Patent Docs

Top Four Stories of 2020

January 14, 2021

By Donald Zuhn –-

After reflecting upon the events of the past twelve months, Patent Docs presents its 14th annual list of top patent stories. For 2020, we identified eight stories that were covered on Patent Docs last year that we believe had (or are likely to have) a significant impact on patent practitioners and applicants. On Monday, we counted down stories #8 to #5, and today we count down the top four stories of 2020. As with our other lists (2019, 2018, 2017, 2016, 2015, 2014, 2013, 2012, 2011, 2010, 2009, 2008, and 2007), links to our coverage of these stories (as well as a few links to articles on related topics) have been provided in case you missed the articles the first time around or wish to go back and have another look. As always, we love to hear from Patent Docs readers, so if you think we left something off the list or disagree with anything we included, please let us know. In addition, we will be offering a live webinar on the "Top Patent Law Stories of 2020" on January 20, 2020 from 10:00 am to 11:15 am (CT). Details regarding the webinar, which will focus on a few of the most important stories on this year's list, can be found here.

4. Arthrex and Other PTAB Developments

In October, the Supreme Court granted petitions for a writ of certiorari to review the Federal Circuit's decision in Arthrex, Inc. v. Smith & Nephew, Inc., in which the Court of Appeals determined that the manner in which administrative patent judges were appointed to the Patent Trial and Appeal Board violated the Appointments Clause of the Constitution (Art. II, sec. 2, cl. 2). A decision in the case is likely to be issued by the Supreme Court this June, so it is quite possible that Arthrex will make our 2021 list.

In addition to Arthrex, there were several other developments involving the PTAB that occurred in 2020. In Facebook, Inc. v. Windy City Innovations, LLC, Facebook tried to join its own IPR to attack the claims asserted against it, which worked before the PTAB, but not before the Federal Circuit, which determined that joinder was only permitted for other parties who were seeking review of the same issues, and not for the same party seeking to change the scope of the review. In Bozeman Financial LLC v. Federal Reserve Bank, the Federal Circuit held that the twelve regional Federal Reserve Banks, which sought to invalidate two Bozeman Financial patents in covered business method (CBM) review proceedings, are "persons" under the AIA, and therefore entitled to seek PTAB review. In Argentum Pharmaceuticals LLC v. Novartis Pharmaceuticals Corp., Pfizer Inc. v. Chugai Pharmaceuticals Co., and Adidas AG v. Nike, Inc., the Federal Circuit continued its explication of the standing issue for unsuccessful petitioners in inter partes reviews. In Amneal Pharmaceuticals LLC v. Almirall, LLC, the Federal Circuit determined that attorney's fees and an exceptional case determination were not available for fees and costs incurred when a patent owner defends an inter partes review challenge before the PTAB. And in Uniloc 2017 LLC v. Hulu, LLC, the Federal Circuit found that the PTAB may consider patent eligibility under 35 U.S.C. § 101 for substitute claims.

For information regarding this and other related topics, please see:

• "Supreme Court to Consider Constitutional Propriety of Appointment of PTAB Judges," October 13, 2020
• "Snyders Heart Valve LLC v. St. Jude Medical, LLC (Fed. Cir. 2020)," September 9, 2020
• "USPTO Initiates Fast-Track Appeals Pilot Program," August 11, 2020
• "Uniloc 2017 LLC v. Hulu, LLC (Fed. Cir. 2020)," July 26, 2020
• "Arthrex Files Certiorari Petition in Arthrex Case, July 19, 2020
• "Arthrex Files Certiorari Petition in Arthrex Case," July 14, 2020
• "U.S. Government Petitions for Certiorari in Arthrex Case," July 13, 2020
• "Smith & Nephew File Certiorari Petition in Arthrex Case," July 12, 2020
• "In re Boloro Global Ltd. (Fed. Cir. 2020)," July 9, 2020
• "Adidas AG v. Nike, Inc. (Fed. Cir. 2020)," June 28, 2020
• "Supreme Court Takes Pass on Considering IPR Constitutionality," June 24, 2020
• "Amneal Pharmaceuticals LLC v. Almirall, LLC (Fed. Cir. 2020)," June 8, 2020
• "Pfizer Inc. v. Chugai Pharmaceuticals Co. (Fed. Cir. 2020)," May 5, 2020
• "Argentum Pharmaceuticals LLC v. Novartis Pharmaceuticals Corp. (Fed. Cir. 2020)," May 3, 2020
• "Thryv, Inc. v. Click-to-Call Technologies, LP (2020)," April 20, 2020
• "Bozeman Financial LLC v. Federal Reserve Bank (Fed. Cir. 2020)," April 15, 2020
• "Nike, Inc. v. Adidas AG (Fed. Cir. 2020)," April 13, 2020
• "Genentech, Inc. v. Iancu (Fed. Cir. 2020)," March 30, 2020
• "Facebook, Inc. v. Windy City Innovations, LLC (Fed. Cir. 2020)," March 22, 2020
• "Naples Roundtable Requests PTAB to Make Decisions Precedential," March 20, 2020

3. But cf. American Axle & Mfg. v. Neapco Holdings LLC

In contrast with past years, there was some sense that fewer "major" developments occurred with respect to subject matter eligibility in 2020. For example, stories involving subject matter eligibility took the #2 and #5 spots on our 2019 list; the #2 spot on our 2018 list; the #1, #2, and #4 spots on both our 2016 and 2015 lists; the #1 and #2 spots on our 2014 list; and the #1 spot on our 2013 list. And yet, our #2 and #3 stories for 2020 involve subject matter eligibility.

Coming in at #3 is American Axle & Manufacturing, Inc. v. Neapco Holdings LLC, where the Federal Circuit issued an interesting (and somewhat troubling) decision on the patent eligibility of claims directed to a method for manufacturing a shaft assembly of a driveline system. In October 2019, a divided panel of the Federal Circuit affirmed a District Court finding of patent ineligibility. The Court of Appeals then denied rehearing en banc. And in August, the Federal Circuit withdrew its original opinion and handed down a substitute opinion in response to the petition for rehearing and rehearing en banc (as the Federal Circuit also did in IIllumina, Inc. v. Ariosa Diagnostics, Inc.). The Federal Circuit followed this practice in what we wrote at the time was perhaps its most confusing and controversial application of the Supreme Court's subject matter eligibility jurisprudence under Alice Corp. Pty. Ltd. v. CLS Bank International. Judge Moore, writing in dissent, expressed the view that the Federal Circuit had embarked on a course that resembles "enablement on steroids" and "turns the [Section 101] gatekeeper into a barricade. In October, the Federal Circuit followed up its substitute opinion by denying American Axle's motion to stay issuance of the Court of Appeals' mandate while awaiting the Supreme Court's decision on American Axle's petition for certiorari.

