
• U.S. Patent No. 8,871,445 – claims 1-30
• U.S. Patent No. 8,889,356 – claims 1-30
• U.S. Patent No. 8,889,418 – claims 1-28
• U.S. Patent No. 8,895,308 – claims 1-30
• U.S. Patent No. 8,906,616 – claims 1-30
• U.S. Patent No. 8,932,814 – claims 1-30
• U.S. Patent No. 8,945,839 – claims 1-28
• U.S. Patent No. 8,993,233 – claims 1-43
• U.S. Patent No. 8,999,641 – claims 1-28
• U.S. Patent No. 9,840,713 – claims 1-41
• U.S. Patent Application No. 14/704,551 – claims 2 and 4-18
• U.S. Patent Application No. 15/330,876 – claims 1, 16-21, and 30-40,

In the '132 Interference, the following CVC applications are involved in the Interference:

• U.S. Patent Application No. 15/947,680 – claims 156–185
• U.S. Patent Application No. 15/947,700 – claims 156–185
• U.S. Patent Application No. 15/947,718 – claims 156–185
• U.S. Patent Application No. 15/981,807 – claims 156–185
• U.S. Patent Application No. 15/981,808 – claims 156–170 and 172-185
• U.S. Patent Application No. 15/981,809 – claims 156–170 and 172-185
• U.S. Patent Application No. 16/136,159 – claims 156–184
• U.S. Patent Application No. 16/136,165 – claims 156–184
• U.S. Patent Application No. 16/136,168 – claims 156–184
• U.S. Patent Application No. 16/136,175 – claims 156–184
• U.S. Patent Application No. 16/276,361 – claims 3-31
• U.S. Patent Application No. 16/276,365 – claims 3-32
• U.S. Patent Application No. 16/276,368 – claims 3-31; and
• U.S. Patent Application No. 16/276,374 – claims 3-32.

(In each case these are the same patents and applications involved in the interferences with ToolGen (the '126 and '127 Interferences) and between Broad and CVC (the '115 Interference).

In the '132 Interference, Count 1 is, in the alternative, claim 156 of CVC's involved Application No. 15/981,807 or claim 31 of Sigma-Aldrich's involved Application No. 15/456,204:

Claim 156:

A eukaryotic cell comprising a target DNA molecule and an engineered and/or non-naturally occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-—CRISPR associated (Cas) (CRISPR-Cas) system comprising
    a) a Cas9 protein, or a nucleic acid comprising a nucleotide sequence encoding said Cas9 protein; and
    b) a single molecule DNA-targeting RNA, or a nucleic acid comprising a nucleotide sequence encoding said single molecule DNA targeting RNA; wherein the single molecule DNA-targeting RNA comprises:
        i) a targeter-RNA that is capable of hybridizing with a target sequence in the target DNA molecule, and
        ii) an activator-RNA that is capable of hybridizing with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment,
    wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides; and
    wherein the single molecule DNA-targeting RNA is capable of forming a complex with the Cas9 protein, thereby targeting the Cas9 protein to the target DNA molecule, whereby said system is capable of cleaving or editing the target DNA molecule or modulating transcription of at least one gene encoded by the target DNA molecule.

Claim 31:

A method for modifying a chromosomal sequence in a eukaryotic cell by integrating a donor sequence, the method comprising introducing into the eukaryotic cell:
    (i) a Clustered Regularly Interspersed Short Palindromic Repeats  (CRISPR)/CRISPR-associated (Cas) (CRISPR-Cas) type II protein linked to only one nuclear localization signal (NLS) or a nucleic acid encoding the CRISPR-Cas type II protein linked to only one NLS, wherein the CRISPR Cas type II protein is a Cas9 protein, and the nucleic acid encoding the CRISPR-Cas type II protein is codon optimized for expression in the eukaryotic cell;
    (ii) a guide RNA or DNA encoding the guide RNA, wherein the guide RNA comprises a first region that is complementary to a target site in the chromosomal sequence, which target site in the chromosomal sequence is immediately followed by a protospacer adjacent motif (PAM), and a second region that interacts with the CRISPR-Cas type II protein, and wherein the guide RNA comprises a crRNA and a tracrRNA; and
    (iii) a donor polynucleotide comprising the donor sequence and upstream and downstream sequences;
    wherein the guide RNA guides the CRISPR-Cas type II protein to the target site in the chromosomal sequence, the CRISPR-Cas type II protein introduces a double-stranded break at the target site, and repair of the double-stranded break by a DNA homology-directed repair (HDR) process leads to integration or exchange of the donor sequence into the chromosomal sequence.

