Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 1 of 99
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF MASSACHUSETTS
`
`MODERNATX, INC. and MODERNA US, INC.,
`
`
`Plaintiffs,
`
`
`
`v.
`
`
`PFIZER INC., BIONTECH SE, BIONTECH
`MANUFACTURING GMBH, and BIONTECH
`US INC.,
`
`
`Defendants.
`
`
`
`
`
`
`
`
`
`
`C.A. No. 22-11378-RGS
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`JURY TRIAL DEMANDED
`
`DECLARATION OF DR. DAVID D. HO IN SUPPORT OF PLAINTIFFS MODERNATX,
`INC. AND MODERNA US, INC.’S OPENING CLAIM CONSTRUCTION BRIEF
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`

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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 2 of 99
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`Table of Contents
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`I.
`
`II.
`
`III.
`
`IV.
`
`Introduction and Qualifications .......................................................................................... 1
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`Materials Considered .......................................................................................................... 3
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`Person of Ordinary Skill in the Art ..................................................................................... 3
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`Technology Background ..................................................................................................... 4
`
`A.
`
`B.
`
`Traditional Vaccines ............................................................................................... 4
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`mRNA Vaccines ..................................................................................................... 6
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`1.
`
`2.
`
`3.
`
`4.
`
`mRNA ......................................................................................................... 6
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`Advantages of mRNA Vaccines ............................................................... 10
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`Challenges for mRNA Vaccines: Innate Immune Response ................... 12
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`Betacoronavirus Vaccines ......................................................................... 14
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`V.
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`Claim Construction ........................................................................................................... 16
`
`A.
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`’574 Patent ............................................................................................................ 16
`
`1.
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`“mRNA” ................................................................................................... 16
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`B.
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`’600 and ’127 Patents............................................................................................ 20
`
`1.
`
`2.
`
`3.
`
`“betacoronavirus” ..................................................................................... 20
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`“S protein” ................................................................................................ 25
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`“open reading frame” ................................................................................ 31
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`

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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 3 of 99
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`I.
`
`Introduction and Qualifications
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`1.
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`I have been retained by ModernaTX, Inc. and Moderna US, Inc. (collectively
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`“Moderna”) as an expert consultant in this litigation, and I offer this declaration to provide the
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`Court with an overview of the technology described in U.S. Patent Nos. 10,898,574 (“the ’574
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`patent”), 10,702,600 (“the ’600 patent”), and 10,933,127 (“the ’127 patent”), and my opinion
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`regarding how a person having ordinary skill in the art would understand certain terms in the
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`chart attached as Exhibit A.
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`2.
`
`I have nearly forty-five years of professional experience as a physician scientist,
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`meaning that I have practiced as a clinical physician while also performing research studies in
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`infectious disease, with a particular focus on clinical virology, pathogenesis, prevention of viral
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`transmission, antiviral therapy, and vaccine development. A copy of my curriculum vitae is
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`attached as Exhibit B.
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`3.
`
`I am currently a Professor of Microbiology and Immunology and the Clyde ’56
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`and Helen Wu Professor of Medicine at Columbia University Irving Medical Center. I have
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`served as the Founding Scientific Director and CEO of the Aaron Diamond AIDS Research
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`Center since 1989.
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`4.
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`Before that time, I held faculty positions at UCLA School of Medicine,
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`Massachusetts General Hospital, and Harvard Medical School. I attended the Massachusetts
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`Institute of Technology (“MIT”) and the California Institute of Technology (“CalTech”) for
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`undergraduate studies and earned my Bachelor of Science degree in Biology and Physics from
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`CalTech in 1974. I earned my Medical Degree from Harvard Medical School in 1978. I
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`completed my residency at the UCLA School of Medicine in 1982 and a fellowship in infectious
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`diseases at Massachusetts General Hospital in 1985.
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`1
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`5.
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`I am a member of the National Academy of Medicine and the American Academy
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`of Arts & Sciences, and a fellow of the American Association for the Advancement of Science. I
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`have concurrently served on the boards of both MIT and CalTech as well as on the Board of
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`Overseers at Harvard, and I continue to serve on the CalTech board today.
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`6.
