UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Lassen Therapeutics 1, Inc.
`
`Petitioner
`
`v.
`
`Singapore Health Services PTE LTD., and
`
`National University of Singapore
`
`Patent Owner
`
`CASE: Unassigned
`
`Patent No. 10,106,603
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`DECLARATION STEPHEN LEDBETTER, PH.D.
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`IN SUPPORT OF
`
`PETITION FOR POST GRANT REVIEW
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`
`
`
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`
`
`
`
`
`1
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`Lassen - Exhibit 1004, p. 1
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Lassen Therapeutics 1, Inc.
`
`Petitioner
`
`v.
`
`Singapore Health Services PTE LTD., and
`
`National University of Singapore
`
`Patent Owner
`
`CASE: Unassigned
`
`Patent No. 10,106,603
`
`DECLARATION STEPHEN LEDBETTER, PH.D.
`
`IN SUPPORT OF
`
`PETITION FOR POST GRANT REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
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`Lassen - Exhibit 1004, p. 1
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`
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`I, Steven Ledbetter, declare as follows:
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`I.
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`BACKGROUND AND QUALIFICATIONS
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`1.
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`I, Steven Ledbetter, Ph.D., have been retained by Drinker Biddle &
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`Reath, LLP (“Counsel”) on behalf of Lassen Therapeutics 1, Inc. (“Lassen”) as an
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`independent expert in the field of fibrosis.
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`2.
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`I am currently a consultant at BioRepair Consulting, LLC, which I
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`founded in 2015. As a consultant, I provide my scientific expertise to the
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`biotechnology industry.
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`3.
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`I obtained my Bachelor of Science degree in Biology from the Alma
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`College, Alma, Michigan in 1974. I obtained my Doctoral degree in Cell Biology
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`and Anatomy from the University of Michigan, Department of Anatomy and
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`Cellular Biology, in 1980 with my dissertation on “Deposition of Extracellular
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`Matrix by Cultured Corneal Endothelial Cells.” I performed post-doctoral training
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`in ophthalmology research at the Medical College of Wisconsin and in the
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`Laboratory of Developmental Biology and Anomalies at the National Institutes of
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`Health (“NIH”) in Bethesda Maryland. At the NIH, my research focused on the
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`identification, functional characterization and cloning of the basement membrane
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`heparan sulfate proteoglycan (Perlecan).
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`4.
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`From 1984 to 1996, I was a Research Scientist and then Senior
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`Research Scientist at the Upjohn Company, Kalamazoo, Michigan. I continued my
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`2
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`Lassen - Exhibit 1004, p. 2
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`
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`research on basement membrane structure and function at Upjohn where I also
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`established a laboratory focused on diabetic nephropathy. During my 12 years at
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`Upjohn, my research efforts expanded to include studies in epithelial and hair
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`follicle regeneration, and the role of matrix metalloproteinases as regulators of
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`tumor angiogenesis.
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`5.
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`In 1996, I joined Genzyme Corporation as a Principal Scientist and in
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`2000, I became the Director of Genzyme’s Cell Biology department and a Project
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`leader for its TGFβ (transforming growth factor β) antagonist program. My
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`responsibilities in those roles included establishing a research laboratory focused
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`on the role of TGFβ in chronic tissue injury and fibrosis. In collaboration with
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`Cambridge Antibody Technology (Cambridge, UK), I and my team identified and
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`characterized a novel, pan-neutralizing, human antibody against TGFβ. This
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`antibody was studied in three phase 1 clinical trials for idiopathic pulmonary
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`fibrosis, metastatic melanoma and focal segmental glomerulosclerosis (FSGS).
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`Additional investigator studies with this antibody were also conducted in
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`scleroderma, pulmonary radiation fibrosis, osteogenesis imperfecta, and metastatic
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`breast cancer. A phase 2 study in FSGS was completed in 2015.
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`6.
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`At Genzyme, I held various positions of increasing responsibilities. I
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`was Renal Portfolio Director and Senior Director of Cell Biology in 2002, became
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`Vice-President for the Renal and Fibrotic Diseases Research in 2003, and then
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`3
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`Lassen - Exhibit 1004, p. 3
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`Group Vice-President responsible for renal, cardiovascular and bone and joint
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`diseases in 2008. The acquisition of Genzyme by Sanofi in 2010 expanded my
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`responsibilities to further include allied research efforts based in Paris and the
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`newly created Tissue Injury and Fibrosis portfolio, containing 135 research
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`personnel, and was closely aligned with a dedicated clinical development team. I
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`retired from Genzyme in April 2015.