For information regarding this and other related topics, please see:

• "American Axle & Manufacturing, Inc. v. Neapco Holdings LLC (Fed. Cir. 2020)," October 25, 2020
• "American Axle & Mfg. v. Neapco Holdings LLC (Fed. Cir. 2020)," August 9, 2020

2. Nothing to See Here — Congress and Courts "Move Along" on Patent Eligibility

Aside from American Axle & Manufacturing, Inc., however, Congress and the courts appeared to "move along" on subject matter eligibility. In January, the Supreme Court entered orders denying certiorari in five cases having petitions on subject matter eligibility, including Athena Diagnostics, Inc. v. Mayo Collaborative Services, LLC; Hikma Pharmaceuticals USA Inc. v. Vanda Pharmaceuticals Inc.; and Berkheimer v. HP Inc. One possible conclusion is that the Court is comfortable with the state of diagnostic method patenting (i.e., it no longer exists in the U.S.). Or perhaps the Court believed that its decision not to decide would motivate Congress to change the law. Or maybe the Court was facing up to the reality that it did not have a solution to the problem, in which case Congress would be the only answer. That last hope appeared to have been dashed (or at least put on hold) in February when Senator Thom Tillis, Chair of the Senate's Subcommittee on Intellectual Property, in an interview with the Intellectual Property Owner's association, noted that Congress would not be completing its work on a legislative solution to the patent eligibility problem. Sen. Tillis told the IPO that "[g]iven the reasonable concerns that have been expressed about the draft [legislation] as well as the practical realities of the difficulty of passing legislation, absent stakeholder consensus I don't see a path forward for producing a bill—much less steering it to passage—in this Congress." Sen Tillis noted that "[i]f we're going to get anything done on this issue, everyone will have to compromise," adding that "[a]nything less than that is dead on arrival." So, 2020 provided no judicial or legislative solutions to the patent eligibility problem, and yet this lack of solutions was still good enough for this story to take the #2 spot on our list (which somehow seems fitting for 2020).

For information regarding this and other related topics, please see:

• "Simio, LLC v. FlexSim Software Products, Inc. (Fed. Cir. 2020)," December 29, 2020
• "Adaptive Streaming Inc. v. Netflix, Inc. (Fed. Cir. 2020)," December 22, 2020
• "An Analytic Approach to Patent Eligibility," December 16, 2020
• "Gree, Inc. v. Supercell Oy (Fed. Cir. 2020)," December 3, 2020
• "C R Bard Inc. v. AngioDynamics, Inc. (Fed. Cir. 2020)," November 15, 2020
• "On the Patent Eligibility of Graphical User Interfaces: Part II," November 9, 2020
• "On the Patent Eligibility of Graphical User Interfaces: Part I," November 8, 2020
• "Stupid § 101 Tricks," November 1, 2020
• "Realtime Data LLC v. Reduxio Systems, Inc. (Fed. Cir. 2020)," October 26, 2020
• "Reconsidered: The Federal Circuit's Enfish Interpretation of Mayo-Alice," September 13, 2020
• "Illumina, Inc. v. Ariosa Diagnostics, Inc. (Fed. Cir. 2020)," August 3, 2020
• "XY, LLC v. Trans Ova Genetics, LC (Fed. Cir. 2020)," August 2, 2020
• "The Three Properties of Patent-Eligibility: An Empirical Study," July 30, 2020
• "Federal Circuit Rules Public Key Cryptography Algorithm Invalid Under 35 U.S.C. § 101," July 22, 2020
• "Packet Intelligence LLC v. NetScout Systems, Inc. (Fed. Cir. 2020)," July 20, 2020
• "Electronic Communication Technologies, LLC v. ShoppersChoice.com, LLC (Fed. Cir. 2020)," July 16, 2020
• "In re Zunshine (Fed. Cir. 2020)," July 8, 2020
• "Barbaro Technologies, LLC v. Niantic, Inc. (N.D. Cal. 2020)," May 28, 2020
• "Uniloc USA, Inc. v. LG Electronics USA, Inc. (Fed. Cir. 2020)," May 6, 2020
• "USPTO Assesses the Impact of Patent Eligibility's Changing Landscape," April 27, 2020
• "Cardionet, LLC v. Infobionic, Inc. (Fed. Cir. 2020)," April 19, 2020
• "Boehringer Ingelheim Pharmaceuticals Inc. v. Mylan Pharmaceuticals Inc. (Fed. Cir. 2020)," April 5, 2020
• "Mallinckrodt Files Certiorari Petition in iNO v. Praxair," March 19, 2020
• "Illumina, Inc. v. Ariosa Diagnostics, Inc. (Fed. Cir. 2020)," March 17, 2020
• "What is an Abstract Idea, Anyway?" March 1, 2020
• "A Step-by-Step Approach to Patent Subject Matter Eligibility Reform," February 17, 2020
• "Pebble Tide LLC v. Arlo Technologies, Inc. (D. Del. 2020)," February 13, 2020
• "CareDX, Inc. v. Natera, Inc. (D. Del. 2020)," February 12, 2020
• "The Zombie Apocalypse of Patent Eligibility Reform and a Possible Escape Route," February 4, 2020
• "iLife Technologies, Inc. v. Nintendo of America, Inc. (N.D. Tex. 2020)," January 27, 2020
• "U.S. Supreme Court on Eligibility: Nothing to See Here, Move Along," January 13, 2020

1. Pandemic Impacts Patent Practice

On March 11, World Health Organization Director-General Tedros Adhanom declared that the COVID-19 outbreak "can be characterized as a pandemic," cautioning that the WHO has "rung the alarm bell loud and clear." At the time of the announcement, the WHO noted that there were 118,000 cases reported globally in 114 countries. In its latest situation report, issued on January 12, 2021, the WHO indicates that there have been 88,387,352 cases globally. The Director-General also stated in March that the pandemic was "not just a public health crisis, it is a crisis that will touch every sector — so every sector and every individual must be involved in the fight."

As it has for nearly every single industry, the COVID-19 pandemic has had a profound impact on patent practice. The pandemic has changed how most of us work, where most of us work, and what many of us work on. In the early weeks and months of the pandemic, the U.S. Patent and Trademark Office, World Intellectual Property Organization, European Patent Office, IP Australia, Intellectual Property Office of New Zealand (IPONZ), Brazilian Patent and Trademark Office (INPI), Canadian Intellectual Property Office (CIPO), Mexican Institute of Industrial Property (IMPI), National Office of Intellectual Property (ONAPI) in the Dominican Republic, Intellectual Property India, National Intellectual Property Office (NIPO) in Sri Lanka, Israel Patent Office, Intellectual Property Office of Vietnam (NOIP), and Directorate General of Intellectual Property (DGIP) in Indonesia, among numerous other patent offices, modified deadlines and procedures to accommodate applicants and their representatives.

In addition to providing some deadline relief at the beginning of the pandemic, the USPTO implemented a COVID-19 prioritized examination pilot program, in which applicants that qualify for small or micro entity status can request prioritized examination without paying the fees typically associated with such prioritized examination. In September, the USPTO also implemented a deferred-fee provisional patent application pilot program in order to promote the expedited exchange of information about inventions designed to combat COVID–19. And in June, USPTO Director Andrei Iancu sent a letter to the Chairmen and Ranking Members of the Senate and House Committees on the Judiciary, Senate Subcommittee on Intellectual Property, and House Subcommittee on Courts, Intellectual Property, and the Internet, to provide information regarding the Office's transition to full time telework, the status of patent and trademark filings and fee collections, and cost saving measures that the Office had taken in response to the COVID-19 pandemic-related economic downturn. In his letter, the Director stated that the trends through mid-May were "troubling and the current economic uncertainty could lead us to revise FY 2020 and FY 2021 revenue estimates further downward." Even though the U.S., like many other countries, is currently confronting a third wave of the COVID-19 pandemic, the USPTO, like many other patent offices, has tried to return to something akin to "normal" operations (or at least what must pass for normal during a pandemic). The hope is that the coming spring will see sufficient distribution and adoption of vaccines such that we can all return to something that is not merely akin to normal.