In the '133 Interference, Count 1 is, in the alternative, claim 18 of Broad's involved Patent No. 8,697,359 (dependent on claim 15) or claim 31 of Sigma-Aldrich's involved Application No. 15/456,204:

Claim 15:

An engineered, programmable, non-naturally occurring Type II CRISPR-Cas system comprising a Cas9 protein and at least one guide RNA that targets and hybridizes to a target sequence of a DNA molecule in a eukaryotic cell, wherein the DNA molecule encodes and the eukaryotic cell expresses at least one gene product and the Cas9 protein cleaves the DNA molecules, whereby expression of the at least one gene product is altered; and, wherein the Cas9 protein and the guide RNA do not naturally occur together.

Claim 18:

The CRISPR-Cas system of claim 15, wherein the guide RNAs comprise a guide sequence fused to a tracr sequence.

All claims of all applications and patents of each party in each Interference were designated as corresponding to the Count.

The PTAB gave CVC a priority date that is the filing date of U.S. Provisional Application No. 61/757,640, filed January 28, 2013, and Sigma-Aldrich a priority date of U.S. Provisional Application No. 61/734,256, filed December 6, 2012.

The PTAB gave Broad a priority date that is the filing date of U.S. Provisional Application No. 61/736,527, filed December 12, 2013, and Sigma-Aldrich a priority date of U.S. Provisional Application No. 61/734,256, filed December 6, 2012.

It might be recalled (see "Sigma-Aldrich Wants Its Piece of CRISPR Pie" and "Sigma-Aldrich Tries Again") that Sigma-Aldrich, in its petition that the PTAB declare interferences with Broad and CVC, set forth the following priority timeline:

which certainly suggests the timing milieu that will be relevant to the Parties' priority positions.

The Board set a date of August 3, 2021, for the initial conference regarding proposed Preliminary Motions for each party.  The details of these motions, and those the Board granted leave for each party to file, will be the subject of the next post.

* Our apologies for turning to these interferences in a somewhat untimely fashion.  However, a review of the blog over the past several months suggests that posts involving these two interferences, in addition to the '115,'126,and '127 Interferences, might have been unnecessarily confusing.

By Kevin E. Noonan —

An enduring and persistent (albeit until now unresolved) issue in the patent interferences involving the Broad Institute, Harvard University, and MIT (collectively, "Broad") as Senior Party and the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") as Junior Party has been the question of whether Broad had committed inequitable conduct in prosecuting its patents- and applications-in-interference.  CVC raised the issue in its proposed motions in Interference No. 105,048 (see "CRISPR Interference Motions Set" and "PTAB Redeclares CRISPR Interference and Grants Leave for Some (But Not All) of Parties' Proposed Motions") and in this '115 Interference (see "CRISPR Interference Parties Propose Motions").  In both interferences, the Board denied CVC authorization to file its motions grounded in inequitable conduct as being premature but granted leave for CVC to file a motion for authorization to file their inequitable conduct motion at the end of the priority phase.

That day never came in the '048 Interference, because the Board granted Broad's motion that there was no interference-in-fact and the Broad prevailed (see "PTAB Decides CRISPR Interference — No interference-in-fact").  In this '115 Interference, CVC made much the same allegations made in the earlier interference (see "CRISPR Interference Parties Propose Motions").  According to CVC, "Broad made at least one affirmative material misstatement during prosecution of each of Broad's involved patents, applications, or parent applications to which they claim priority" — specifically, in a declaration by named inventor Zhang regarding actual reduction to practice of CRISPR-Cas9 in eukaryotic cells prior to May 2012.  CVC asserted that these statements were untruthful because the CRISPR system did not comprise tracrRNA, which is necessary for CRISPR to be functional.  CVC asserted that it was undisputed that tracrRNA is necessary for CRISPR function, using disclosure from U.S. Provisional Patent Application No. 61/736,527 as well as in the Broad's involved patents and independent prior art.  CVC also asserted that Dr. Zhang's "conception" arose only after reading a Berkeley prior art disclosure.  The proposal for this motion extensively analyzed purported evidence for actual reduction to practice to show the Broad's asserted failure, alleging that the Broad "cherry-picked data" that "intentionally omitted the context that shows his claims of successful DNA cleavage to be false."  This motion applied to all the Broad's patents- and applications-in-interference because the alleged untruthful statements were submitted in all applications.