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`7.
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`In 2016, I co-founded Omdana Therapeutics and served as Chief
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`Development Officer until April 2017.
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`8.
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`I have been involved in active fibrosis research beginning in 1978 as
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`part of my doctoral dissertation and continuing to the present time via my
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`consulting activities. My experience, as indicated in my attached curriculum vitae,
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`includes the isolation, characterization of connective tissue proteins in the setting
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`of normal tissue homeostasis and in pathologic fibrosis. Beginning in 1984, my
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`activities were focused entirely on the functional and physiologic impact of
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`maladaptive tissue remodeling (fibrosis) and exploration of potential therapeutic
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`approaches for the treatment of fibrotic diseases with principal focus in heart, lung,
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`kidney, liver, skin and bone diseases.
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`9.
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`I have published or co-authored more than 80 journal publications,
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`conference proceedings, technical reports, and technical presentations, and have
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`been named as an inventor on numerous U.S. patents and patent applications. A
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`4
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`Lassen - Exhibit 1004, p. 4
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`complete list of my publications is also contained in my curriculum vitae attached
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`as Appendix A.
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`10.
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`I have actively participated as a speaker at multiple national and
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`international meetings. Recent examples include co-organizer of the 2014
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`Keystone Symposium on Fibrosis, 2014 International Society of Nephrology
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`meeting on novel renal therapeutics (co-organizer and speaker) and scientific
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`advisor to the EU program on systemic kidney diseases (SysKid).
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`11. My professional qualifications are described in further detail in my
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`curriculum vitae, which is attached as Appendix A.
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`12.
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`I am being compensated at my usual rate of $300 per hour for work on
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`this case. My compensation does not depend in any way on my opinions, my
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`performance, or the outcome of the case. I have no current or past financial ties
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`with Drinker, Biddle, and Reath LLP outside of my engagement in this proceeding.
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`13.
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`I am currently a paid consultant to Lassen separately from providing
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`this Declaration. I own no Lassen stocks.
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`14.
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`I have not testified in a U.S. court or in any U.S. administrative
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`proceeding in the past ten years.
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`15.
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`I have reviewed United States Patent No. 10,106,603 (“the ’603
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`patent”) to Cook et al and its file history.
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`
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`5
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`Lassen - Exhibit 1004, p. 5
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`
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`II.
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`INFORMATION PROVIDED TO ME
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`16.
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`I understand from Counsel that the meaning of the claims of a patent
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`are to be construed in accordance with the federal court claim construction
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`standard that is used to construe a claim in a civil action under 35 U.S.C. § 282(b).
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`I have been informed by Counsel that the Patent Trial and Appeal Board (“PTAB”)
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`applies the same construction standard used in district courts, where the claims are
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`given their ordinary meaning as understood by one skilled in the art at the time of
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`the invention, informed by the claim language itself, the specification, and the
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`prosecution history. I also understand that “extrinsic evidence” – i.e., evidence
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`other than the patent and prosecution history – can be relevant in determining how
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`a skilled artisan would understand terms of art used in the claims. I have been
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`informed, however, that extrinsic evidence may not be used to contradict the
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`meaning of the claims as described in the intrinsic evidence – i.e., evidence in the
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`claim language itself, the specification, and the prosecution history. In comparing
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`the claims of the ’603 patent to the known prior art, I have carefully considered the
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`’603 patent and the ’603 patent’s file history from the perspective of a person of
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`ordinary skill in the art using my experience and knowledge in the relevant field.
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`17.
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`I am informed that the application for the ’603 patent was filed on
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`May 24, 2018, but that it claims to be related to an application dated December 16,
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`6
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`Lassen - Exhibit 1004, p. 6
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`2016. For purposes of this declaration only, I have assumed a priority date of
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`December 16, 2016, in determining whether a reference constitutes prior art.
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`18.
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`19.
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`I have been informed that the ’603 patent has not expired.
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`In comparing the claims of the ’603 patent to the known prior art, I
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`have carefully considered the ’603 patent and the ’603 patent’s file history from
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`the perspective of a person of ordinary skill in the art using my experience and
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`knowledge in the relevant field.
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`20.