For information regarding this and other related topics, please see:

• "Inherited Neanderthal Gene Encodes Genetic Risk for COVID-19," November 4, 2020
• "USPTO Announces Deferred-Fee Provisional Application Pilot Program to Encourage COVID-19 Related Inventions," September 17, 2020
• "USPTO Announces Additional Extension of Certain Patent Deadlines for Small and Micro Entities," June 29, 2020
• "USPTO Director Updates Congress Regarding Impact of COVID-19 Pandemic on USPTO Operations," June 18, 2020
• "USPTO Announces Extension for Petitioning for Restoration of Right of Priority or Benefit," June 14, 2020
• "Impact of COVID-19 Pandemic on Patent Offices – June 10 Update," June 10, 2020
• "USPTO News Briefs," June 2, 2020
• "USPTO Announces Further Extension of Certain Patent Deadlines for Small and Micro Entities," May 27, 2020
• "USPTO Announces COVID-19 Prioritized Examination Pilot Program," May 18, 2020
• "Life Sciences Court Report & COVID-19 Impact on District Court Filings," May 17, 2020
• "USPTO Announces Further Extension of Certain Patent Deadlines," April 30, 2020
• "Impact of COVID-19 Pandemic on Patent Offices and Federal Courts – April 12 UPDATE," April 12, 2020
• "USPTO Answers FAQs on Extension of Patent Deadlines under CARES Act," April 6, 2020
• "USPTO Announces Extension of Certain Patent Deadlines," March 31, 2020
• "Impact of COVID-19 Pandemic on Patent Offices and Federal Courts — March 29 UPDATE," MARCH 29, 2020
• "Impact of COVID-19 Pandemic on Patent Offices and Federal Courts — March 26 UPDATE," March 26, 2020
• "Impact of COVID-19 Pandemic on Patent Offices and Federal Courts — March 19 UPDATE," March 19, 2020
• "Impact of COVID-19 Pandemic on Patent Offices and Federal Courts — March 18 UPDATE," March 18, 2020
• "Impact of COVID-19 Pandemic on Patent Offices and Federal Courts — March 17 UPDATE," March 17, 2020
• "Impact of COVID-19 Pandemic on Patent Offices and Federal Courts — UPDATED," March 16, 2020
• "Impact of COVID-19 Pandemic on Patent Offices and Federal Courts," March 15, 2020
Separate Interferences Declared between Toolgen and Broad and CVC over CRISPR Priority Question

January 13, 2021

By Kevin E. Noonan —

One of the most notable movie taglines, "Just when you thought it was safe to go back in the water," was used to market the sequel to the original summer blockbuster movie, Jaws.

It is perhaps impossible to not think of that message upon learning that the Patent Trial and Appeal Board of the U.S. Patent and Trademark Office on December 20, 2020 declared two interferences: the first, Interference No. 106,126 involving the Broad Institute, Inc., the Massachusetts Institute of Technology, and the President and Fellows of Harvard College, and the second, Interference No. 106,127, involving the Regents of the University of California, the University of Vienna, and Emmanuelle Charpentier (each designated as the Junior Party) and each Interference naming Toolgen Inc. as Senior Party.

The '126 interference involves the following Broad patents and applications (and their involved claims, which constitute all of the granted claims of all of the Broad patents):

• 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,

against only one pending application for Toolgen:

• U.S. Patent Application Publication No. US20150344912 (Application No. 14/685,510) – claims 66-68, 70-74, 83, 85-88, and 90-94.

None of the claims of any of the patents or applications of either party were designated as not corresponding to the Count.

The count of the interference is set forth in the alternative, either as claim 18 of the Broad's U.S. Patent No. 8,697,359 (dependent on claim 15), which taken together recites the following invention:

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, wherein the guide RNAs comprise a guide sequence fused to a tracr sequence.

(where the underlined portion recites the relevant language from claim 18);

or Claim 85 of Toolgen's U.S. Application No. 14/685,510:

An isolated mammalian cell comprising a Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas system for site specific, cleavage of a double-stranded target nucleic acid sequence in the isolated mammalian cell, wherein the CRISPR/Cas system comprises:
    a) a nucleic acid encoding a Cas9 polypeptide, wherein the Cas9 polypeptide comprises a nuclear localization signal and wherein said nucleic acid is codon-optimized for expression in mammalian cells, and
    b) a chimeric guide RNA comprising a CRISPR RNA (crRNA) portion and a transactivating crRNA (tracrRNA) portion,
    wherein the target nucleic acid sequence comprises a first strand having a region complementary to the crRNA portion of the chimeric guide RNA and a second strand having a trinucleotide protospacer adjacent motif (PAM), and
    wherein the Cas9 polypeptide and the chimeric guide RNA form a Cas9/RNA complex in the isolated mammalian cell and mediate double stranded cleavage at the target sequence.

The Declaration gives Broad the priority benefit to U.S. Provisional Application No. 61/736,527, filed December 12, 2012, and to Toolgen U.S. Provisional Application No. 61/717,324, filed October 23, 2012.

The '127 interference involves the following CVC applications (and their involved claims, which constitute all of the pending claims of all of the CVC patent applications):

• 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.

against only one pending application for Toolgen:

• U.S. Patent Application Publication No. US20150344912 (Application No. 14/685,510) – claims 66-68, 70-74, 83, 85-88, and 90-94.

The count of this interference is set forth in the alternative, either as claim 156 of the CVC's U.S. Application No. 15/981,807:

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 DNAtargeting 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.

or Claim 85 of Toolgen's U.S. Application No. 14/685,510:

An isolated mammalian cell comprising a Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas system for site specific, cleavage of a double-stranded target nucleic acid sequence in the isolated mammalian cell, wherein the CRISPR/Cas system comprises:
    a) a nucleic acid encoding a Cas9 polypeptide, wherein the Cas9 polypeptide comprises a nuclear localization signal and wherein said nucleic acid is codon-optimized for expression in mammalian cells, and
    b) a chimeric guide RNA comprising a CRISPR RNA (crRNA) portion and a transactivating crRNA (tracrRNA) portion,
    wherein the target nucleic acid sequence comprises a first strand having a region complementary to the crRNA portion of the chimeric guide RNA and a second strand having a trinucleotide protospacer adjacent motif (PAM), and
    wherein the Cas9 polypeptide and the chimeric guide RNA form a Cas9/RNA complex in the isolated mammalian cell and mediate double stranded cleavage at the target sequence.

The Declaration gives CVC the priority benefit to U.S. Provisional Application No. 61/757,640, filed January 28, 2013, and to Toolgen U.S. Provisional Application No. 61/717,324, filed October 23, 2012.