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`I have been a physician scientist since becoming a physician in 1978. I have
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`directed a research group that studies how viruses affect patients and I have also treated patients
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`suffering from viral illnesses, including HIV.
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`7.
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`In the mid-1990s, I co-authored a series of studies that elucidated the dynamics of
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`HIV replication in the human body. This knowledge contributed to the clinical community’s focus
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`on treating HIV at the earliest stage of infection. Our research also demonstrated for the first time
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`that combination antiviral therapy can provide durable antiviral control. Combination antiviral
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`therapy has been and continues to be widely used. The introduction of combination antiviral therapy
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`is considered to have been the turning point in HIV treatment when an AIDS diagnosis changed from
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`a death sentence to a manageable condition.
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`8.
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`My research in science and medicine has been recognized in several ways. Several
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`significant honors that I have received are described below. In 1996, I was named the “Man of the
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`Year” by Time Magazine. In 2001, I received the Presidential Citizen Medal from President Bill
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`Clinton. In 2006, I was inducted into the California Hall of Fame. In 2017, I received the Portrait of
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`a Nation Prize from the National Portrait Gallery at the Smithsonian. I have received 14 honorary
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`doctorates.
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`9.
`
`Prior to the outbreak of the COVID-19 pandemic, I conducted several research
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`studies on the betacoronavirus SARS-CoV, including studying its spike protein and potential
`
`vaccines. Since the outbreak of the COVID-19 pandemic, I have been actively involved in the
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`development and evaluation of vaccines and therapeutics for the prevention and treatment of
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`2
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`

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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 5 of 99
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`COVID-19. I have appeared on national broadcast news media and made regular appearances on
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`MSNBC and CNN to discuss issues relating to COVID-19. My research group’s COVID-19
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`research was also featured on Sixty Minutes on three occasions, including to discuss variants of
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`SARS CoV-2 and potential therapeutic treatments for COVID-19.
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`10. My research group has also published around 60 papers relating to COVID-19,
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`including over a dozen in the New England Journal of Medicine, Nature, and Cell. Many of
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`these papers discuss SARS CoV-2 variants and their impact on antibody responses to mRNA
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`vaccines.
`
`II. Materials Considered
`
`11.
`
`In preparing this declaration, I reviewed the ’574 patent, the ’600 patent, and the
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`’127 patent, and their respective file histories, including the provisional applications to which
`
`these patents claim priority. I considered my own experience in the virology and immunology
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`field, as well as several scientific publications. A list of materials I considered can be found in
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`Exhibit C.
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`III.
`
`Person of Ordinary Skill in the Art
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`12.
`
`I have been asked to develop and offer opinions related to how a person of
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`ordinary skill in the art (a “skilled artisan”) would have understood the ’574 patent, the ’600
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`patent, and the ’127 patent. I understand that the skilled artisan is a hypothetical person and can
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`possess the skills and experience of multiple individuals working together as a team. I have been
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`informed that factors that may be considered in determining the level of ordinary skill in the art
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`may include (1) the educational level of the inventors; (2) the types of problems encountered in
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`the art; (3) prior art solutions to those problems; (4) the rapidity with which innovations are
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`made; (5) the sophistication of the technology; and (6) the educational level of active workers in
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`the field.
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`3
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`13.
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`I understand that the claims should be interpreted from the perspective of a skilled
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`artisan as of the priority date of the invention. For the purposes of this analysis, I have assumed
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`that the priority date for the ’574 patent is April 2, 2012, the filing date of the first utility
`
`application that the ’574 patent claims priority to; however, my opinions in this declaration
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`would not change even if the priority date were March 31, 2011, the filing date of the earliest
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`provisional application that the ’574 patent claims priority to. I have assumed that the priority
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`date for the ’600 and ’127 patents is October 21, 2016, the filing date of the first utility
`
`application the ’600 and ’127 patents claim priority to; however, my opinions herein would not
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`change even if the priority date were October 22, 2015, the filing date of the earliest provisional
`
`applications that the ’600 and ’127 patents claim priority to. When I refer to the views of a
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`skilled artisan in this declaration, unless stated otherwise, I am referring to the views of a skilled
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`artisan as of April 2, 2012, for the ’574 patent and October 21, 2016, for the ’600 and ’127
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`patents.