CVC also made similar allegations for another declaration submitted by a different inventor, which they contend evinced "a larger pattern of deception."  These allegations were supported by an e-mail from a Zhang lab member and named inventor on the Broad's provisional application (albeit in a context where there seems to exist an axe to grind against Dr. Zhang):

The 15-page declaration of [Feng Zhang] and Le Cong's luciferase data is mis- and overstated to change the examiner's decision, which seems to be a joke. . . .

After seeing your in virto [sic, in vitro] paper, Feng Zhang and Le Cong quickly jumped to the project without letting me know.  My lab notebooks, emails and other files like dropbox or gel pictures recorded every step of the lab's failure process.  I am willing to give more details and records if you are interested or whoever is interested to clear the truth. . . .

We did not work it out before seeing your paper, it's really a pity.

It appears, however, that CVC's time may have come.  On June 25th, CVC by e-mail requested leave to file its inequitable conduct motion which included an assertion that "there are new justifications for [the] requested motion" (which Broad opposed).  The Board denied this request by Order under 37 C.F.R. § 41.104(a) on July 8th.  However, on November 12th, the Board entered an Order under 37 C.F.R. § 41.104(a) granting CVC leave to file a paper of no more than five pages that listed its "additional justifications" for filing its inequitable conduce motion.  On November 18th, in a Paper entitled "CVC's Additional Justifications Supporting Authorizing a Motion for Unpatentability due to Inequitable Conduct," CVC filed its list pursuant to the Board's November 12th Order.  In that Paper, the CVC provided the following allegations:

1.  That Dr. Zhang testified in the '115 Interference that "demonstrate[ed] that his 2014 Declaration [in the '048 Interference] knowingly mischaracterized his March 2011 experiments.

2.  That "the record in this ['115] interference shows that Zhang's 2015 Declaration misrepresents his alleged possession of 'a single molecule' guide RNA."

Regarding the first allegation, CVC argues that statements made by Dr. Zhang in a Declaration dated January 30, 2014 were "knowingly false."  The statement in question reads as follows:

Exhibit 7 [i.e., experiments conducted in March 2011, as first revealed in this interference] shows that prior to May 2012, I conceived and reduced to practice . . . [a]n engineered, programmable, non-naturally occurring Type II CRISPR-Cas system . . . . [Ex. 3424]

The bases for CVC's allegation of knowing falsehood include 1) that Dr. Zhang had "since conceded that those experiments did not include any tracrRNA, which he knew was a necessary component when he signed his 2014 Declaration"; (2) that Dr. Zhang in two instances (during cross-examination and in a 2020 inventor declaration) "admitted . . . , that he did not begin introducing any form of tracrRNA into his experiments until April of 2011," supported by his further admission that "he learned about the existence of tracrRNA only after reading Deltcheva et al. (Ex. 3214), which first published in Nature on March 30, 2011" made during his deposition and that he began adding "the native tracrRNA" on April 5, 2011.  From this CVC drew the conclusion that because this was after the March 2011 experiments, Dr. Zhang had made a materially false statement in this regard in his earlier declaration.  CVC then argues that this timeline and truthful testimony (after the fact) was consistent with the deposition testimony CVC elicited from Dr. Marraffini (see "CVC Files Motion in Opposition to Broad Priority Motion") regarding CVC's contention that "[Dr.] Zhang did not know that tracrRNA was part of the DNA-cleavage complex until June 26, 2012."  Because "[b]y the time [Dr.] Zhang signed his 2014 Declaration, however, he did know that tracrRNA was a necessary part of the Type II CRISPR-Cas9 system" and "[Dr.] Zhang knew that his March 2011 experiments did not include any form of tracrRNA," CVC contends that "[i]t was therefore knowingly false to declare that these experiments 'describe and enable' and 'reduced to practice' the claimed Type II CRISPR-Cas9 system," which was Dr. Zhang's testimony in his 2014 declaration.