As a reminder, an interference proceeds in two stages. The first stage involves the parties presenting motions that can modify the count, have certain claims declared outside the scope of the count (or vice versa), seek to establish an earlier priority date, and ask for a finding that the claims are invalid under any of the provisions of the patent statute. If these motions are not decided in a way that would disqualify one or both parties, then the interference will move to a second stage, where the Junior Party (Broad or CVC, respectively, unless either can establish an earlier priority filing date) will present its proofs of conception and reduction to practice and the Senior Party will be permitted to oppose. The Senior Party is under no obligation to present proofs earlier than its earliest filing date unless the Junior Party evinces evidence of (at least) earlier conception. In practice, the parties can both be expected to submit their priority evidence.

The declaration of each Interference also contains a scheduling statement; in the '126 Interference there will be a telephone conference between APJ Katz and the parties on February 4th at 1:00 pm EST, and in the '127 Interference there will be a telephone conference between APJ Katz and the parties on February 4th at 3:00 pm EST. In each Interference, four business days prior to the telephone conference the parties will submit a list of motions it proposes to file. (Except in instances where this list is vanishingly small, it is unlikely that the Board will grant the parties' motions to file all these proposed motions.) It is likely that one or both of Broad and CVC will ask the Board to redeclare the interference between all three of these parties.

What motions the parties file should be available on the PTAB website shortly after the February 4th teleconference and will be the subject of a future post.
Top Stories of 2020: #5 to #8

January 11, 2021

By Donald Zuhn –-

After reflecting upon the events of the past twelve months, Patent Docs presents its 14th annual list of top patent stories. For 2020, we identified eight stories that were covered on Patent Docs last year that we believe had (or are likely to have) a significant impact on patent practitioners and applicants. Today, we count down stories #8 to #5, and later this week we will count down the top four stories of 2020. As with our other lists (2019, 2018, 2017, 2016, 2015, 2014, 2013, 2012, 2011, 2010, 2009, 2008, and 2007), links to our coverage of these stories (as well as a few links to articles on related topics) have been provided in case you missed the articles the first time around or wish to go back and have another look. As always, we love to hear from Patent Docs readers, so if you think we left something off the list or disagree with anything we included, please let us know. In addition, we will be offering a live webinar on the "Top Patent Law Stories of 2020" on January 20, 2020 from 10:00 am to 11:15 am (CT). Details regarding the webinar, which will focus on a few of the most important stories on this year's list, can be found here.

8. Patenting and Artificial Intelligence

In October, the U.S. Patent and Trademark Office, which had earlier issued a request for comments on patenting artificial intelligence (AI) based inventions and then collated the comments it received from stakeholders, released a report entitled "Public Views on Artificial Intelligence and Intellectual Property Policy." In its report, the USPTO noted that most commenters believed the current framework for examining computer-implemented software inventions should be suitable for examining AI-based inventions, but that it may be difficult to meet the requirements of 35 U.S.C. § 112(a) for certain AI-based inventions; that most commenters believed that AI may lead to changes in how the standard of a person of ordinary skill in the art is interpreted; and that some commenters expressed concerns that AI would lead to a proliferation of prior art making it difficult for examiners to conduct searches for relevant prior art. Shortly after releasing that report, the USPTO released a study entitled "Inventing AI," which highlighted the increasing prevalence of AI-based patent applications in the U.S. over the past few decades. The study, prepared by the Office of the Chief Economist of the USPTO, surveyed publicly available granted U.S. patents and U.S. patent application pre-grant publications published from 1976 through 2018. In the study, the USPTO sets forth the perhaps unsurprising finding that the number of AI patent applications increased by more than 100% between 2002 and 2018, and the more surprising finding that the share of applications relating to AI grew from 9% to nearly 16% of all patent applications over that same time period. The study suggests that it is clear that AI-based patents will remain an important part of the U.S. patent landscape going forward.

For information regarding this and other related topics, please see:

• "New USPTO Study Shows Rapid Growth, Regional Spread of AI-Based Patenting," October 27, 2020
• "USPTO Publishes Report on AI-Related Policies," October 11, 2020
• "'Creativity Machine' Cannot Be Named As Inventor," August 18, 2020

7. CRISPR Interference Progresses

Five years ago, the journal Science picked the CRISPR (clustered regularly interspaced short palindromic repeats) technology as its "Breakthrough of the Year," declaring that the technology had "matured into a molecular marvel." Not surprisingly, CRISPR's status as breakthrough molecular marvel has resulted in a battle over who has the best patent position with respect to this technology. And despite an ongoing and worsening pandemic, Interference No. 106,115 between the Broad Institute, Harvard University, and the Massachusetts Institute of Technology (as Senior Party) and the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (as Junior Party) moved forward in 2020 with the two Parties presenting various motions and oppositions to those motions. CRISPR interferences have now made three of our last four top stories lists, and could very well be on next year's list as well.

In a related development, the Opposition Division of the European Patent Office revoked European Patent No. EP 2771468 in its entirety in January. The patent, which named as Proprietors the Broad Institute, MIT, and Harvard College, had been opposed by Novozymes and CRISPR Therapeutics. In December, the Technical Board of Appeal affirmed the revocation, finding that because Rockefeller University had not been named as an Applicant, the named Proprietors could not validly claim priority to several provisional applications, and by the filing date of the provisional application to which the named Proprietors could validly claim priority, there had published prior art that invalidated the granted claims.

For information regarding this and other related topics, please see:

• "Broad Files Priority Motion in CRISPR Interference*," December 31, 2020
• "CVC Files Substantive Motion No. 3 (for Improper Inventorship) and Broad Opposes," December 30, 2020
• "Broad Files Motion Opposing CVC's Motion to Subpoena Witnesses," December 28, 2020
• "Broad Institute Loses Appeal in European Patent Office, Patents Remain Revoked," December 8, 2020
• "CVC Discloses Priority Evidence and Earliest Conception Date in Interference," November 19, 2020
• "CRISPR Housekeeping," October 29, 2020
• "PTAB Grants Broad Motion No. 4 for Priority Benefit to U.S. Provisional Application No. 61/736,527," October 6, 2020
• "PTAB Denies Broad Motion No. 3 to De-designate Claims as Not Corresponding to Count No. 1," October 4, 2020
• "CVC Takes Its Turn at Filing Dispositive Motion to End Interference," September 28, 2020
• "PTAB Denies Broad Motion No. 2 to Substitute the Interference Count," September 27, 2020
• "Claim Construction by PTAB in CRISPR Interference Decision," September 24, 2020
• "PTAB Decision Denying Broad's Substantive Motion No. 1 in CRISPR Interference," September 20, 2020
• "PTAB Decides Parties' Motions in CRISPR Interference," September 11, 2020
• "PTAB Hears Oral Argument on Motions in Interference No. 106,115," May 19, 2020
• "The Plot Thickens: Sigma Aldrich Has Allowed Claims," May 14, 2020
• "PTAB Sets Date for Oral Argument in CRISPR Interference," April 30, 2020
• "CVC Files Reply to Broad Opposition to CVC's Motion to Exclude Broad Evidence," April 26, 2020
• "Broad Reply No. 4 to CVC's Opposition No. 4 to Broad's Motion No. 4 for Priority to U.S. Provisional Application No. 61/736,527," April 22, 2020
• "Broad Reply No. 3 to CVC's Opposition No. 3 to Broad's Motion No. 3 to De-designate Claims as Not Corresponding to Count No. 1," April 22, 2020
• "Broad Reply No. 2 to CVC's Opposition No. 2 to Broad's Motion No 2 to Substitute the Count," April 21, 2020
• "CVC Files Motion to Exclude Broad Evidence; Broad Opposes," April 16, 2020
• "CVC Reply No. 2 to Broad's Opposition No. 2 to CVC's Motion No. 2 to Be Accorded Benefit of Priority," April 14, 2020
• "CVC Reply No. 1 to Broad's Opposition No. 1 to CVC's Motion No. 1 to Be Accorded Benefit of Priority," April 12, 2020
• "CRISPR Housekeeping," March 3, 2020
• "CVC Files Motion in Opposition to Broad's Substantive Motion No. 4," February 20, 2020
• "CVC Files Motion No. 3 in Opposition to Broad's Substantive Motion No. 3 to De-designate Claims as Not Corresponding to Count No. 1," February 10, 2020
• "CVC Submits Motion No. 2 in Opposition to Broad's Substantive Motion No. 2 to Substitute the Count," February 5, 2020
• "Broad Files Opposition to CVC's Motion No. 1 for Priority Benefit," January 30, 2020
• "Meanwhile, Back at the Broad-CVC Interference . . .," January 29, 2020
• "Broad Institute Patents Remain Revoked in Europe," January 28, 2020

