Substantially Similar--A Blog on IP Issues, Writing and Film

CRISPR's Gene Editing: Too Hot Not to Cool Down, A Little?

by John Aquino on 06/19/18

News coverage of the gene-editing technology CRISPR-Cas9 had until recently mostly been on its potential to repair or remove flawed genes, the ongoing clinical trial on human subjects in China and the one that will start next year in the U.S., and on the legal fight as to who controls its patents. The technology has been labeled "revolutionary and it has been predicted that it will change the face of modern medicine. But a new study titled “Unexpected mutations after CRISPR-Cas9 editing in vivo.” published in the journal Nature Methods has raised concern that CRISPR can also introduce unintended mutations into the genome. A study that sounded a broader alarm last year was widely criticised. What sort of effect will this new study have?

Clustered Regularly Interspaced Palidronic Repeat (CRISPR)-Cas9 allows researchers to alter DNA sequences and modify gene function. It has the potential to prevent genetic defects and curb the spread of a disease. The potential is so great that it has caused alarm about its potential misuse in breeding "designer babies" and superhumans.

The technology is thought to be worth billions of dollars. The patent fight has been between the University of California at Berkeley and the Broad Institute of MIT and Harvard. In 2017, the Patent and Trademark Office's Patent Trial and Appeal Board (PTAB) found in favor of the Broad Institute, and UC appealed to the U.S. Court of Appeal for the Federal Circuit. I covered both the PTAB ruling https://www.bna.com/gene-editing-patent-n57982084034/ and UC’s filing of its appeal https://www.bna.com/university-california-fight-n57982086696/ . A three-judge panel of the Federal Circuit heard oral arguments on April 30, 2018. Most prognosticators suggested that after the arguments they felt that the court would affirm the PTAB’s ruling in favor of the Broad Institute. Judge Kimberly Moore openly and dramatically questioned UC’s argument that its efforts showed a reasonable expectation that the technology would work. But, as I’ve suggested in this blog, prognostication based on oral arguments has been wrong on occasion. The court's ruling is due any time.

But around the same time as the PTAB ruling, the alarms about potential problems with CRISPR began to focus on its potential side effects. In May 2017, the journal Nature Methods published a Columnia University Medical Center study that suggested CRISPR can cause collateral damage to the genome. There was an outcry that the methodology of the study was flawed, and the journal on March 30, 2018 published a retraction.

In two papers in the same journal published this June 8, researchers described how they had sequenced the entire genome of mice that had undergone CRISPR gene editing in the team’s previous study and looked for all mutations. They found that CRISPR corrected a gene that causes blindness but also that the genomes of two independent gene therapy recipients had experienced more than 1,500 single-nucleotide mutations.

In a June 19 online chat, Sharon Begley, chief writer for science and discovery for STAT News, tried to put the two papers in perspective. She stated that the studies reported a possible link between CRISPR and a cancer-preventing protein called p53. "CRISPR did not turn cells cancerous. Instead, the two independent teams of scientists (at Novartis and the Karolinska Institute) reported cells already lacking a functional p53 were more likely to have their genome successfully edited by CRISPR." This would mean that the absence of p53 in a cell may make the CRISPR process easier but it also makes a cell more likely to be cancerous.

"[I]n the worst case," Begley stated, "the exact cells that seem therapeutic might, when returned to the patient, seed cancer. BUT the finding is preliminary. It needs to be confirmed by other investigators. Lots of mice have been CRISPR'd, and no one has reported any cancer epidemic in them."

In a June 13 Bloomberg News article, Max Nisen, noting that it is very early in the technology's history, sounded a cautious note. "[T]he studies' findings are a reminder about how little we know about unintended consequences. And either way, these papers may have a cooling effect on investment, trial recruitment, and the FDA's [Food and Drug Administration's] willingness to give a broad or rapid green light to crispr testing."

Many breakthrough technologies have experienced setbacks and a longer development role than originally anticipated, Nisen noted.