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`I understand from Counsel that a patent claim is unpatentable if its
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`subject matter is anticipated and obvious over one reference. I further understand
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`from Counsel that anticipation of a claim requires that every element of a claim be
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`disclosed expressly or inherently in a single prior art referenced, as claimed. I
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`understand that a document can inherently teach a claim as follows. I understand
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`that for example, if a method was used to treat a condition and that condition
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`arising from an underlying mechanism taught in the publication wherein the
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`publication teaches a method of treating a condition mediated by the underlying
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`mechanism, but the publication fails to describe the condition, then the publication
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`would inherently teach the undescribed condition, because by the publication by
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`treating such a disorder would in effect treat the condition.
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`21.
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`I further understand from Counsel that the obviousness of a patent
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`claim requires that the claim be obvious from the perspective of a person of
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`7
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`Lassen - Exhibit 1004, p. 7
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`
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`ordinary skill in the art at the time the ’603 patent was filed. I further understand
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`that a patent claim can be found unpatentable as obvious where the differences
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`between the subject matter sought to be patented and the prior art are such that the
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`subject matter as a whole would have been obvious to a person of ordinary skill in
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`the art at the time of the invention. I understand that an obviousness analysis
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`requires a consideration of (1) the scope and content of the prior art, (2) the
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`differences between the claimed invention and the prior art, and (3) the level of
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`ordinary skill in the pertinent field.
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`22.
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`I further understand that certain factors, that I understand may be
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`referred to as secondary considerations, may support or rebut the obviousness of a
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`patent claim. I understand that such secondary considerations may include, among
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`other things, the commercial success of the patented invention, any skepticism of
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`those having ordinary skill in the art at the time of invention, unexpected results
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`obtained during the process of claiming the invention, any long-felt but unsolved
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`need in the art that was satisfied by the alleged invention, the failure of others to
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`make the alleged invention, praise of the alleged invention by those having
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`ordinary skill in the art, and copying of the alleged invention by others in the field.
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`I understand that there must be a nexus—a connection—between any such
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`secondary considerations and the alleged invention. I also understand that
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`8
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`Lassen - Exhibit 1004, p. 8
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`
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`contemporaneous and independent invention by others is a secondary consideration
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`tending to show obviousness.
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`23.
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`I further understand from Counsel that a claim is obvious if it unites
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`old elements with no change to their respective functions, or alters prior art by
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`mere substitution of one element for another known in the field and that
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`combination yields predictable results. While it may be helpful to identify a reason
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`for this combination, common sense should guide and no rigid requirement a
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`teaching, suggestion or motivation to combine is required. When a product is
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`available, design incentives and other market forces can prompt variations of it,
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`either in the same field or different one. If the POSITA can implement the claimed
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`invention from the prior art with no or limited modification such that the result is
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`predictable, then obviousness likely bars its patentability. I understand that a
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`patent claim may be obvious if common sense directs a POSITA to combine
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`multiple prior art references or add missing features to reproduce the alleged
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`invention as recited in the claims, and that this can be done with a reasonable
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`expectation of scientific predictability. I understand that a POSITA is a person of
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`ordinary creativity, not an automaton.
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`24.
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`I have been asked to consider the following:
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`a) U.S. Application Publication No. 2014/0219919 to Edwards et al.
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`(“Edwards”) (Ex. 1008);
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`9
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`Lassen - Exhibit 1004, p. 9
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`
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`b) U.S. Application Publication No. 2008/0300147 to Chegini et al.
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`(“Chegini”) (Ex. 1065);
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`c) T. A. Wynn, “Fibrotic Disease and the T(H)1/T(H)2 Paradigm,” 4
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`Nat. Rev. Immunol. 583 (2004); “Wynn” (Ex. 1010);
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`d) Kristin Reilly, “Cardiac Fibrosis: New Treatments in
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`Cardiovascular Medicine,” 40 U.S. Pharmacist 32 (Feb. 18, 2015)
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`“Reilly (Ex. 1054);
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`e) T.A. Wynn, “Cellular and molecular mechanisms of fibrosis,” 214
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`J. Pathology 199 (2008); “Wynn” (Ex. 1068);
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`f) Benoît Lebeau et al., “Reconstitution of two isoforms of the human
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`interleukin-11 receptor and comparison of their functional
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`properties,” 407 FEBS Lett. 141 (1997); “Lebeau (Ex. 1067);
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`g) Eleanor Minshall et al., “IL-11 expression is increased in severe
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`asthma: Association with epithelial cells and eosinophils,” 105 J.