6. IP Decisions Implicate Sovereign Immunity

Last year, the question of sovereign immunity in patent cases — more particularly whether tribal sovereign immunity could protect the St. Regis Mohawk Indian Tribe from being named as a party in an inter partes review (IPR) proceeding, and whether the University of Minnesota, as an "arm of the state," could assert sovereign immunity in an IPR — made our top stories list (coming in at #3). The issue of sovereign immunity with respect to IP cases has once again made our list for 2020. In two recent cases, the Federal Circuit determined in Gensetix, Inc. v. Board of Regents of the University of Texas System that Gensetix was without remedy for a claim of infringement asserted against the Baylor College of Medicine, Diakonos Research, and William Decker with respect to patents licensed from the University of Texas (UT), because UT refused to join as a necessary party on sovereign immunity grounds. In this case, the Federal Circuit found that the Eleventh Amendment precluded involuntary joinder of a State in a lawsuit brought by a citizen of the State or other States. And last month, in Board of Regents of the University of Texas System v. Baylor College of Medicine, the Federal Circuit found that state sovereign immunity did not prevent a petitioner from instituting an IPR against a state or arm of the state in view of its decision in Regents of the University of Minnesota v. LSI Corp. (for which certiorari was denied in 2020).

For information regarding this and other related topics, please see:

• "Board of Regents of the University of Texas System v. Baylor College of Medicine (Fed. Cir. 2020)," December 23, 2020
• "Gensetix, Inc. v. Board of Regents of the University of Texas System (Fed. Cir. 2020)," July 27, 2020
• "Allen v. Cooper (2020)," March 23, 2020

5. Doctrine of Equivalents Continues to Make Comeback

The doctrine of equivalents is a Supreme Court-created patent doctrine that arose in Graver Tank & Mfg. Co. v. Linde Air Products Co., 339 U.S. 605 (1950). However, the doctrine fell into disfavor at the Federal Circuit during the 1990's and arguably provided the first inkling to the Supreme Court that the Federal Circuit's patent jurisprudence would benefit from the Court's closer oversight. In Warner-Jenkinson Co. v. Hilton Davis Chem. Co. and Festo v. Shoketsu Kinzoku Kogyo Kabushiki, the Supreme Court reiterated the vibrancy of the doctrine; nevertheless, its successful assertion continued to decline.

As we noted in our top stories list last year, the doctrine of equivalents began to make a bit of a comeback in 2019 (enough to make last year's top stories list, coming in at #10), and this comeback continued in 2020. In March, the Federal Circuit continued its recent willingness to affirm findings of infringement under the doctrine of equivalents in Galderma Laboratories, L.P. v. Amneal Pharmaceuticals LLC, affirming the District Court's decision regarding infringement under the doctrine of equivalents with respect to some asserted patents (while reversing as to infringement under the doctrine of equivalents with respect to other asserted patents). And then last month, in Eli Lilly & Co. v. Apotex, Inc., the Federal Circuit again affirmed a finding of infringement under the doctrine of equivalents. Between those two decisions, however, the Federal Circuit, in Eagle Pharmaceuticals Inc. v. Slayback Pharma LLC, applied the dedication-disclosure doctrine to affirm a District Court dismissal on the pleadings of infringement allegations under the doctrine of equivalents.

For information regarding this and other related topics, please see:

• "Eli Lilly & Co. v. Apotex, Inc. (Fed. Cir. 2020)," December 27, 2020
• "Supreme Court Denies Another Certiorari Petition on Doctrine of Equivalents," June 16, 2020
• "Eagle Pharmaceuticals Inc. v. Slayback Pharma LLC (Fed. Cir. 2020)," May 11, 2020
• "Galderma Laboratories, L.P. v. Amneal Pharmaceuticals LLC (Fed. Cir. 2020)," March 29, 2020
• "DOE Infringers Petition for Certiorari over PHE "Tangential Relationship" Test," March 18, 2020
CVC Files Reply to Broad’s Opposition to CVC’s Miscellaneous Motion No. 6; Board Issues Orders

January 10, 2021

By Kevin E. Noonan —

Motion practice continues in Interference No. 106,115 between Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") and Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC"), with CVC filing on January 6th its Reply to Broad's opposition to CVC's Miscellaneous Motion No. 6 for leave to subpoena discovery (including depositions) from Luciano Marraffini and Shuailiang Lin, neither of whom is a party to this interference (pursuant to an Order authorizing filing of this Reply issued by the Board on December 28th).

CVC's motion was predicated on its contention that these witnesses had relevant testimony regarding Broad's priority, dates of conception, and activities related to reduction to practice, that Broad would not voluntarily provide these witnesses for deposition, and that such testimony would contradict allegations in Broad's priority statement. CVC also asserted that it had attempted to obtain their testimony voluntarily but had been refused, making subpoena the only avenue available for obtaining their evidence.

Broad in its opposition contended that any such evidence would be redundant over evidence available from other witnesses and documents, and that much of any such testimony was not relevant to Broad's priority proofs. Broad further argued that there were no inconsistencies between whatever testimony CVC could adduce from these witnesses and the "allegations" in its priority statement and evidence it would proffer with its (at the time, to be filed) Motion for Priority.

Since filing its Opposition, Broad has filed its Priority Motion and CVC's Reply to Broad's Opposition depends in large part on that Motion, CVC contending that it supports their asserted reasons why testimony from Drs. Marraffini and Lin is relevant and necessary, most notably that "both Dr. Marraffini and Dr. Lin have personal knowledge concerning Dr. Zhang's work, including his prior unsuccessful attempts to achieve genomic cleavage in human cells."

