PROTIVA - EXHIBIT 2023
`Moderna Therapeutics, Inc. v. Protiva Biotherapeautics, Inc. - IPR2018-00739
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`lilm IN FOCUS
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`By 2010. large pharmaceutical compa-
`nies were also losing their appetite for RNAi.
`severing collaborations and ending inter-
`nal research programmes. “By and large. big
`pharma left RNAi for dead," says Fambrough.
`Safety concerns dealt the field another blow
`in 2016, when Alnylam abandoned one ofits
`leading RNAi programmes after finding a pos—
`sible link to patient deaths in a clinical trial (see
`‘Ups and downs’).
`But gradually. some RNAi companies began
`to iron out the kinks in their delivery systems.
`Alnylam experimented with a number ot'deliv-
`ery routes and target organs. encasing some
`ofits RNA molecules in fatty nanoparticles
`or chemically modifying the RNAs to help
`them survive the perilous journey through
`the bloodstream.
`
`UPS AND DOWNS
`The bloteeh firm Alnyiarn raced several setbacks
`before winning US government approval for its
`first RNAsmterlerenee drug.
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`is testing RNAi therapies that target proteins in o
`the kidneys and the eye. Alnylam is develop-
`ing ways to target the brain and spinal cord.
`and Arrowhead Pharmaceuticals of Pasadena.
`California. is working on an inhalable RNAi
`treatment for cystic fibrosis.
`“I‘ve never been more optimistic about the
`future of RNAl.” says Fambrough. “All ofthose
`tear-your-hair-out days were worth it to get to
`today?
`Advances in RNA delivery might also benefit
`researchers who are developing gene-editing
`therapies based on the popular technique
`CRISPR—Ca59.'1hat system usesa DNA- cutting
`protein called Cas9. which is guided to the
`desired site in the genome by an RNA molecule.
`Like RNAi before it. CRISPR—CasS'I has
`become a common tool in genetics lahtira-i
`tories. But it might still face a difficult and
`lengthy path to the clinic. Much like ordinary
`drugs, RNAi therapies will break down over
`time; a gene edit. however, is intended to be
`permanent. which amplifies safetyconcerns.
`“I hope they can do it more quickly than
`we did it, but i would not expect it to be so
`smooth." says Fambrough. “i wish them the
`best of luck.” I
`
`RNAs protected in this way and injected
`into the bloodstream tended to accumulate in
`the kidneys and liver. This led the company
`N. Engi. I. Med. 379, 11—21; 2018). Walking
`to look at transthyretin. which is produced
`speed declined in the placebo group.
`In the future. Alnylani and others will be
`mainly in the liver. In a clinical trial in 225 peo-
`ple with hereditary transthyretin amyloidosis
`able to move beyond the liver. says company
`co-founder Thomas Tuschl. a biochemist
`who showed signs of nerve damage, average
`at Rockefeller University in New York City.
`walking speed significantly improved in those
`Quark Pharmaceuticals of Fremont. California
`who received the treatment (D. Adams at at.
`
`
`Outrage over changes to
`EPA chemical assessments
`
`Critics any US environment agency ’3 revisionsfavour industry over academic research.
`
`it JEFF TOLLEFSDN
`
`he US Environmental Protection
`
`Agency is making major changes to
`the way in which it evaluates chemicals
`for environmental and public-health effects.
`The latest push includes changes to chemical—
`safety guidelines that place greater weight on
`industry-Sponsored research. among other
`things. and is a part of efforts by US President
`Donald Trump's administration to reshape
`how the agency uses science to make decisions.
`The Environmental Protection Agency
`(EPA) issued its chemical-assessment guidance
`in May. and is soliciting public comments until
`16 August. The guidance contains changes
`dictating the kind of data that studies must
`include in order to be considered in the EPA’s
`
`decision-making process. Researchers and
`environmental and publiohealth advocates
`say that the guidelines provide a non-peer-
`
`required by law to do these evaluations, but the
`guidance defines how officials conduct them.
`At stake are tens of thousands of chemicals
`
`destined for public use and governed by the
`1976 Toxic Substances Control Act (TSCA).
`The guidance dovetails with a rule proposed
`in April by then—EPA administrator Scott
`Pruitt. which. if finalized and implemented.
`would reduce the role of published scientific
`studies in decision—making across the agency.
`The changes also coincide with attacks on the
`EPA’s ccire chemical-assessrnent programme,
`known as the Integrated Risk Information
`System (IRIS). by industry and Republican
`politicians over the past year.
`In a statement to Nature. the EPA says the
`changes are meant to provide clear criteria to
`help determine the quality ofthe research used
`to evaluate chemicals — and that the guid-
`ance is a work in progress that can be revised
`in response to new information. But Scientists
`
`Jennifer Sass, a senior scientist at the Natural
`Resources Defense Council, an advocacy
`group based in New York City. suspects that
`the goals are to promote science from industry
`and change the calculations that the EPA uses
`to develop regulations and estimate safe expo-
`sure limits for chemicals.
`
`MEETINE TI-IE flEflIIIIlEMEII'I'S
`
`The guidelines introduce many data report—
`ing requirements — including statistical
`analyses that measure whether a study cor-
`rectly identifies the presence of an effect
`— that are standard for industry-funded
`resaarch. But because such criteria vary
`among peer-reviewed journals. many aca-
`demic studies would be disqualified, says
`Tracey Woodruff, who led the development
`ofa chemical-evaluation process at the Uni-
`versity of California, San Francisco. “Only
`industry studies will survive."
`
`