Accordingly, should the Board agree that Dr. Zhang's testimony amounts to a knowingly false statement, CVC argues that under Therasense, Inc. v. Becton, Dickinson & Co., 649 F.3d 1276, 1292 (Fed. Cir. 2011) (en banc), these statements would be material to patentability per se.  Because Dr. Zhang's averments in his declaration were "for the purpose of removing prior art to obtain allowance of claims" (and indeed "the examiner expressly relied on Zhang's 2014 Declaration in her reasons for allowance in each of Broad's 13 involved patents and involved '551 application), CVC argues that an intent to deceive was an appropriate inference for the Board to draw (supported by Dr. Zhang's statement in his declaration that "I understand that . . . if I can show conception and actual reduction to practice prior to the filing dates of the [art] . . . then I have removed the [art] from being prior art . . . ." (emphasis added in CVC's brief).

Regarding the second allegation, CVC raises Dr. Zhang's 2015 declaration wherein "[Dr.] Zhang attests that Figure 4B in a 2012 grant proposal to the National Institutes of Health ("the NIH grant") showed that "a single RNA can be used as a guide in the CRISPR-Cas9 system."  Ex. 3424.  This testimony is inconsistent with Dr. Zhang's testimony (and Broad's arguments) in this interference, wherein "[Dr.] Zhang and Broad have represented in this proceeding that the same Figure 4B of the NIH grant shows a dual-molecule guide system and not a single-molecule guide system" (emphasis added).  CVC adds Dr. Zhang's further assertions from his 2015 declaration:

Having generated the figure of part B in the above illustration from the January 12, 2012 R01 NIH grant application, prior to January 12, 2012, I appreciated the mammalian expression system illustrated could be constructed, and when introduced into a mammalian cell could express products and function in vivo for cleavage and genome editing, as illustrated above, and as actually done prior to November 30, 2011, with appreciation that a single RNA can be used as a guide in the CRISPR-Cas system, including as shown by . . . the illustration of the NIH R01 grant application . . . . [Ex. 3424]

CVC then cited the phrase "used as a guide" in this passage of Dr. Zhang's deposition testimony in contrast with Dr. Zhang's deposition testimony in this interference to refer to "RNA that's guiding Cas9 to the target" and consequently that "[Dr.] Zhang declared to the Office that Figure 4B 'show[ed]' that he appreciated that 'a single RNA can be used as a guide in the CRISPR-Cas system.'"  Once again, CVC argues that this statement is "knowingly false" because here "[Dr.] Zhang has admitted in this proceeding [i.e., in his 2020 inventor declaration in this interference] that Figure 4B in fact shows a dual-molecule guide system."  CVC also notes that Broad has taken this position (that Figure 4B shows a dual-molecule embodiment of CRISPR) in this interference, inter alia, "[i]n support of its motions to change the count and de-designate claims corresponding to the count (both of which the Board denied), citing several arguments in Broad's motions and replies to CVC's oppositions to these motions.  Further, CVC argues that a proper interpretation of Figure 4B as not showing a single-molecule RNA-comprising embodiment of CRISPR is consistent with Dr. Maraffini's testimony "that he first conveyed such a system to Zhang on June 26, 2012, by showing him CVC's work" (neatly wrapping in CVC's arguments that if Df. Zhang had achieved a single-molecule RNA-comprising embodiment of CRISPR in eukaryotic cells he had done so by deriving the invention from CVC's inventors).  Once again, CVC argues that Dr. Zhang's statements in this instance are "unmistakably false and thus per se material" and that the examiner relied upon these statements in allowing the '551 application.  And, CVC argues, the Board can infer an intent to deceive in view of Dr. Zhang's participation inter alia in an examiner interview "that involved discussion of 'whether there need be consideration of interference [sic] as to [CVC] applications.'"

CVC further asserts that the Board should hear its motion before Final Judgment, based on circumstances where "the factual record is complete, no discovery is required, and resolution is in the public interest," citing  McDonald v. Miyazaki, Interference No. 104,544, Paper 149.  There, where "an inventor submitted a declaration during prosecution that misrepresented certain experiments and activities in an effort to antedate prior art," the Board entered judgment cancelling all involved claims on inequitable conduct grounds saying these circumstances were "the sort of over-reaching and truth-shaving that Rule 56 was enacted to prevent."  According to CVC, Dr. Zhang's and Broad's inequitable conduct here has been "[e]ven more egregious and pervasive."