Regarding Dr. Marraffini, CVC contends (perhaps most relevantly) in its Reply that communications between Dr. Marraffini and Broad's inventor Dr. Zhang were used in support of Broad's Priority Motion, making Broad's position that any testimony from Dr. Marraffini would not be relevant evidence. CVC responds by stating that "Broad's argument is misleading as its own priority evidence and Dr. Marraffini's public statements confirm that he has relevant information beyond the emails Broad produced in this proceeding. This evidence includes discussions between Dr. Marraffini and Dr. Zhang that CVC contends establish Dr. Zhang's failures prior to June 2012, as well as "discussions where Marraffini conveyed to Zhang CVC's presentation of its work with chimeric RNA." CVC also contends that "Dr. Marraffini's recollection of events contradicts Dr. Zhang's assertion that he successfully achieved genomic cleavage in human cells by November 2011," relying on statements from Dr. Marraffini that it took several months after starting a collaboration with Dr. Zhang and that Dr. Marraffini's collaboration did not start until 2012.

Regarding Dr. Lin's testimony, CVC asserts that denying them an opportunity to depose him is inconsistent with Broad's reliance on experiments he conducted, and that substituting another witness (Dr. Sanjana) to provide testimony regarding Dr Lin's experiments would be improper. CVC argues that "Dr. Lin is the person most competent to testify regarding his lab notebook, his experimental work and his communications with Dr. Zhang, all of which Broad relies on to support its priority motion" (emphasis in Reply). This evidence is specifically relevant, according to CVC, because Broad relies on it to establish successful CRISPR cleavage in human cells in 2011. CVC also argues that Dr Lin's testimony is necessary to reconcile Broad's assertions in its Priority Motion that Dr. Zhang "realized" the components necessary for successful CRISPR cleavage in eukaryotic cells and Dr. Lin's apparent comments to the contrary.

CVC's Reply closes by noting that "Broad identifies no authority for its request for deposition time and waived any right to such time by not timely raising a request for discovery," and mentions that this request "undermines its assertions that these depositions will be redundant of other testimony, and also confirms the absence of any cognizable prejudice to Broad." But like Broad, CVC also argues a fallback position, that should the Board permit cross-examination time to Broad it should be limited in substance to issues raised and examined by CVC and to "no more than one hour," which CVC apparently believes would prevent Broad from taking away any advantage of these depositions.

Separately, the PTAB issued an Order authorizing CVC to file an Opposition to Broad's Contingent Responsive Motion No. 6, and the Broad to file a Reply to any such opposition.
Conference & CLE Calendar

January 10, 2021

January 13, 2021 – "Second Medical Use Patents — Understanding Infringement and Enforcement" (Gowling WLG) – 9:00 to 10:00 am EST

January 14, 2021 – "Priority Entitlement in Europe — Current Best Practice" (J A Kemp) – 2:30 to 3:30 pm GMT

January 26, 2021 – "Second Medical Use Patents — Verifying Validity" (Gowling WLG) – 9:00 to 10:00 am EST
Webinar on Priority Entitlement in Europe

January 9, 2021

J A Kemp will be offering a webinar entitled "Priority Entitlement in Europe — Current Best Practice" on January 14, 2021 from 2:30 to 3:30 pm GMT (Greenwich Mean Time). Marc Wilkinson and Chris Milton of J A Kemp will provide a concise review of European case law and practice with respect to a patentee's legal entitlement to a claim of priority, and briefly discuss what went wrong and why for the patentees in a recent high-profile case before the Board of Appeal of the European Patent Office (decision T844/18), where a high-value patent in the field of gene editing (CRISPR) was revoked for lack novelty over intervening prior art following a loss of priority. The webinar will also outline practical steps and measures that can be taken by applicants to help safeguard priority claims in Europe.

Those wishing to register can do so here.
Webinars on Second Medical Use Patents

January 9, 2021

Gowling WLG will be offering two webinars on second medical use patents from 9:00 to 10:00 am EST on January 13, 2021 and from 9:00 to 10:00 am EST on January 26, 2021. The first webinar, entitled "Understanding Infringement and Enforcement," will outline the key opportunities and obstacles surrounding second medical use patent protection, focusing on the United Kingdom, Canada, Russia, and China. The panel, consisting of John Norman, Alex Gloor, Jenny Davies, Vladislav Ugryumov, and Jian Xu, will help attendees understand what to expect when a second medical use patent reaches the court, and explore the following questions:

• What form can second medical use claims take?
• What must be established for a second medical use patent to be infringed?
• How do you enforce a second medical use patent?
• Can you prevent off-label use?

The second webinar, entitled "Verifying Validity," will look at the validity of second medical use patents across the United Kingdom, Canada, Russia, and China, and help attendees understand what to expect when the validity of a second medical use patent is called into question. The same panel will explore the following questions:

• What does it take for a second medical use to be sufficiently disclosed? A list of indications in the application? Clinical data? Or something in-between?
• How do Courts address inventiveness of a second medical use patent in light of the first medical use?
• What issues arise with disclosure of clinical trial protocols?

Those wishing to register for these webinars can do so here and here.
Horizon Pharma, Inc. v. Dr. Reddy’s Laboratories Inc. (Fed. Cir. 2021)

January 6, 2021

By Kevin E. Noonan —

Indefiniteness under U.S. patent law is a failure to satisfy the statutory requirements of 35 U.S.C. § 112(b), which reads: "The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention" (emphasis added). The meaning of the statute was most recently explicated by the Supreme Court in Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898, 910 (2014), which established the standard that the inherent imprecision of language cannot create "ambiguity . . . so great that it creates a 'zone of uncertainty' around the patent claims." In practice, this led the Court to require "reasonable certainty" in claim language, a standard the patent claims at issue failed to satisfy in the Federal Circuit's recent decision in Horizon Pharma, Inc. v. Dr. Reddy's Laboratories Inc.

The case arose in litigation of over a combination therapy of a non-steroidal anti-inflammatory (NSAID) medication and a proton-pump inhibitor (PPI) that minimized the gastrointestinal complications of NSAID administration. The asserted patents, U.S. Patent Nos. 9,220,698 and 9,393,208, claimed methods of treating certain diseases with such combination formulations; claim 1 of the '698 patent was deemed representative by the Federal Circuit panel:

1. A method for treating osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis comprising orally administering to a patient in need thereof an AM unit dose form and, 10 hours (±20%) later, a PM unit dose form, wherein:
the AM and PM unit dose forms each comprises:
naproxen, or a pharmaceutically acceptable salt thereof, in an amount to provide 500 mg of naproxen, and
esomeprazole or a pharmaceutically acceptable salt thereof in an amount to provide 20 mg of esomeprazole;
said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said AM and PM unit dose forms at a pH of 0 or greater,
the AM and PM unit dose forms target:
    i) a pharmacokinetic (pk) profile for naproxen where:
        a) for the AM dose of naproxen, the mean C_max is 86.2 µg/mL (±20%) and the median T_max is 3.0 hours (±20%); and
        b) for the PM dose of naproxen, the mean C_max is 76.8 µg/mL (±20%) and the median T_max is 10 hours (±20%); and
    ii) a pharmacokinetic (pk) profile for esomeprazole where:
        a) for the AM dose of esomeprazole, the mean area under the plasma concentration-time curve from when the AM dose is administered to 10 hours (±20%) after the AM dose is administered (AUC_0–10,am) is 1216 hr*ng/mL (±20%),
        b) for the PM dose of esomeprazole, the mean area under the plasma concentration-time curve from when the PM dose is administered to 14 hours (±20%) after the PM dose is administered (AUC_0–14,pm) is 919 hr*ng/mL (±20%), and
        c) the total mean area under the plasma concentration-time curve for esomeprazole from when the AM dose is administered to 24 hours (±20%) after the AM dose is administered (AUC_0–24) is 2000 hr*ng/mL (±20%); and
the AM and PM unit dose forms further target a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period after reaching steady state that is at least about 60%.