`
`14.
`
`In my opinion, a person of ordinary skill in the art for the ’574, ’600, and ’127
`
`patents would have had an M.D. and/or a Ph.D. in immunology, virology, biochemistry,
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`chemistry, or a related discipline, and three or more years of work experience in such fields, and
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`would have been part of a team including biochemists, chemists, drug delivery scientists, and/or
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`clinicians.
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`15.
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`I have been a skilled artisan since well before April 2, 2012, according to this
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`definition. At that time, I had an M.D. and over 30 years of experience working in immunology
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`and virology.
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`IV.
`
`Technology Background
`
`A.
`
`Traditional Vaccines
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`4
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`16.
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`Vaccines train the body’s immune system to recognize and fight pathogens, such
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`as viruses.1 They work by presenting the body with an “antigen,” which can be a version of the
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`pathogen that has been modified or inactivated, or a part of the pathogen. The antigen triggers a
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`response from the body’s adaptive immune system, which is the part of the body’s immune
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`system that can learn to recognize new pathogens. As part of that immune response, the body
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`learns to make antibodies specific to the antigen. The antibodies bind to the antigen. When
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`presented with the antigen in the context of the live, native pathogen in the future, the adaptive
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`immune system can “remember” how to make those antibodies, which bind to the antigen and
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`mark the pathogen displaying it for destruction by other cells. Because the adaptive immune
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`system has previously been exposed to the antigen, it can respond both more quickly and more
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`strongly than if it had never seen the antigen before. The rapid, strong adaptive immune
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`response results in less severe disease, or even prevention of disease altogether.
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`17.
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`Traditional viral vaccines work by directly introducing viral antigens to the body.
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`There are several different types of traditional viral vaccines. Some vaccines, such as Sabin’s
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`polio vaccine, are live attenuated virus vaccines, which are made by starting with a virus and
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`attenuating it to make it much less virulent. Other vaccines, such as Salk’s polio vaccine, are
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`inactivated virus vaccines, which are made by starting with a live virus and destroying its
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`infectivity (i.e., by killing it). The annually updated influenza vaccine is another example of an
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`inactivated virus vaccine that is typically administered. Protein-based vaccines, such as the
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`Hepatitis B vaccine, include one or more viral proteins—for example, proteins found on the
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`outer surface of a virus—synthesized in the lab, without including an entire virus. Similar to
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`1 A pathogen is a microorganism that can cause infectious disease (e.g., viruses, bacteria, fungi,
`etc.).
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`5
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`protein-based vaccines, virus-like particle vaccines, such as the human papillomavirus (HPV)
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`vaccine, are particles that are made of viral proteins, but do not contain viral genetic material
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`(e.g., viral RNA).
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`B.
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`mRNA Vaccines
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`18.
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`In contrast to conventional vaccines, mRNA vaccines are a new category of
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`vaccines that rely on the body’s cells to create the viral antigens that the adaptive immune system
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`learns to respond to.
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`1.
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`mRNA
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`19. Messenger RNA (“mRNA”) was discovered as a result of pioneering studies in
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`the mid-twentieth century and since that time has been widely studied. In human cells (and cells
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`of other mammals), genetic information is stored in the genome, consisting of deoxyribonucleic
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`acid (“DNA”). That genomic DNA contains the information for proteins produced by the human
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`body. mRNAs are the “messengers” that convey that information from the DNA to the cellular
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`machinery that makes proteins. The “central dogma” of biology explains the classical direction
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`of informational flow in a cell: DNA is transcribed into mRNA, and mRNA is then translated
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`into a polypeptide, or protein.2 Proteins are basic components of cells, tissues, and organs, and
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`play an essential role in nearly all biological functions in the body.
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`2 Polypeptides are polymers of amino acid residues that are joined together by peptide bonds.
`Proteins are made up of one or more polypeptides.
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`6
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`Figure 1: The central dogma of biology, as shown in National Human Genome Research Institute, Genetics
`Glossary, genome.gov (May 16, 2023), https://www.genome.gov/genetics-glossary/Central-Dogma
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`20.