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`Allergy Clin. Immunol 232 (2000); “Minshall” (Ex. 1069); and
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`h) U.S. Patent No. 8,182,814 B2 to Baca (“Baca”) (Ex. 1005).
`
`25.
`
`I provide opinions in this declaration based on my education, training,
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`background, and experience, as well as the documents I have reviewed to date.
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`Those documents, and the other materials cited in this declaration, are listed in
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`Appendix B. To the extent I am provided with additional documents or
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`10
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`Lassen - Exhibit 1004, p. 10
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`
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`information, including any declarations in this proceeding, I reserve the right to
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`modify or expand upon my opinions based on any new information that may arise
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`and in response to any additional reports and testimony.
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`26.
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`I have also been asked to consider whether the techniques and
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`procedures discussed in each of the aforementioned references, alone or in view of
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`other cited prior art, read on each limitation of independent claim 1 and dependent
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`claims 2-10 (collectively, the “Challenged Claims”) of the ’603 patent.
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`27. For the reasons I set forth below, I conclude that all the Challenged
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`Claims of the ’603 patent are unpatentable as anticipated by or rendered obvious
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`over Edwards (Ex. 1008) alone or in combination with Chegini (Ex. 1065) and
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`Wynn (Ex. 1010).
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`III. THE ’603 PATENT (Ex. 1001)
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`28. The claims (claims 1-10) of the ’603 patent recite a method of treating
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`fibrosis in human subject comprising administering to a human subject in need of
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`treatment a therapeutically effective amount of an Interleukin 11 receptor α (IL-
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`11Rα) antibody, which is capable of inhibiting Interleukin 11 (IL-11) mediated
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`signaling, wherein the fibrosis is fibrosis of the heart, liver, kidney, or eye.
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`29.
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`I understand that each of the claims requires an anti-IL-11Rα antibody
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`defined only by its binding function rather than any sequence or structure. I
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`understand that claim 1 recites a method of treatment for fibrosis by administering a
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`11
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`Lassen - Exhibit 1004, p. 11
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`
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`therapeutic amount of an anti-IL-11Rα antibody of a genus that includes any
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`antibody that binds to IL-11Rα:
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`1. A method of treating fibrosis in a human subject, the
`method comprising administering to the human subject in
`need of treatment a therapeutically effective amount of
`an interleukin 11 receptor α (anti-IL-11Rα) antibody
`which is capable of inhibiting interleukin 11 (IL-11)
`mediated signaling, wherein the fibrosis is fibrosis of the
`heart, liver, kidney and eye.
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`30.
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`I understand that claims 2 to 10 depend from claim 1 and state
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`additional antibody functional features based on the antibodies’ mechanism of action
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`and based on the application of the antibody to treat different fibrosis indications.
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`31.
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`I understand that for this proceeding, the claim terms are to be construed
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`under the same claim construction standard as civil actions in federal district court.
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`I understand that under this approach, the claims are generally given their ordinary
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`and customary meaning as understood by a person of ordinary skill in the art at the
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`time of the invention (“the POSITA”) in the context of the entire claim and in the
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`context of the entire patent. However, I also understand that only terms subject to a
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`legitimate dispute need to be construed. Therefore, below I have provided
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`constructions for terms in legitimate dispute. In my analysis, I have used the plain
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`and ordinary meaning for the remaining terms.
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`12
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`Lassen - Exhibit 1004, p. 12
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`
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`A.
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`32.
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`“method of treating fibrosis”
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`I understand that this phrase occurs in the preamble of the claims. I
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`further understand that claim preambles do not always limit the meaning of the
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`claim. However, I have been informed by Counsel that, for purposes of this
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`proceeding, this claim preamble is to be construed as limiting. I understand that a
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`method of treating fibrosis must be sufficiently described and enabled in order for
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`the claims to be patentable.
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`33.
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`I understand that the ’603 patent specification broadly defines
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`“fibrosis” as referring to “the formation of excess fibrous connective tissue as a result
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`of the excess deposition of extracellular matrix components.” (Ex. 1001, col. 33,
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`lines 26-28). Specifically, I understand from the ’603 patent that the “fibrosis” to
`
`be treated using the anti-11Rα antibody is described in col. 3, lines 46-56 (Ex. 1001):
`
`In some embodiments the fibrosis to be treated or
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`prevented is fibrosis of the heart, liver or kidney. In some
`embodiments the fibrosis to be treated or prevented is
`fibrosis of the eye. In some embodiments the fibrosis is
`in the heart and is associated with dysfunction of the
`musculature or electrical properties of the heart, or
`thickening of the walls or valves of the heart. In some
`embodiments the fibrosis is in the liver and is associated
`with chronic liver disease or liver cirrhosis. In some
`embodiments the fibrosis is in the kidney and is
`associated with chronic kidney disease.