The District Court granted summary judgment in favor of defendants that this claim (and the remaining asserted claims) in the '968 and '208 patents were invalid for indefiniteness. Among all the terms, technical and otherwise, in this claim the basis for the District Court's decision is the term "target," which the District Court construed to have its ordinary meaning of "set as a goal." In so construing this claim term, the District Court rejected patentee Horizon's alternative construction, to "produce," because the specification used the words "produce" and "target" in ways that the term were not necessarily interchangeable. Under this construction, the District Court held that "while the goal itself was clearly defined, the 'act of targeting that goal' was not." Specifically, the District Court said that "'pills cannot be said to set goals,' and even if the claims were understood to say that it is a treating physician who sets the goals, the claims would require a treating physician to 'avoid having a subjective intent to achieve the defined outcomes.'" Finally, the District Court found that the differing views of plaintiff's and defendant's experts as to the meaning of the term did not raise issues of material facts because the dispute involved opinion not fact. This appeal followed.

The Federal Circuit affirmed, in an opinion by Judge Hughes, joined by Judges Moore and O'Malley. The panel found the term in this case to be readily construed according to its plain meaning, saying that "the claim term 'target' is a commonly understood word, and nothing Appellants point to in the specification or the prosecution history suggests that it should be given anything other than its ordinary meaning," which was the meaning used by the District Court, i.e., "set as a goal." (Somewhat parenthetically, the opinion rejected patentee's argument that case law favors a construction that preserves validity, because this principle applies only where "the court concludes, after applying all the available tools of claim construction, that the claim is . . . ambiguous," citing LiebelFlarsheim Co. v. Medrad, Inc., 358 F.3d 898, 911 (Fed. Cir. 2004), and that was not the case here in the Court's opinion).

While relying expressly on the Supreme Court's Nautilus opinion, the Federal Circuit also opined that "[o]ne circumstance in which claims are indefinite is where the claims, as properly construed, are nonsensical," citing Trs. of Columbia Univ. v. Symantec Corp., 811 F.3d 1359, 1366–67 (Fed. Cir. 2016). In upholding the District Court's construction, and finding of indefiniteness, the panel asserted that "the 'target' clauses of claim 1 render the claim indefinite because '[t]he fact that a goal is clearly defined does not mean that the act of targeting that goal is clearly defined, and this is the crux of the definiteness problem here.'" Simply put (as the District Court had) "a dose form, which is an inanimate object, cannot set a goal."

After agreeing with the District Court that a dispute between experts does not raise a genuine issue of material fact that would preclude summary judgment, the panel affirmed the construction and the District Court's decision that the claims were indefinite and consequently invalid.

Horizon Pharma, Inc. v. Dr. Reddy's Laboratories Inc. (Fed. Cir. 2021)
Panel: Circuit Judges Moore, O'Malley, and Hughes
Opinion by Circuit Judge Hughes
Molecular Mechanism for (In)Famous Warburg Effect in Cancer Elucidated

January 5, 2021

By Kevin E. Noonan —

Cancer, the "Emperor of All Maladies" as it has been termed, has been studied for millennia. President Nixon's "War on Cancer" resulted in slow but steady progress, aided by the biotechnology revolution, the development of monoclonal antibodies (see Herceptin®) and more recent developments in immunological interventions like CAR-T cells (see "Global CAR-T Cell Therapy Market (2021 to 2027) – Size, Forecasts, Trials and Trends -ResearchAndMarkets.com").

But the basis for many characteristics of cancer biology remain elusive, including what is classically termed the Warburg effect, i.e., the tendency of cancer cells to be dependent upon aerobic glycolysis instead of oxidative phosphorylation even in the presence of oxygen and thus not being an adaptation for low oxygen conditions as it is in normal cells. (Those with long memories will remember the saga of the eminent Efraim Racker being fooled by a graduate student who presented falsified evidence of a protein kinase cascade that regulated glycolysis.) This effect has been known since the 1920's (during the Golden Age of research into the biochemical basis of intermediary metabolism) when Otto Heinrich Warburg found that depriving tumor cells of oxygen and glucose resulted in cell death. But the change has remained phenomenology perhaps until now.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) which is an inherited form of kidney cancer is characterized by deficiency in fumarate hydratase (FH), which catalyzes the reaction:

as part of the Krebs (TCA) cycle in the mitochondria. Until now there has been no understanding of why or whether this metabolic deficiency results in tumors that rapidly grow and metastasize. In a recent paper, a team of university and National Institutes' researchers* recently reported that the growth aggressive phenotype is associated with expression of the Warburg effect, in a paper entitled "Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer," in Science Signaling. These researchers show that the enzymatic deficiency is associated with an accumulation of fumarate in the cells, and this results in increased mutation rates in mitochondrial DNA as a consequence of fumarate accumulation. The authors draw the conclusion that these cancer cells are "rewired" to promote tumor progression and metastasis due to a loss of mitochondria and a "metabolic shift" to aerobic glycolysis.

FH is encoded by a nuclear-encoded gene but the enzyme is necessary for competent mitochondrially mediated metabolic function. The basis for high fumarate's deleterious effects on mitochondria is the "nonenzymatic formation of an S-(2-succinyl)-cysteine (2SC) adduct that inactivates multiple proteins involved in tumor biology and metabolism." The researchers found that there was a loss of respiratory-chain components encoded by mitochondrial DNA and with S-(2-succinyl)-cysteine (2SC) adduct-mediated inhibition of mitochondrial DNA replication. This in turn was caused by inactivation of the sole mitochondrial DNA polymerase as well as mtDNA maintenance and repair proteins, leading to mitochondrial depletion in these cells. The authors termed this mitochondrial depletion a "defining feature" of this tumor type and its aggressive growth and metastasis phenotype.

The researchers studied a cohort of 24 HLRCC patients aged 21-70 with the majority (75%) having advanced metastatic disease. Assessment of proteins in the respiratory chain showed disruption associated with morphological defects on the mitochondrial inner membrane (where these proteins are located in normal cells). As summarized by the authors, "[t]ogether, these data demonstrate an impairment in the assembly of respiratory CI, CIII, and CIV in HLRCC tumor mitochondria with a substantial loss of protein abundance of mitochondrially encoded subunits."