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Lerner and Loewe's Camelot: Inevitably, Affectionately Imperfect

by John Aquino on 06/17/18

I've always had a special affection for the musical Camelot about King Arthur, which premiered in 1960. Focused on King Arthur's attempt to create a kingdom in which might was used not to establish power but to defend the powerless, it was critically-derided at the time as being inferior to its creators' prior work, My Fair Lady. Critics also contended the show confusingly started happy and ended sad (indicating they were unfamiliar with the source material, Thomas Mallory's Morte D'Arthur and T. H. White's Once and Future King). I have such affection for Camelot that I am, perhaps, not a good judge. President John F. Kennedy, was also a fan of the musical, which led to its name being used as the label for his years as president. I saw it again at the Shakespeare Theatre in Washington D.C. three weeks ago.

While watching the latest production, I realized that Camelot has become a lot like Candide, Leonard Bernstein's 1956 musical based on Voltaire's novella. Candide had a glittering Bernstein score and a much-criticized book by Lillian Hellman. It only ran 73 performances, but its original cast recording was treasured because it preserved Bernstein's music. Candide was revived on Broadway in 1974 with a new book by Hugh Wheeler and additional lyrics by Stephen Sondheim. Opera companies expressed an interest, and the show was reworked again, with songs that had been cut from the 1956 production being added. In 1988, Bernstein wanted a new production that reflected his original intentions, and, Wheeler having died, his book was adapted by John Wells. There are, then, a number of versions of Candide around, and your view of it will depend on which version you've seen.

Camelot is like that, and this may reflect its troubled gestation. In its Toronto tryout, it ran four hours. It was reworked and reworked. The director Moss Hart had a heart attack, and its composer Frederick Loewe became ill as well. Its lyricist and librettist Alan Jay Lerner experienced bleeding ulcers. Songs were added and some, such as a duet by Morgan Le Fey and Mordred, were cut. A song for Arthur's knights, "Fie on Goodness," in which they express discontent in living in a kingdom that is at peace, was written to hide a scene change--the knights sang in front of a curtain while the crew changed the scenery. It was subsequently cut, although it and another cut number, "Then You May Take Me to the Fair," are on the original case album. "Then You May Take Me to the Fair," however, was restored for the movie version. In one production I saw, "Follow Me," a song originally sung by the enchantress Nimue to lure Merlin away, became a love song sung by Lancelot to Guenevere. So, there has always been some fluidity associated with Camelot. In the Shakespeare Theatre production, they restored "Fie on Goodness."

I have seen Camelot five times. This doesn't include Joshua Logan's atrociously-directed 1967 film version. I saw the national touring company in 1963 at the National Theatre from seats in the second balcony that cost my mother $2.50 at the time. George Wallace played King Arthur, Anne Jeffreys, Guenevere, and Arthur Treacher (who later founded fish and chip restaurants), King Pellimore. A few years later, my mother took us to a forgettable version at either the Burn Brae or Harlequin dinner theatre near Washington. In 1980, my wife and I and her mom and dad saw Richard Burton in New York recreate the role of King Arthur he had created in 1960. In 1993, my wife and I saw Robert Goulet, who had originated the role of Lancelot, phone in a performance on Broadway as King Arthur. And then a 25-year hiatus until my wife took me to the Shakespeare Theatre for my birthday.

It was an uneven production. It was very well sung. But to offset the concern that the musical begins happy and ends sad, they interpolated an opening scene in which the older Arthur, on the eve of his last battle, asks his mentor Merlin to show him how he had come to such a sad end. The actual first scene of the original musical has a young Arthur hiding in a tree to catch a glimpse of Guenevere, his bride-to-be. At the Shakespeare Theatre, a giant, metal-seeming tree filled the stage. It was so large actors walking around it or under it had to dodge being slammed in the face by a silver branch. The song "The Lusty Month of May" prompted a listless and non-lusty dance number. Sexist dialogue from 1960 was replaced. In dialogue that is part of Arthur's song, "How to Handle a Woman," he no longer says that Merlin told him, "Never be too disturbed that you don't understand what a woman is thinking. They don't do it very often," but, instead, "Never be too disturbed that you don't understand what a woman is thinking. She'll tell you when she wants you to know." And Guenevere becomes much more of a contributor to the idea that leads to the formation of the Round Table.