Under these circumstances, CVC asserts in support of its demand that the Board hears (and presumably decides this motion before Final Hearing) that "the PTAB has a duty to protect the public from inequitably procured patents and to enforce Rule 56 to prevent abuse of declaration practice, as the examining corps is not equipped to police such misconduct."

By Kevin E. Noonan —

It is well to recall that the battle over inventorship and thus ownership of CRISPR technology is not limited to the parties in the various interferences surrounding the Doudna and Zhang patents and applications (see "CRISPR Battle Joined Again" and "The CRISPR Chronicles: Enter Toolgen"), as well as remembering that the technology continues to be developed and those developments are or will also be subject to patent protection.  Another party already identified in the space is The Rockefeller University, and on Thursday its scientists prevailed in an interference proceeding before the Patent Trial and Appeal Board captioned SNIPR Technologies Ltd. v. The Rockefeller University (naming Luciano Marraffini as one of this party's inventors).

In the Declaration of Interference No. 106,123, SNIPR was designated as the Junior Party and all claims of all five of its patents were involved (10,463,049; 10,506,812; 10,524,477; 10,561,148; and 10,582,712).  Senior Party The Rockefeller University had all claims of its pending U.S. Application No. 15/159,929 designated as corresponding to the Count.  The PTAB recited the Count in this interference in the alternative, as either Claim 1 of Patent No. 10,582,712 or Claim 24 of the 15/159,929 application:

SNIPR '712 patent, claim 1:

1.  A method of modifying a mixed population of bacteria, wherein the mixed population comprises a first bacterial sub­population and a second bacterial sub-population,
    wherein the first bacterial sub-population comprises a first bacterial species and the second bacterial sub-population comprises host cells of a second bacterial species,
    wherein the second bacterial species is a different species than the first bacterial species, the method comprising
        a.  contacting the mixed population of an engineered nucleic acid sequence for producing a host modifying crRNA (HM-crRNA), and
        b.  producing the HM-crRNA in the host cells,
    wherein the HM-crRNA is operable with a Cas nuclease in the host cells,
    wherein the engineered nucleic acid sequence and the Cas nuclease are comprised by an HM-CRISPR/Cas system, and
    wherein the HM-crRNA comprises a nucleic acid sequence that is capable of hybridizing to a target sequence in the host cells to guide the Cas nuclease to modify the target sequence in the host cells;
    whereby the host cells are killed or growth of the host cells is reduced, thereby reducing the proportion of the host cells and altering the relative ratio of the first and second bacterial sub-populations in the mixed population of bacteria; and
    wherein the mixed population of bacteria comprises E. coli.

or

Rockefeller '929 application, claim 24:

24.  A method for killing targeted bacteria in a mixed bacterial population comprising:
    providing a pharmaceutical composition comprising a pharmaceutically acceptable carrier and packaged, recombinant phagemids that are packaged in phage capsids,
    wherein the packaged phagemids comprise a clustered regularly interspaced short palindromic repeats (CRISPR) system,
    wherein the CRISPR system comprises DNA encoding: i) a type II CRISPR-associated enzyme; and ii) a targeting RNA that targets at least one bacterial chromosome at a target site; and
    contacting the bacterial population with the pharmaceutical composition,
    wherein the contacting with the pharmaceutical composition introduces at least some of the phagemids into at least some of the bacteria in the bacterial population,
    wherein subsequent to the introduction of the phagemids, the bacteria into which the phagemid is introduced expresses the targeting RNA and the type II CRISPR-associated enzyme,
    wherein the expressed type II CRISPR-associated enzyme cleaves the bacterial chromosome at the target site of the targeting RNA, and
    wherein the cleavage of the bacterial chromosome at the target site kills the bacteria and
    wherein the mixed bacterial population comprises one or a combination of bacterial species selected from the group consisting of Staphylococcus, Clostridium, Bacillus, Salmonella, Helicobacter pylori, Neisseria gonorrhoeae (wherein the italicized portions of the claim are recited in independent claim 20 from which claim 24 depends).

The interference was declared on June 11, 2020 (about eight months before the Board declared Interference Nos. 106,126 and 106,127), but the Board reached a Final Judgment in this interference on Friday, while the '126 and '127 Interferences have not reached the end of the Preliminary Motions phase.  This in large part is due to SNIPR's decision not to file priority statement (presumably because as Junior Party they were obliged to do so to avoid judgment, 37 C.F.R. § 41.204(a)(3), and could not bear the burden of this standard).