`
`13
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`Lassen - Exhibit 1004, p. 13
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`34.
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`I understand that the ’603 patent describes Figure 3 as showing that
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`“inhibition of IL-11 with a neutralizing antibody prevents TGFβ1-induced fibrosis.”
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`(Ex. 1001, col. 7).
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`35.
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`I understand that the ’603 patent defines “fibrosis” as follows (Ex.
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`1001, col. 33, lines 26-44):
`
`As used herein, “fibrosis” refers to the formation
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`of excess fibrous connective tissue as a result of the
`excess deposition of extracellular matrix components, for
`example collagen. Fibrous connective tissue is
`characterised by having extracellular matrix (ECM) with
`a high collagen content. The collagen may be provided in
`strands or fibers, which may be arranged irregularly or
`aligned. The ECM of fibrous connective tissue may also
`include glycosaminoglycans.
`
`As used herein, “excess fibrous connective tissue”
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`refers to an amount of connective tissue at a given
`location (e.g. a given tissue or organ, or part of a given
`tissue or organ) which is greater than the amount of
`connective tissue present at that location in the absence
`of fibrosis, e.g. under normal, non-pathological
`conditions. As used herein, “excess deposition of
`extracellular matrix components” refers to a level of
`deposition of one or more extracellular matrix
`components which is greater than the level of deposition
`in the absence of fibrosis, e.g. under normal, non-
`pathological conditions.
`
`From this definition in the ’603 patent, I understand that “fibrosis” means a condition
`
`as defined by the provided pathological characteristics.
`
`14
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`Lassen - Exhibit 1004, p. 14
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`36.
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`I also understand that the ’603 patent teaches “that inhibition of IL-11
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`activity leads to a reduction in the molecular basis for fibrosis. Accordingly, in some
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`aspects of the present invention treatment, prevention or alleviation of fibrosis may
`
`be provided by administration of an agent capable of preventing or reducing the
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`expression of IL-11 by cells of the subject, e.g. by fibroblasts or myofibroblasts.”
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`(Ex. 1001, col. 19, lines 10-16.) I understand that the ’603 patent later states
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`“[r]educing the amount of IL-11R available for binding to IL-11 and initiation of
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`productive signalling provides an alternative means of reducing the level of IL-11
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`stimulated signalling. Accordingly, in related aspects of the present invention,
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`treatment, prevention or alleviation of fibrosis may be provided by administration of
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`an agent capable of preventing or reducing the expression of IL-11R by cells of the
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`subject, e.g. by fibroblasts or myofibroblasts.” (Id., at lines 60-67.)
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`37. For purposes of this proceeding, therefore, I have used the following
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`construction for “method of treating fibrosis”: “method of treating the formation of
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`excess fibrous connective tissue as a result of the excess deposition of extracellular
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`matrix components.”
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`B.
`“administering to a human subject in need of treatment a
`therapeutically effective amount”
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`38.
`
`I understand that the ’603 patent defines “therapeutically effective
`
`amount” as referring to “an amount sufficient to show benefit to the human subject.”
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`(Ex. 1001, col. 33, lines 11-13)
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`15
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`Lassen - Exhibit 1004, p. 15
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`
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`39. Because the phrase, “therapeutically effective amount”, is used in
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`conjunction with a method of treating fibrosis, I understand that the therapeutic
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`benefit to be shown must be related to treatment of fibrosis, which thereby limits the
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`claims 1-10.
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`40. The ’603 patent does not limit the extent of the benefit to the human
`
`subject. Accordingly, any benefit would fall within the scope of “therapeutically
`
`effective amount,” and thus would fall within the scope of the phrase “method of
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`treating fibrosis” to which the “therapeutically effective amount” phrase is further
`
`defining.
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`41. For purposes of this proceeding, I have used the following construction
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`for the phrase “administering to a human subject in need of treatment a
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`therapeutically effective amount”: “administering a human subject in need of
`
`treatment for fibrosis an amount sufficient to show benefit to the human subject
`
`regarding the subject’s fibrosis.”