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`Genomic DNA is typically found in the form of a characteristic “double helix”
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`structure consisting of two long complementary strands, where each strand is a polymer made up
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`of monomeric units called deoxyribonucleotides. A deoxyribonucleotide consists of three parts:
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`one or more phosphate groups, a deoxyribose sugar, and a nucleobase. While the phosphate
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`group and the deoxyribose sugar remain the same for each deoxyribonucleotide unit and form the
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`“backbone” of the DNA double helix, there are four different naturally occurring nucleobases:
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`adenine (A), cytosine (C), guanine (G), and thymine (T). Adenine (A) pairs with thymine (T)
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`and cytosine (C) pairs with guanine (G) to form the complementary base pairs of the double
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`stranded DNA helix.
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`7
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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 10 of 99
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`Figure 2: The DNA double helix, as shown in National Human Genome Research Institute, Genetics
`Glossary, genome.gov (May 16, 2023), https://www.genome.gov/genetics-glossary/Double-Helix
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`21.
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`Genetic information is stored in the sequence of the DNA, i.e., the identity and
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`arrangement of the four deoxynucleotides which serve as “letters” of an “alphabet.” The DNA
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`contains the information for all proteins that are naturally produced by the body. DNA is
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`replicated when cells divide so that this information is maintained. During replication, the two
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`strands of the double helix are separated into individual strands and a complementary strand is
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`synthesized for each.
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`22.
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`In the cell, proteins known as RNA polymerases transcribe DNA into mRNA.
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`mRNAs are single-stranded polynucleotides made from monomeric ribonucleotides. Similar to a
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`deoxyribonucleotide, a ribonucleotide consists of three parts: one or more phosphate groups, a
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`ribose sugar (instead of a deoxyribose sugar found in DNA), and a nucleobase, with the
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`phosphate group and ribose sugar forming the “backbone” of mRNA. Three ribonucleotides
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`include the same nucleobases as their counterparts in DNA: adenine (A), guanine (G), and
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`8
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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 11 of 99
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`cytosine (C). The fourth nucleobase in RNA is uracil (U), instead of the thymine (T) found in
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`DNA. A nucleobase attached to a sugar (without the phosphate groups) is known as a
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`nucleoside. The nucleoside incorporating the uracil nucleobase is called uridine. The process is
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`called “transcription” because the polymerases are copying the information embedded in a
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`segment of DNA sequence—made from the deoxyribonucleotides A, G, C, and T—and
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`reproducing it into a corresponding mRNA sequence—made from ribonucleotides A, G, C, and
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`U—like the process of writing the same message in a different alphabet.3 For example, the DNA
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`sequence “ATGCGTTAA,” when transcribed, becomes the RNA sequence “AUGCGUUAA,”
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`using the same bases, but substituting U for T.
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`Figure 3: Chemical structures of the five nucleobases found in DNA and RNA, classified by the type of ring
`structure (purine or pyrimidine).
`
`
`
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`3 There are other types of RNA with different functions from mRNA. For example, transfer
`RNAs serve as adaptor molecules to assist amino acids in joining together in a growing
`polypeptide chain during protein synthesis. Ribosomal RNAs are components of ribosomes,
`which “read” the mRNA sequence during translation. Other RNAs called ribozymes have
`enzymatic activity.
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`9
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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 12 of 99
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`Figure 4: Chemical structure of a nucleotide, showing the difference between ribonucleotides (in RNA) and
`deoxyribonucleotides (in DNA). The sugar is called “pentose” because it contains five carbon atoms.
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`23.
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`The mRNA is not itself replicated. Its function is to guide the translation of the
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`polypeptide that it encodes by proteins known as ribosomes. This process is known as
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`“translation” because the ribosomes are taking a polynucleotide—made from the RNA
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`ribonucleotides A, G, C, and U—and turning it into a polypeptide, like the process of translating
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`a message into another language. In humans, every mRNA typically encodes and is translated to
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`produce a particular polypeptide.
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`2.
`
`Advantages of mRNA Vaccines
`
`24.
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`Advances in molecular biology over the past century led to the in vitro
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`transcription (“IVT”) methods that allow for the artificial synthesis of mRNA outside of living
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`cells—i.e., exogenously. In IVT, a DNA template is combined with appropriate reagents and
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`nucleotides (in the form of a nucleoside with three phosphate groups) to prepare an mRNA that
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`can encode a polypeptide of interest, for example, a therapeutic protein of interest (e.g., a protein
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`that is deficient in patients having a genetic disorder), or a polypeptide that is an antigen, such as
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`a protein that is part of a pathogen (for example, a virus), for use in a vaccine.