Camelot begins happy and ends sad because that has often happened with civilizations and the ideas behind them. The Roman Empire was followed by the Dark Ages, and the Renaissance by the Reformation and religious wars. Alan Jay Lerner's phrase "one brief shining moment" was applied after Kennedy's assassination to his 1,000 days in office to reflect a great sense of loss. Perhaps the story of Arthur struck critics in 1960 as an odd one for a musical, but that was before Sweeney Todd, Little Shop of Horrors, Titanic, and Assassins. It was, perhaps, ahead of its time.

Camelot's score is one of Broadway's finest: "If Ever I Would Leave You," "What Do the Simple Folks Do?", "Before I Gaze on You Again," :"I Loved You Once in Silence," "How to Handle a Woman." "Sweeping" and "luscious" are good words to describe Loewe's music. Stephen Sondheim in his book Finishing the Hat writes that in his lyrics Lerner wasn't as clever as he thought he was. But I've always been impressed by the internal rhyming in the Camelot lyrics: "If ever I would leave you/It wouldn't be in springtime/Knowing how in spring I'm bewitched by you so" or "The wee folk and the grown folk/Who wander to and fro/Have ways known to their own folk/We throne folk don't know." And it is no overstatement that his lyrics for the "Camelot" reprise--"Don't let it be forgot/That once there was a spot/For one brief shining moment/That was known as Camelot"--have touched several generations.

There may never be a perfect production of Camelot. I didn't see the 1960 production, but, as I've mentioned, it was a work-in-progress. When we saw Burton in 1980, his voice was still magnificent, but his arms were so weakened by bursitis and arthritis that he could barely lift a sword. Camelot, which is about great idea of a peaceful world that is imperfectly implemented, is itself imperfect. But its relevance will always be with us.

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Tribal Sovereign Immuity and Patents: The Federal Circuit Arguments

by John Aquino on 06/08/18

The U.S. Court of Appeals for the Federal Circuit heard oral arguments June 4 in the case of St. Regis Mohawk Tribe v. Mylan Pharmaceuticals, which concerns the patentability of Allergan's claims for the dry-eye drug Restasis. I took a special interest in the case because I once managed a tribal nonprofit association.

Mylan challenged the validity of the patents before the Patent and Trademark Offices Patent Trial and Appeal Board (PTAB) in an inter partes review (IPR) proceeding. Alergan transferred the patents' ownership to the tribe, which then argued that the IPR proceedings could not go forward because of its tribal sovereign immunity. The PTAB held that it wasn't subject to tribal sovereign immunity. The tribe appealed the PTAB decision to the Federal Circuit.

It is always difficult to predict which way a court will go based on oral arguments. When I covered the Supreme Court argument in 2017 in the dispute between Amgen and Sandoz over interpretations of the biosimilar statute, the justices began shooting questions to the Sandoz attorney before he had barely said a word of his prepared remarks. When the attorney for Amgen had his turn, the justices scarcely asked him a question. Some interpreted this to mean that they had no issues with the Amgen argument. And yet, the high court ruled in favor of Sandoz. The barrage of questions was likely indicative of them solidifying their opinions, dotting the i's, crossing the t's.

On June 4, all three judges on the Federal Circuit panel peppered Jonathan Massey, who argued on behalf of Allergan and the St. Regis Mohawk Tribe, with questions, as they did the attorney representing Mylan. Mark Freeman of the Department of Justice, arguing for the U.S. government, took the position that the IPR proceedings should proceed despite the tribe's sovereign immunity argument. He seemed to have an easier time.

