• By Kevin E. Noonan

    Sigma-AldrichOn 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:

    Image
    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 Donald Zuhn

    Tillis  ThomEarlier this month, Sen. Thom Tillis (R-NC), the Ranking Member of the Subcommittee on Intellectual Property of the Senate Committee of the Judiciary, wrote to United States Trade Representative Katherine C. Tai to express his opposition, yet again, to the Biden Administration's support for a proposal by India and South Africa to waive certain provisions of the World Trade Organization (WTO) Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement) in relation to the prevention, containment, or treatment of COVID-19.  In Sen. Tillis' letter, which was his fifth letter to the U.S. Trade Representative, the Senator called the Administration's support for waiving international obligations under the TRIPS Agreement "disastrous" (using that word three times in the two-page letter).

    Sen. Tillis (at right) "urge[d] the Administration to abandon its misguided attempts to negotiate any waiver of American intellectual property (IP) rights –- at home or abroad," and argued that "[t]he Administration's continued focus on destroying American IP rights serve not only as a threat to future life-saving innovation, but also as a distraction from the very real problems hindering vaccine access."  Noting that half of the 92 lower-income countries supported by the World Health Organization's COVID-19 Vaccines Global Access (COVAX) program have used less than 75% of the vaccine doses they have received, Sen. Tillis argued that barriers to the delivery of vaccines, rather than vaccine supply, are the biggest issue with expanding access to COVID-19 vaccines.  Among the barriers to delivery, Sen. Tillis pointed to shortages of syringes as one example, and urged the Administration "to focus on resolving urgent trade issues, including export restrictions, supply chain restrictions, ensuring vaccines can clear customs, and financing production."  According to the Senator "these logistical and supply chain issues — not the IP rights of hardworking American inventor — -are delaying global vaccinations and should be the Administration's priority."

    Sen. Tillis also noted that South Africa, who with India put forth the initial waiver proposal, is also "struggling to overcome vaccine hesitancy," which the Senator believes makes clear that South Africa's "desire for a TRIPS waiver has less to do with vaccination efforts and more to do with their long-standing efforts to steal American intellectual property by forced technology transfer."

    The Senator concluded his letter by disputing the fundamental assumption that intellectual property is a barrier to production and sharing vaccines.  According to Sen. Tillis, "IP is an enabler — allowing companies to share information to work together to develop and distribute complex, sophisticated medical treatments."  He therefore asked the Administration to "not sacrifice our ability to combat future diseases for political points."

    For additional information regarding this topic, please see:

    • "U.S. Trade Representative Responds to Letters from Senators Regarding TRIPS Waiver," November 14, 2021
    • "U.S. Chamber of Commerce Urges Administration to 'Double Down' on Global Vaccine Distribution," November 3, 2021
    • "Is This the WTO Waiver End Game?" July 25, 2021
    • "BIO Declaration on Global Access to COVID-19 Vaccines and Treatments and Role of IP," June 24, 2021
    • "GOP Legislators Write in Opposition to Proposed TRIPS Waiver," May 16, 2021
    • "Population of Patents at Risk from Proposed WTO Patent Waiver," May 12, 2021
    • "Sen. Daines Urges Biden Administration to Withdraw Support for COVID-19 IP Waiver," May 12, 2021
    • "Pfizer CEO Pens Open Letter on COVID-19 Vaccine IP Waiver," May 10, 2021
    • "If the Devil of the WTO IP Waiver Is in the Details, What Are the Details?" May 9, 2021
    • "The Road to Hell Is Paved with What Everybody Knows," May 6, 2021
    • "BIO & IPO Issue Statements on Biden Administration's Support for Proposed WTO Waiver," May 6, 2021
    • "Biden Administration Supports Waiver of IP Protection for COVID-19 Vaccines," May 5, 2021
    • "Suspending IP Protection: A Bad Idea (That Won't Achieve Its Desired Goals)," April 26, 2021
    • "Sen. Tillis Asks Biden Administration to Oppose WTO Waiver Proposal," April 21, 2021
    • "IP Organizations Support Continued Opposition to Waiver Proposal," April 5, 2021
    • "Industry Coalition Supports Continued Efforts to Oppose Waiver Proposal," March 29, 2021
    • "BIO and PhRMA Urge Biden Administration to Oppose Proposed WTO TRIPS Waiver," March 11, 2021
    • "IPO Sends Letter on IP Law and Policy to President-Elect and Vice President-Elect," January 4, 2021