These results were consistent with the detected down-regulation of mitochondrial mRNA synthesis in these cells which was not seen in the expression of nuclear gene-encoded mRNAs members of Krebs cycle or respiratory chain proteins, as illustrated in this Figure:

As stated in the paper "[o]ur transcriptome analyses indicated that the underlying cause of respiratory chain dysfunction in HLRCC FH^−/− tumors was the selective loss of expression of mtDNA-encoded subunits" of the respiratory chain"; the authors were able to correlate this reduction in mtDNA gene expression with a reduction in the number of mitochondria per cell, from an average of 833 mtDNA molecules in normal renal cells to between 344 and 294 copies in primary and metastatic HLRCC tumors, respectively.

These changes were mirrored in HLRCC tumor-derived cell lines, albeit not entirely consistently. To evaluate these inconsistencies the researchers restored normal FH levels by introducing heterologous FH-encoding constructs that showed "[r]obust FH activity." Nevertheless, functional respiratory chain function was not established in these cells, consistent with the defect being associated with mitochondrial loss rather than merely FH disfunction: "[o]ur observations indicate that loss of FH activity had a lasting impact on mitochondrial function even after FH activity was restored and fumarate levels were reduced in the tumor-derived cells."

These results led the researchers to evaluate the status of mtDNA in these cell lines by DNA sequencing. These experiments showed multiple deactivating mutations in several mtDNA-encoded genes involved in respiration, including mutations not found in the Human Mitochondrial DNA database (HmtDB), which the authors assert suggested that "these mutations are not tolerated in normal human tissues." When similar experiments were performed in the HLRCC tumor samples, almost all (22) showed one or more somatic changes in mtDNA, each sample having on average 2.27 (range, 1-7) mutations in the mtDNA, wherein more than half of these mutations resided in protein-encoding mtDNA. Such patterns of mtDNA mutations were not found in other types of renal cell carcinoma not associated with FH deficiencies.

Finally, an analysis of the protein components of mtDNA, which encode proteins known to be involved in maintaining DNA integrity, were found by these researchers to be covalently modified by succinylation at cysteine (Cys) residues, resulting in their inactivation. These results were consistent with the loss of mitochondria population in these cells. These results were observed in both cells from HLRCC tumor cell lines and HLRCC patient samples.

These researchers summarized their results with this diagram:

and by noting that FH deficiency resulted in inactivation of core enzymes involved in mtDNA integrity, repair, and replication and irreversible mitochondrial loss. Mitochondrial loss "obligates cells to compensate for energy loss by shifting to dependence on aerobic glycolysis as an energy source."

These changes were also associated with upregulation of enzymatic activity that promoted lipid synthesis, necessary for rapid tumor growth. As summarized by the authors:

[T]he metabolic compensations dictated by loss of mtDNA may result in features of the aggressive growth phenotype that characterizes HLRCC tumors, including increased fatty acid biosynthesis contributing to formation of new cell membranes, generation of the intermediates of the citric acid cycle that are used in anaplerotic reactions, and synthesis of other precursors necessary for biosynthesis of amino acids and nucleotides that are needed for rapid growth and invasiveness of this type of cancer.

And:

In summary, mitochondrial dysfunction forces metabolic remodeling in HLRCC tumors that favors anabolic pathways offering crucial bioenergetic and biosynthetic advantages for tumor growth and metastasis. Understanding that mtDNA mutations and deletions represent the fundamental cause for the shift to complete dependence on aerobic glycolysis in this aggressive form of inherited, genetically defined RCC will hopefully provide insights into the development of effective forms of therapy for patients with HLRCC and other related cancers.

* National Institutes of Health, National Cancer Institute, National Institute of Child Health and Human Development, Frederick National Laboratory for Cancer Research, and the University of Kentucky
IPO Sends Letter on IP Law and Policy to President-Elect and Vice President-Elect

January 4, 2021

By Donald Zuhn —

Last month, Intellectual Property Owners Association (IPO) President Daniel J. Staudt sent a letter on behalf of the IPO to President-Elect Joe Biden and Vice President-Elect Kamala Harris "to recommend that intellectual property (IP) law and policy be priorities in your administration." The letter states that:

The IP system is fundamental to the nation's economic growth and job creation and to our global competitiveness. The importance of innovation is clearer than ever at this moment in our nation's history as we face challenges such as the coronavirus pandemic and related economic instability, the climate crisis, and the need to ensure diverse and inclusive representation of viewpoints.

With respect to the COVID-19 pandemic, the letter notes that "[t]he ability to leverage and build upon scientific research conducted over many years, made possible by the IP system, enabled industry to expedite the vaccine development process." The letter also points out that developments with respect to personal protective equipment and innovative computer-implemented technologies that have allowed us to stay connected during the pandemic were also the result of years of investment in innovation.

As for the climate crisis, the letter states that "IP is an integral part of developing new global environmental policies aiming for a more sustainable lifestyle based on green technologies," and expresses support for the incoming administration's pledge to invest $400 billion in clean energy and innovation.

The letter also declares that "[c]losing the diversity gap in innovation is also vitally important to our economic growth and global competitiveness," noting that women, people of color, and other minority groups are vastly underrepresented in the patent system. The letter points out that recent "scholarship indicates that increasing participation in inventing by underrepresented groups could increase U.S. GDP by as much as 4.4%," and suggests that "[i]t is imperative that the public and private sectors work together to close this gap and harness our country's potential to innovate at greater levels than ever before."

Included with the letter is an Appendix providing several IP issues that "threaten sound innovation policy in the U.S. and worldwide," including clarifying patent subject matter eligibility; protecting trade secrets; ensuring predictable legal systems for all industries and technologies; addressing counterfeiting and trademark infringement; and providing high quality, enforceable IP rights and predictable legal systems in the U.S. and abroad.

With respect to subject matter eligibility, the letter notes that the IPO "continue[s] to believe that legislative action is needed" to address Supreme Court decisions that have "detrimentally affected areas such as precision medicine & artificial intelligence and risk[] a chilling effect on further developments and investment in these critical technologies." On the issue of trade secret protection, the letter states that "[i]nadequate protection of trade secrets abroad harms not only companies whose property is stolen, but also the country where the theft occurs, because companies are then less likely to form joint ventures and make high-value investments in those countries."

The letter also argues that unfounded assertions continue to be made that IP rights constitute a barrier to innovation in order to justify compulsory licenses and forced technology transfer. In particular, the letter states that:

IPO members continue to witness concerted efforts to weaken intellectual property rights in the name of development, access to health, and environmental concerns. Intellectual property rights have been unfairly portrayed as a barrier to technology transfer based on arguments that they limit availability of technologies and make them more expensive to secure. The threat of intellectual property erosion, however, actually increases the cost of technology and slows its adaptation and deployment.

The letter notes that the IPO continues to strongly oppose compulsory licensing of intellectual property rights with respect to all industries and technologies, adding that "[a]lthough IPO recognizes that compulsory licenses of IP rights may be legally permissible in limited and rare situations, IPO believes that licensing of IP rights is best accomplished through voluntary efforts."

The Appendix concludes by touching on the issue of backlogs and other bars to securing IP protection, noting that "[i]ncreasing global competition drives IPO members to innovate faster than ever before, and in many cases product life cycle times are becoming extremely short" (as, for example, the unprecedented short timeline in which multiple COVID-19 vaccines have been developed). In view of shorter product life cycles, the letter contends that "debilitating application backlogs at patent and trademark offices are at odds with the pace of innovation."

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