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`10
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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 13 of 99
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`25.
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`Unlike traditional vaccines, which deliver the viral antigen directly—e.g., in the
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`form of an attenuated, inactivated, or partial virus—mRNA vaccines deliver mRNA encoding
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`the viral antigen to the body. Once inside cells, the mRNA is translated to produce the encoded
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`antigen. The adaptive immune system then identifies that antigen as foreign and, among other
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`responses, produces antibodies against it. In the future, when challenged with the same or a
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`similar antigen on a live virus, the immune system can use its prior training to recognize the
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`antigen and neutralize the virus, preventing or ameliorating infection and disease.
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`26. mRNA vaccines are an excellent alternative to conventional vaccines, such as
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`live-attenuated virus vaccines, because they produce a robust adaptive immune response but
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`cannot replicate and do not and cannot cause a viral infection. mRNA vaccines have also shown
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`adaptability, as exemplified by the switch from monovalent to bivalent versions of COVID-19
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`mRNA vaccines. Experience with COVID-19 mRNA vaccines also showed that mRNA
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`vaccines could be developed and tested rapidly.
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`27.
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`The COVID-19 mRNA vaccines at issue in this litigation are the first and, to date,
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`only mRNA vaccines licensed/approved in the United States. Notably, scientists have sought to
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`develop other nucleic acid-based platforms to take advantage of the potential to program the
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`body’s cells. Potential DNA-based vaccines include DNA containing the genetic information for
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`the antigen, which cells in the body transcribe into mRNA, which is then translated into a protein
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`(the antigen). Potential viral vector-based vaccines are made by starting with a virus (e.g., an
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`adenovirus), removing portions of the DNA/RNA of the virus to make it replication incompetent,
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`and using it as a vector to package the genetic information for the antigen of another virus.
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`There are currently no licensed or approved DNA or viral vector vaccines for human use in the
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`United States.
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`11
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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 14 of 99
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`3.
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`Challenges for mRNA Vaccines: Innate Immune Response
`
`28.
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`Despite the potential advantages, there were obstacles to creating a working
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`mRNA vaccine.
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`29.
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`For example, in order for exogenously delivered mRNA to have its intended
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`effect, it must reach the body’s cells and be translated into the polypeptide of interest. Initial
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`attempts to deliver mRNA were unsuccessful in large part because the mRNA triggered a strong
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`innate immune response.
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`30.
`
`The immune system is made up of two parts: the innate immune system and the
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`adaptive immune system. These two systems take on different tasks and collaborate with each
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`other.
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`31.
`
`The innate immune system is the body’s first line of defense against pathogens
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`entering the body. The innate immune system can identify foreign pathogens and substances that
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`fit a fixed set of patterns distinguishing them from the body’s own cells. The innate immune
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`response is a general defense mechanism; it responds in the same way to a variety of pathogens
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`and foreign substances (to the extent they are recognized), and it is triggered very rapidly.
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`Although the innate immune system has some receptors outside of cells, most of them are inside
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`cells, which means that the foreign substance must enter a cell before it is recognized. Upon
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`recognizing a foreign pathogen, the cell responds by, among other things, inducing expression of
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`certain proteins called cytokines, particularly interferons, and releasing them from the cell.
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`Specialized immune cells, including macrophages and natural killer cells, are then recruited to
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`kill the cells that have recognized the foreign pathogen. The innate immune response does not
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`provide immunological memory—upon repeated exposure to the same pathogen, the strength of
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`the innate immunity is unchanged.
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`12
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`32.
`
`By contrast, the adaptive immune system, as discussed above (¶ 16), can learn to
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`recognize specific pathogens, and provide a stronger response upon repeated exposure. The
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`adaptive immune system takes days/weeks after the initial entry of a foreign pathogen to be
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`activated and successfully create antibodies to flag the pathogen so that specialized cells can then
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`destroy the pathogen. In this way, the adaptive immune system is responsible for immunologic
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`memory, that is, the effective and rapid immune response upon subsequent exposure to the same
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`or similar pathogens. The adaptive immune response forms the basis for vaccination.