Each Party asked for and the Board granted leave to file certain Preliminary Motions:

For Senior party Rockefeller: 3 motions, where:

Motion No. 1 is a Motion of unpatentability under Section 112(a)
Motion No. 2 is a Motion of unpatentability under Section 112(b)
Motion No. 3 is a Motion contingent on the Board granting SNIPR Motion No. 2

For Junior party SNIPR: 6 motions, where:

Motion No. 1 is a Motion to Terminate because its effective filing dates were after AIA
Motion No. 4 is a Motion to Deny Rockefeller priority benefit to 61/761,971
Motion No. 6 is a Motion to designate claims as not corresponding to count
Motion No. 2 is a Motion of unpatentability under Section 112
Motion No. 5 is a Motion to Substitute the Count.

The Board substantively decided only two motions, both from SNIPR.  The most significant is Motion No. 1 (which the Board denied), where SNIPR argued that the Director through the Board had exceeded his authority by declaring the interference, because none of its involved patents had a priority date earlier than the effective date of the Leahy-Smith America Invents Act (AIA) (the earliest effective filing date accorded SNIPR was an International Filing Date of May 6, 2016).  Rockefeller's involved application was entitled to the prior "first to invent" provisions of the 1952 Patent Act because the Board had accorded this application the benefit of U.S. Provisional Application No. 61/761,971, filed February 7, 2013 (i.e., prior to the March 16, 2013 effective date of the AIA).  As set forth in the Decision on Motions, SNIPR bore the burden of establishing this interpretation of the statute under 37 C.F.R. § 41.208(b) and § 41.121(b).

SNIPR's argument was simple:  because none of their patents had earliest filing dates before March 16, 2013, Congress had abolished interferences as a method of determining priority for these patents and thus the Declaration was contrary to the statute.  Concomitant with this argument was the dispositive one that accordingly, the prior "first to invent" standard under 35 U.S.C. § 102(g) did not apply.  If there were to be a Patent Office determination of priority, SNIPR argued it was cabined to the derivation statute newly enacted with the AIA (and under the particular factual circumstances in this case undoubtedly Rockefeller could not prevail should the Board grant this motion).

The Board rejected SNIPR's argument on several grounds.  First, the Board took recourse in the provisions of the AIA that explained the effective date for each of the various changes that accompanied the transition to a "first inventor to file" regime.  Specifically, the Board cited Section 3(n)(2) of the AIA that specified that for interfering patents, "[t]he provisions of sections 102(g), 135, and 291 of title 35, United States Code" would continue to apply to any patent that "contains or contained at any time" a claim having an effective filing date prior to [18 months from the AIA's enactment, i.e., March 16, 2013] or contained a "specific reference" to any patent or application having such a claim.  The Board interpreted this provision to contradict (and provide basis for them to reject) SNIPR's argument that interferences were abolished after March 16, 2013.

Second, the Board did not interpret Section 3(j) of the AIA (as SNIPR does) to have abolished interferences between patents or applications that satisfy Section 3(n)(2) and those that do not (as the SNIPR patents do not).

Third, the Board posed the rhetorical question of what is the remedy for patent applicants like Rockefeller here if it were to adopt (or Congress intended, which the Board's opinion suggests they do not think it does) SNIPR's position that interferences were precluded to involve patents such as theirs against applications like Rockefeller's that do satisfy Section 3(n)(2)?  This question is posed in the context of the plain language of the statute maintaining interferences for patents such as Rockefeller's that satisfy Section 3(n)(2) AIA.  In other words, would Congress have enacted a nullity for such patents or applications under circumstances as here where the interfering subject matter is disclosed and claimed in a patent or application that does not satisfy Section 3(n)(2)?  "Congress could have ended all interferences at the implementation of the AIA," according to the Board, and under those circumstances "different parties may both be issued claims for the same patentable invention even when one party has an effective filing date before 16 March 2013" (an unlikely scenario in view of the consistent interpretation of the statute that the phrase "a patent" in the statute indicates a single inventive entity), but that is not the law Congress enacted in the Board's view.  The point as the Board interpreted Congressional intent was that "Congress did not expressly qualify its choice to continue interferences as being only when both parties' claims have an effective filing date before 16 March 2013."  And the Board further did not give credit to SNIPR's suggestion that priority to Rockefeller's claims could be established in "a different proceeding," any detailed of which SNIPR left unspecified in its brief.