  • CalendarDecember 14, 2021 – 15th Annual USPTO IP Attaché Roundtable (U.S. Chamber of Commerce Global Innovation Policy Center) – 8:30 am to 10:30 am (ET)

    December 14, 2021 – "PTAB Trial Proceedings: Best Practices and Emerging Trends" (Intellectual Property Owners Association) – 2:00 pm to 3:00 pm (ET)

  • IPO #2The Intellectual Property Owners Association (IPO) will offer a one-hour webinar entitled "PTAB Trial Proceedings: Best Practices and Emerging Trends" on December 14, 2021 from 2:00 pm to 3:00 pm (ET).  Hon. Alyssa Finamore, Administrative Patent Judge, U.S. Patent and Trademark Office; Alyssa Holtslander of Unified Patents; Hon. Eric Jeschke, Administrative Patent Judge, U.S. Patent and Trademark Office; Mark Stewart of Eli Lilly and Co.; and Todd Walters of Buchanan Ingersoll & Rooney PC will discuss the best practices and emerging trends from pre-institution through final hearing, including strategies focused on petition drafting, preliminary patent owner responses, discretionary denial considerations, replies, protective orders, discovery practice, cross-examination practice, motions practice, motions to amend, demonstratives, and oral hearings.

    There is no registration fee for the webinar.  However, those interested in attending the webinar should register here.

  • U.S. Chamber of CommerceThe U.S. Chamber of Commerce Global Innovation Policy Center (GIPC) will be offering its 15th Annual USPTO IP Attaché Roundtable with the U.S. Patent and Trademark Office's IP Attachés on December 14, 2021 from 8:30 am to 10:30 am (ET).  The program provides a unique opportunity to engage with the assembled IP Attachés for a discussion about recent trends and challenges in IP protection and enforcement in regions around the world.

    Those interested in registering for the program, can do so here.

  • By Kevin E. Noonan

    Cat_2The domestic cat has been the subject of much study, recently involving its genetic structure, genomic DNA sequence, and comparisons with other felines.  The first such study was published in 2014, when an international effort led by Stephen J. O'Brien at the Oceanographic Center, Nova Southeastern University, Ft. Lauderdale, Florida reported the complete genomic sequencing of the domestic cat, Felix catus.  The report, entitled "Annotated features of domestic cat – Felis catus genome," was published in GigaScience 2014, 3:13 (August 5, 2014) (see "Domestic Cat Genome Sequenced").  The study reported sequencing of a female Abyssinian cat named Cinnamon, a mixed-breed cat from Russian named Boris, and Sylvester, a wildcat ancestor of domestic cats.  The report showed that domestic cats have retained "a highly conserved ancestral mammal genome organization" in comparison with ancestral cats (see Driscoll et al., 2007, "The near eastern origin of cat domestication," Science 317: 519–23).  Both species, F. catus and Felix silvestris, have 38 chromosomes, 18 pairs of autosomes, and two pairs of dimorphic gender-determining chromosomes.  Details of the domestic cat genome structure included the presence of 217 loci of endogenous retrovirus-like elements (amounting to 55.7% of the entire genome, comprised of long interspersed elements (LINEs), short interspersed elements (SINEs), satellite DNA, retroviral long terminal repeats (LTRs) and "others"); 21,865 protein coding genes (open reading frames or ORFs), detected by comparison with eight mammalian genomes (from human, chimpanzee, macaque, dog, cow, horse, rat, and mouse); and a wealth of genetic variability in single nucleotide polymorphisms (SNPs), insertion/deletion events (indels); novel families of complex tandem repeat elements; and short terminal repeat (STR) loci.