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`33.
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`The innate immune response and the adaptive immune response also work
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`together. When confronted with a pathogen, the innate immune response activates and prepares
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`the adaptive immune system to respond appropriately.
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`34. When an exogenous mRNA is delivered into cells, the innate immune response
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`normally is activated immediately. The cells identify the exogenous mRNA as “foreign” and
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`induce the expression and release of cytokines as described above, leading to cell death. Such an
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`innate immune response is undesired in the context of developing an mRNA vaccine (or any
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`other mRNA therapeutic) because it reduces the expression of the polypeptide of interest
`
`encoded by the mRNA.
`
`35.
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`Accordingly, it is necessary to limit the innate immune response against the
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`mRNA itself so that (1) the mRNA can be expressed by the cells into the polypeptide antigen it
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`encodes and (2) the expressed antigen can trigger an adaptive immune response against the
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`polypeptide antigen. An mRNA vaccine that triggers too strong of an innate immune response
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`would not be effective as a vaccine because it would not have a chance to express the antigen
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`and train the adaptive immune system.
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`13
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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 16 of 99
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`36.
`
`The ’574 patent teaches that the introduction of certain chemical modifications
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`into mRNA can reduce the innate immune response as compared to a corresponding unmodified
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`mRNA. For example, the uridines in the mRNA sequence may be replaced with 1-
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`methylpseudouridine (sometimes abbreviated as “1mΨ”). Exogenous mRNA sequences
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`modified to include 1-methylpseudouridine trigger a significantly reduced innate immune
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`response. See, e.g., ’574 patent at 15:50-16:9; 84:63-67; Table 19. Because of the reduction of
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`innate immune response, these modified mRNAs can enhance intracellular retention of nucleic
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`acids and viability of contacted cells; they also increase the efficiency of the production of their
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`encoded polypeptides of interest. Id. at 5:5-9; 5:18-21.
`
`Figure 5: Uridine and 1-methylpseudouridine
`
`4.
`
`Betacoronavirus Vaccines
`
`
`
`37.
`
`Betacoronaviruses are a genus of viruses that include OC43, HKU1, MERS-CoV,
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`SARS-CoV, and the more recently discovered SARS-CoV-2. Betacoronaviruses have long been
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`of clinical importance given the continued emergence of new betacoronaviruses that infect
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`humans. All betacoronaviruses have many copies of a protein known as the “spike protein,” or
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`“S protein,” which stick out from the surface of the viral particle, forming the appearance of a
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`“corona,” or crown, which gives coronaviruses their name. See Figure 6 below. As part of a live
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`betacoronavirus, the spike protein has the function of mediating viral entry into the host cell—in
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`14
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`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 17 of 99
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`other words, it provides the mechanism by which the viral membrane fuses with the host cell
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`membrane—causing infection.
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`
`
`Figure 6: Figure 3e from Virus Taxonomy: Classification and Nomenclature of Viruses, Ninth Report of the
`International Committee on Taxonomy of Viruses, at 3 (2012). S = spike protein, HE = hemagglutinin-
`esterase protein, M = membrane glycoprotein, N = nucleocapsid protein, E = envelope protein.
`
`38.
`
`The’600 and ’127 patents teach mRNA-LNP4 vaccines against betacoronaviruses
`
`that employ mRNA encoding for a betacoronavirus spike protein. As part of the vaccines
`
`disclosed in the patents, however, the spike protein encoded by the spike mRNA does not
`
`mediate viral entry into the host cell; instead, it acts as an antigen to induce an immune response
`
`against the spike protein without the slightest risk of causing viral infection. The vaccine trains
`
`the immune system to neutralize a future infection by a betacoronavirus.
`
`39.
`
`The SARS-CoV-2 vaccines Spikevax® and Comirnaty® are mRNA-LNP vaccines
`
`that contain 1-methylpseudouridine-modified mRNA encoding a spike protein. These mRNA-
`
`LNP vaccines were the first mRNA vaccines to receive approval from US and European health
`
`regulatory authorities.