The issue beomes a choice, according to the Board, of whether SNIPR is correct that "Congress's express choice to subject a subset of applications and patents to the previous interference provisions reinforces Congress's intent to exclude applications and patents outside that subset, like SNIPR's, from interference proceedings" or whether the Board's view that "the decision to continue interferences, in section 3(n)(2), indicates that Congress contemplated interferences between pre-AIA and post-AIA applications and patents," it being self-evident which view the Board would consider most consistent with Congressional intent.

Finally, the Board rebutted SNIPR's contention that the Director has the discretion to terminate the interference sua sponte, citing the statutory mandate under pre-AIA 35 U.S.C. § 135(a) that "[t]he Board of Patent Appeals and Interferences shall determine questions of priority of the inventions and may determine questions of patentability" (emphasis added), as well as Junior Party's contention that the "Board should clarify that any priority of invention showing by Rockefeller cannot invalidate SNIPR's claims."  Under pre-AIA 35 U.S.C. § 135(a), the Board believes it is bound to render a judgment against SNIPR if it cannot establish priority over Rockefeller (which it cannot do because it failed to file any priority statement).  Accordingly, the Board denied SNIPR Motion No. 1.

The Board also denied SNIPR's Motion No. 6 to designate certain claims as not corresponding to the Count.  This motion was based on these claims all reciting the limitation that the claimed method "reduces the growth of the host cells by at least 5-fold."  In order to prevail, the Board noted, SNIPR's burden was to show that these claims would not have been obvious over disclosure of methods "whereby the host cells are killed or growth of the host cells is reduced" or whereby targeted bacteria are killed, as recited in the language of the Count.  SNIPR's assertions in support of its motion included expert testimony and interpretations of what was known in the prior art.  These were unavailing because the Board determined that the Count itself rendered the claims obvious.  While issues of what was known in the art can be relevant, the Board stated properly that "the main issue is whether the subject matter of the count renders obvious the subject matter claimed, not whether the prior art does."  In reciting and reviewing SNIPR's arguments, the Board concluded that "SNIPR fails to meet its burden in seeking the requested relief" under 37 C.F.R. §§ 41.208(b) and 41.121(b) and hence denied the motion.

The Board dismissed as moot SNIPR Motion No 4, to deny Rockefeller priority benefit (which would make both parties' patents have a priority date after March 16, 2013 and hence be governed by the AIA without the prior law's interference provisions; indeed, SNIPR expressly asked the Board to terminate the interference on those grounds as part of its relief requested in the motion is granted.  The Board noted that SNIPR failed to provide sufficient basis in its motion to support its assertions that Rockefeller's provisional application did not provide a constructive reduction to practice of Count 1 of this interference, and even without its priority claim Rockefeller has a first filing date that antedated SNIPR's earliest priority date.

The Board made its priority determination in Rockefeller's favor and dismissed (as moot or otherwise) all remaining motions and entered judgment for Rockefeller.

While too early to know whether SNIPR will file an appeal of this decision, the question of whether the AIA precludes the Director from declaring an interference between an application entitled to the Section 3(n) provisions of the AIA and an application or patent clearly outside the scope of prior law by virtue of an earliest priority date later than March 16, 2013 is unsettled (except for this decision) and is likely to arise in any such appeal in view of the position taken by SNIPR in the interference.  While the Board's reasoning appears sound, certainty (to the extent it can be attained) can only be reached by Federal Circuit or, if the question intrigues the Justices, Supreme Court review (the unlikeliness of which is tempered by the Court's tendency to grant certiorari on many statutory interpretation questions regarding the AIA; see "Thryv, Inc. v. Click-to-Call Technologies, LP (2020)"; "Return Mail, Inc. v. United States Postal Service (2019)"; "Helsinn Healthcare S. A. v. Teva Pharmaceuticals USA, Inc. (2019)"; "Oil States Energy Services, LLC. v. Greene's Energy Group, LLC (2018)"; "SAS Institute Inc. v. Iancu (2018)"; Cuozzo Speed Technologies LLC v. Lee (2016)).