    Since that time more individual cat genomic sequences have been determined and assembled in the 99 Lives Cat Genome Consortium.  These efforts resulted in a more comprehensive elucidation of the feline genome and insights into genetic bases for disease.  A paper published in the Public Library of Science, entitled "A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism," PLoS Genetics 16(10): e1008926 on October 20, 2020, reported a revisit of the genomic sequence of Cinnamon, an Abyssinian breed domestic cat previously sequenced.  Rather than focusing on one cat, this group* performed whole genome sequencing (WGS) of 54 domestic cats and aligned the sequences to detect single nucleotide variants (SNVs) and structural variants (SVs).  As a consequence of these studies, sequences comprising the ~300,000 gaps in the annotated sequence reported to the Cinnamon Abyssinian were obtained, to produce a new reference cat genome denoted in relevant databases as Felis_catus_9.0.  This genome comprised 2.84 gigabasepairs (Gb), of which only 1.8% (1.38 megabasepairs, Mb) was not assigned to a specific chromosomal location.

    While such assessments of global genetic structure are informative, analysis of genes resulting in well-known phenotypes have been slower to arrive.  One such study was published in March 2021 in Animal Genetics 52: 321-32, entitled "Mining the 99 Lives Cat Genome Sequencing Consortium database implicates genes and variants for the Ticked locus in domestic cats (Felis catus)."  In this paper, scientists from the U.S. and Australia* reported the genetic basis of the Ticked tabby coat pattern, a phenotype whose genetics long have been used empirically by cat breeders.  (Amathematically, the Consortium database contains genetic information from 195 individual cats.)

    Three autosomal alleles at a single genetic locus in wild and domestic cats are understood to control the tabby coat pattern: Abyssinian (Ta, also known as "ticked"); mackerel (Tm, aka striped); and blotched (tb, aka classic, blotched) (where these allelic abbreviations follow the convention that capital letters indicate Mendelian dominant traits and lower-case letters are inherited as recessive genes); the blotched phenotype was designated as the "classic" tabby by Linnaeus in 1758.  Various combinations of these alleles result in complicated coat patterns involving the legs, head/face, tail, and torso.

    Failure of this understanding to explain cats that have spotted coats, like Egyptian mau and ocicat, induced further genetic analyses that uncovered at least three other loci involved in coat pattern; these include Tabby and Ticked, where the Tabby locus affects the mackerel and blotched patterns.  Located on the cat A chromosome, the candidate gene encoded by this locus, laeverin (LVRN) or transmembrane aminopeptidase Q, Taqpep, encodes 'a membrane-bound metalloprotease and plays a regulatory role in extravillous trophoblast migration."  The genetic bases for coat patterns involving the Tabby locus were found to be even more complex, involving genes in a pigment switching signaling pathway, and can have a phenotype having individual hairs in the coat pattern that alternates between melanin types that are seen illusorily to be brown.

    The other locus, the Ticked locus, had been localized on the cat B1 chromosome but the gene residing at the locus had not been determined until this report.  The famous Cinnamon had the ticked pattern and accordingly her DNA was used by these researchers in one strategy as having the "reference" allele and in another as having the "variant" allele in performing their search for the gene or genes at the Ticked locus.  Of the 195 cats in the 99 Cat Consortium database, 80 had either solid or white coats and their ticked-tabby phenotype could not be determined (regardless of their underlying genotype).  Among the cats whose genomic DNA was assessed were two obligate heterozygous ticked cats identical by descent for their ticked allele as they are parent–offspring bred from a ticked Somali"; three known Abyssinians, including Cinnamon; and three other cats showing the ticked phenotype.

    The researchers used eight short tandem repeats that segregated with the Ticked phenotype as identified by genome scanning methods to find a 17 centoMorgan (cM) linked region on cat chromosome B1 for their analysis of candidate variants.  Seven phenotype filters were applied (e.g., "eliminate intergenic, intronic and synonymous variants; (ii) consider the variant zygosity for the [whole genome sequencing entry for Cinnamon;" etc.) to identify increasingly rare variants in this region of the B1 chromosome; after filtering only one variant remained, located in the gene for Dickkopf Wnt Signaling Pathway Inhibitor 4 (DKK4).  The protein encoded by this gene is known to be "a member of the dickkopf (Dkk) family of cysteine-rich secretory proteins that are antagonists of Wnt signaling pathways, involved in antero-posterior axial patterning, limb development, somitogenesis and eye formation."  These researchers report finding a G>A transition mutation at position 188 of this gene, resulting in a Cys63Tyr amino acid sequence change in the encoded protein.  The researchers also reported finding at lower frequency another transition mutation (C>T) in this gene, resulting in a change at amino acid 18 from Ala to Val.  The position of these mutations is shown in the following Figure:

    Image 1
    These researchers further report that protein structure modeling suggests that these mutations disrupt "a key disulfide bond" in a "cysteine-rich domain" in the first mutation or a signal peptide cleavage site in the Dkk protein in the second mutation.  The resulting change in protein conformation for the first mutation is illustrated in the following Figure:

    Image 2
    In either case the researchers conclude that disrupting the function of this protein (as the consequences of these mutations suggest) results in the observed ticked phenotype.

    The authors recognize that the ticked phenotype is rare in outbred cats (and the observed allele frequency, wherein no other cats from the 195 cats in the database have this allele, is consistent with its rarity) and dominant, suppressing patterning and resulting in cats having no discernable coat pattern.  But they also recognize the search for genes that influence coat pattern in cats is not concluded, stating:

    Additional genotyping of the proposed variants, in a large cohort of phenotyped cats, as well as supportive functional data, would clarify the role of these variants in cat coat pattern development.  The identified variants do not clarify the pathways leading to the production of the spotted coat phenotype in cats, suggesting that additional genes influence other tabby patterns in domestic cats.  The allelic series for the Ticked locus is suggested as TiA = TiCK > Ti+, where the TiA allele represents the p.Cys63Tyr variant and the TiCK allele represents the p.Ala18Val variant.

    * From the Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri – Columbia, Columbia, MO and the School of Health and Behavioural Sciences, University of the Sunshine Coast, Sippy Downs, Australia; the paper in an appendix credits the hundreds of researcher who have contributed to the 99 Live Cat Genome Consortium.

  • 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.

    University of California-BerkleyThat 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

    USPTO SealIt 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)).

  • CalendarDecember 6, 2021 – "UPC Crash Course" (Hoffmann Eitle) – 12:00 pm (EST)

    December 8, 2021 – "Getting Ready for the New European Patent System" (Hoffmann Eitle) – 9:00 am to 12:00 pm (CET)

    December 8, 2021 – "A 15-Year Future of China IP System – Implications of the New China IP Policy Roadmap (2021-2035)" (GEN Law Firm) – 8:00 am (ET)

    December 8, 2021 – "Navigating Parallel BPCIA and PTAB Proceedings – Recent Developments and Strategic Considerations" (Biotechnology Innovation Organization IP Counsels Committee) – 1:00 pm (ET)

  • Hoffmann-EitleHoffmann Eitle will be offering two online seminars regarding the Agreement on the Unified Patent Court (UPCA).

    The first online seminar, entitled "UPC Crash Course," will be held on December 6, 2021 at 12:00 pm (EST).  C. Thomas Becher, Morten Garberg, and Niels Hölder will discuss the Unitary Patent and the Unified Patent Court, including status, timing, provisional application, unitary protection, unified enforcement, costs and savings, opting out, what do to by when, and best practice.

    The second online seminar, entitled "Getting Ready for the New European Patent System," will be held on December 8, 2021 from 9:00 am to 12:00 pm (CET).  Thorsten Bausch, Esther Pfaff, Dirk Schüßler-Langeheine, C. Thomas Becher, and Niels Hölder will discuss the Following topics:

    Overview and status
    • Provisional application: the way into the shimmer
    • Brexit: filling the gaps
    • Decision of constitutional court: enough is enough

    The Unitary Patent
    • Structure/nature
    • Costs/Savings

    The UPC
    • Structure: local vs. central
    • Jurisdiction: UPs and EPs
    • Procedure: speed matters
    • Remedies: tabula rasa
    • UPC revocation vs. EPO opposition

    Opting out?
    • Procedure
    • Criteria/pros and cons
    • Best practice

    Case examples: Product/Process/Use Claims

    Those interested in attending the first seminar can register here, and those interested in attending the second seminar can register here.