`
`
`4 The patents disclose mRNA formulated in a lipid nanoparticle (“LNP”) to protect the mRNA
`from degradation and clearance on its journey to cells.
`
`15
`
`

`

`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 18 of 99
`
`V.
`
`Claim Construction
`
`40.
`
`I understand that patent claims are interpreted from the perspective of a person of
`
`ordinary skill in the art at the time of the patent’s relevant priority date. I understand that claim
`
`terms generally are afforded their plain and ordinary meaning to a person of ordinary skill in the
`
`art, when read in the context of the claims, the patent specification, and the prosecution history.
`
`Based on my experience and the materials I reviewed, I set forth my opinions about how a
`
`person of ordinary skill in the art would have understood the following disputed claim terms.
`
`A.
`
`’574 Patent5
`
`1.
`
`“mRNA”
`
`Moderna’s Proposed Construction
`
`Defendants’ Proposed Construction
`
`Plain and ordinary meaning; “messenger
`RNA, i.e., a ribonucleic acid (RNA)
`polynucleotide that encodes a polypeptide of
`interest and can be translated to produce the
`encoded polypeptide of interest.”
`
`
`
`“a messenger ribonucleic acid (RNA) that acts
`as a template for protein synthesis through the
`process of translation”
`
`41.
`
`I reviewed the claim term “mRNA” in the context of the claims and specification
`
`of the ’574 patent, as well as the parties’ proposed constructions. I agree with Moderna’s
`
`proposed construction.
`
`42.
`
`The term “mRNA” appears in claims 1 and 2 of the ’574 patent. These claims are
`
`reproduced below:
`
`1. A method of producing a polypeptide of interest in a cell in a
`subject in need thereof, comprising administering to the subject a
`pharmaceutical composition comprising a modified messenger
`RNA (mmRNA) such that the mmRNA is introduced into the cell,
`wherein the mmRNA comprises a translatable region encoding the
`polypeptide of interest and comprises the modified nucleoside 1-
`methyl-pseudouridine, and wherein the pharmaceutical
`composition comprises an effective amount of the mmRNA
`
`
`5 I understand from counsel that the patent expressly defines the term “unmodified” and therefore
`I have not been asked to offer an opinion on the construction of “unmodified mRNA.”
`
`16
`
`

`

`Case 1:22-cv-11378-RGS Document 75 Filed 05/26/23 Page 19 of 99
`
`providing for increased polypeptide production and substantially
`reduced innate immune response in the cell, as compared to a
`composition comprising a corresponding unmodified mRNA.
`
`2. A pharmaceutical composition comprising:
`
`a plurality of lipid nanoparticles comprising a cationic lipid, a
`sterol, and a PEG-lipid,
`
`wherein the lipid nanoparticles comprise an mRNA encoding a
`polypeptide, wherein the mRNA comprises one or more uridines,
`one or more cytidines, one or more adenosines, and one or more
`guanosines and wherein substantially all uridines are modified
`uridines.
`
`43.
`
`Claim 1 is directed to a method “of producing a polypeptide of interest.” The
`
`claim refers to both “modified messenger RNA (mmRNA)” and “unmodified mRNA.” The
`
`mmRNA “comprises a translatable region encoding the polypeptide of interest.” The claim
`
`requires that the mmRNA “provides for increased polypeptide production.” Because the claim is
`
`focused on polypeptide production, a skilled artisan would have understood that the mRNA
`
`encodes a polypeptide of interest so that it can be translated to produce that polypeptide of
`
`interest.
`
`44.
`
`I also reviewed the specification of the ’574 patent, which, in my opinion, would
`
`have confirmed a skilled artisan’s understanding based on claim 1.
`
`45.
`
`The ’574 patent specification repeatedly emphasizes that mRNA encodes and
`
`produces a “polypeptide of interest.” Several examples where the ’574 patent’s specification
`
`refers to mRNA encoding and producing a polypeptide of interest are below:
`
`•
`
`•
`
`’574 patent at 27:62-28:1 (“a cell into which the ribonucleic acid enters and encodes the
`polypeptide of interest and the composition is characterized in that a unit quantity of
`composition has been determined to produce the polypeptide of interest”);
`
`’574 patent at 28:7-8 (“one or mor