The judges' questions during the arguments may tell us nothing of how they will rule. The judges also were given amicus briefs from petitioners, and all of them supported Mylan, none supported Allergan and the tribe. Most patent attorneys who have blogged have been derisive of the tribe taking ownership of the patents for the sole purpose of allowing Allergan to avoid an IPR challenge, referring to it as "rent a tribe." Freeman echoed this view when he said, seemingly in passing to the judges, "We all recognize a shell game when we see one."

And yet, many of the attorneys I have spoken with noted that, in the briefs they submitted to the court, the tribe and Allergan made a very convincing case.

Much of the June 4 arguments dealt with whether an IPR proceeding was intended as a federal agency proceeding or as an alternative substitute for federal court litigation, which was one of the claims put forward by the lawmakers developing the America Invents Act of 2010, which created the IPR process. Freeman argued that an IPR is an agency action that doesn't involve tribal sovereign immunity.

In response to questions from Judge Timothy Dyk that transferring patent ownership to the tribe was a "cirumvention," Massey replied, "I don't think it was a circumvention. It is using a system created by Congress. The system is such that it results in tribal immunity. And if that's the system created by Congress, it's not a circumvention." Maxwell contended that it isn't the court's job to narrow tribal immunity but that of Congress, and he noted that there are bills before Congress to address the issue of tribal sovereign immunity and patents.

Judge Kimberly Moore kept calling the IPR proceedings "a hybrid," implictly questioning the argument that it is clearly an agency proceedings and not a substitute for federal litigation. Freeman agreed with her that it is a hybrid, but he concluded by reiterating his argument that an IPR "is an action by the U.S. government against which a tribe does not have tribal immunity." He asked the court to decide the issue, saying that, if the court did not, the issue would keep coming up.

The court is expected to issue its opinion quickly.

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Kelo v. the City of New London and "Little Pink House"

by John Aquino on 06/01/18

A new film has just received nationwide release after premiering at the Santa Barbara film festival in 2017. It's called Little Pink House and is a fact-based, law-themed movie on the legalistic concept of eminent domain. It's the sort of film I really admire in that it is a small movie about a legal concept that affects the lives of millions. It deals with property owned by individuals and the evolving way it has been viewed by the courts and legislatures.

I have written about how my family was affected by eminent domain in the wake of the 1968 D.C. riots stemming from the assassination of Martin Luther King. I have since been fascinated in how eminent domain, which allows governments to take property for public use, for example when areas are blighted, has been implemented and how some have unsuccessfully strained to implement it, including two attempts by my resident state of Maryland. In 2014, the state threatened to utilize the doctrine of eminent domain to keep the tv-series "House of Cards" filming in the state. The Maryland Assembly killed legislation that would have used the doctrine for this purpose. (The show still films in Baltimore due to generous tax breaks.) Thirty years earlier, the state tried to use eminent domain to keep the Baltimore Colts football team in the city. The team simply moved to Indianapolis in the dead of night.

The story of the Supreme Court case Kelo v. City of New London , 545 U.S. 469 (2005) was told in the 2009 book by Jeff Benedict titled Little Pink House and now in the movie written and directed by Courtney Balaker. They both describe how the pharmaceutical company Pfizer wanted to expand its medical research operations in New London, Connecticut, and, to facilitate the expansion, the city of New London handed over its power of eminent domain to the New London Development Corporation (NLDC). The NLDC then took over the property of Susette Kelo and her neighbors.

The home owners went to court, citing the Takings Clause of the Fifth Amendment of the Constitution, which states, "nor shall private property be taken for public use without compensation." They argued that taking property from individuals for the benefit of another individual or corporation was not an appropriate public use.

The Connecticut Supreme Court and the U.S. Supreme Court, both heavily divided, ruled in favor of the City of New London, equating public purpose with public use. Government policy only has to bear a rational relation to a legitimate government purpose such as job creation, Supreme Court Justice Anthony Kennedy wrote in a concurring opinion. In dissent, Justice Sandra Day O'Connor called the majority's ruling a "reverse Robin Hood," taking from the poor to benefit the rich.

The home owners lost, but public reaction against the ruling was so strong that many states changed their laws so that their governments can't exercise eminent domain for economic development except in order to remove blight. The dispossessed home owners received additional compensation and an apology from the city. Some, including Kelo, moved away anyway, In 2006, President Bush issued an executive order that the federal government can't use eminent domain to advance the economic interests of private parties. Pfizer decided not to expand in New London, and the land at issue remains under-developed.

It's an amazing story that potentially affects all who own real proprty. To one who has covered a Supreme Court argument, the movie does a credible job of making its depiction accurate and compelling. Catherine Keener plays Kelo, and, as always, she is so convincing it doesn't seem like acting. Someone told me that when the movie shows photos of the real-life people, it is jarring because all the actors seemed so real.

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How Films Adapted from Fact Are Developed

by John Aquino on 05/27/18

The death of Richard N. Goodwin on May 20, 2018 calls to mind his many accomplishments. But, not surprisingly given my interests, I remember him most because of how a portion of his career served as the basis of a major motion picture.

Goodwin was a Harvard law graduate, an attorney, counsel for the House Committee on Interstate and Foreign Commerce in investigating the television quiz show scandals of the 1950s, speechwriter and advisor for Presidents Kennedy and Johnson, a university professor, a journalist, playwright, and author. He is credited with having suggested the famous White House dinner of Nobel Prize winners to Mrs. Kennedy, which is described in the recently published Dinner in Camelot by Joseph A. Esposito, and with coining ther term "Great Society" to describe Johnson's domestic programs. He described his work on the 1959 House quiz show scandals in his 1988 book Remembering America: A Voice from the Sixties. His account is anecdotal, with a special focus on the friendship he formed with Charles Van Doren, who ultimately testified before the committee that he had been given the answers in advance for his appearances on the tv quiz show "21."

In 1994, Buena Vista Pictures produced Quiz Show, which was based on Goodwin's book, directed by Robert Redford, and written by Paul Attanasio. Actor Redford had won the Academy Award for directing in 1980 for Ordinary People. It was Attanasio's first screenplay, and he went on to create the television series Homicide: Life on the Street and Bull. I remember how in the mid-1980s he was the film critic for the Washington Post, my hometown newspaper. His shift to screenwriting wasn't a big surprise to me because in several of his reviews he took great pains to describe how he would have written the screenplay in the movie he was panning. Redford and Attanasio portrayed Goodwin as the lead investigator who obtained the answers about the quiz show scandals.

The problem was that most of the answers had been discovered by other people. The journalist Jack O'Brien wrote a series of articles about the scandal in 1958, and Manhattan Assistant District Attorney Joseph Stone investigated and convened two grand juries that prompted the House hearings. Stone described his investigation in a book he wrote with Tim Yohn, Prime Times and Misdemeanors: Investigating the 1950s TV Scandal--a DA's Account, which was published in 1992, two years after Goodwin's book and two years before the movie. It wasn't that Goodwin ignored Stone in his own book. He mentions him and describes meetings with him. But his account isn't presented as a documentary history of the scandals' investigation but, as his book''s title suggests, an account of what he experienced personally. Stone's book, whose title is a pun on the phrase "high crimes and misdemeanors" from the section of the U.S. Constitution on presidential impeachment, was such a history.

Stone's book was available for the filmmakers' use. But Redford's film from Attanasio's screenplay has Goodwin discover what O'Brien and Stone found out, something that Stone himself criticized after the movie was released. Rather than protraying a series of investigations, a single investigation and a lead investigator works better dramatically. Goodwin is the hero of the movie and provides the film's point of view. His friendship with Van Doren and the efforts to get him to testify are the film's focus.

If film audiences don't learn of the efforts of O'Brien and Stone, that's not the filmmakers' problem.Their only job is to tell a good, dramatic story. That's what most filmmakers say. If the film is accurate but dull, people won't pay to see it. And this position conflicts with that abstract thing called truth, even though the film is described as being based on a true story, and sometimes with the emotions of friends and family members of those portrayed, misportrayed, or ignored. The conflict appears to be constant.

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