`
`C.
`
`42.
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`“Interleukin 11 receptor α (IL-11Rα) antibody”
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`I understand that the ’603 patent broadly describes agents that bind to
`
`an IL-11 receptor (IL-11R) and that in preferred embodiments, the IL-11R is IL-
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`11Rα. (Ex. 1001, col. 17, lines 27-34.) The IL-11R binding agents can be an anti-
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`ILR antibody (Id., line 35). The ’603 patent includes many different proteins in the
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`definition of an “IL-11R antibody” which they set forth at col. 18 as follows:
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`16
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`Lassen - Exhibit 1004, p. 16
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`
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`'
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`5
`to Lan
`
`30
`
`Suitable anti-[L-1]1R antibodies will preferably bind to
`IL-11R (the antigen), preferably human IL-11R, and may
`have a dissociation constant (K,,) of one of <1 uM, <100
`nM, <10 nM, =] nM or s100 pM. Binding affinity of an
`antibody for its target is often described in terms ofits
`dissociation constant (K,,). Binding affinity can be measured
`) by methods knowninthe art, such as by Surface Plasmon
`Resonance (SPR), or by a radiolabeled antigen binding
`assay (RLA) performed with the Fab version of the antibody
`and antigen molecule.
`Anti-IL-11R antibodies may be antagonist antibodies that
`inhibit or reduce a biological activity of IL-11R. Anti-IL-
`11R antibodies may be antagonist antibodies that inhibit or
`reduce any function of IL-11R,in particular signalling. For
`example, antagonist IL-11R antibodies may inhibit or pre-
`vent binding of IL-11 to IL-11R, or may inhibit or prevent
`association of [L-11Ra with gp130 to form a functional
`receptor complex capable of productive signalling, e.g. in
`response to IL-11 binding.
`Anti-IL-11R antibodies may be neutralising antibodies
`that neutralise the biological effect of IL-11, e.g.its ability
`to initiate productive signalling mediated by binding of
`IL-11.
`Neutralising activity may be measured by ability to neu-
`tralise IL-11 induced proliferation in the T11 mouse plas-
`macytomacell line (Nordan, R. P. et al. (1987) J. Immunol.
`139:813).
`include
`Examples of known anti-IL-11R antibodies
`monoclonal antibody clone 025 (Sino Biological), clone
`EPR5446 (Abcam), clone 473143 (R & D Systems), clones
`8E2 and 8E4 described in US 2014/0219919 Al and the
`monoclonal antibodies described in Blane et al (J. Immunol
`Methods. 2000 Jul. 31; 241(1-2); 43-59).
`
`40
`
`
`
`17
`17
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`Lassen - Exhibit 1004, p. 17
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`Lassen - Exhibit 1004, p. 17
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`
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`From this description, I conclude that an “IL-11R antibody” may include any kind
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`of antibody that binds to IL-11R and may be an antagonist antibody or a neutralizing
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`antibody. (Ex. 1001, col. 18, lines 24-36). I also understand that an “IL-11R
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`antibody” includes an anti-IL-11Rα antibody.
`
`43.
`
`I understand from reviewing the ’603 patent and its file history that
`
`antibodies to “IL-11R” and to “IL-11Rα” are not limited to the human IL-11R and
`
`IL-11Rα, although human is indicated as preferable. I also understand that the
`
`antibody does not have to be a humanized or human antibody, but rather the
`
`antibodies include a wide variety of types including a fragment or derivative of an
`
`antibody, a monoclonal antibody, or even a polyclonal antibody given the inventors’
`
`characterization at col. 20, line 38 to col. 21, line 64 of the ’603 patent (Ex. 1001).
`
`I therefore conclude that the term “IL-11Rα antibody” is not limited to anti-human
`
`IL-11Rα human or humanized antibodies. From this context, I understand other
`
`animal anti-IL-11Rα antibodies fall within the full scope, including antibodies
`
`directed against other animal IL-11R and IL-11Rα antigens.
`
`44.
`
`I also understand that the ’603 patent defines “antibody” broadly to
`
`include “a fragment or derivative of an antibody, or a synthetic antibody or synthetic
`
`antibody fragment.” (Ex. 1001, col. 20, lines 39-41). I understand that the ’603
`
`patent also teaches “”[s]ynthetic antibodies which bind to IL-11 or IL-11R may also
`
`18
`
`Lassen - Exhibit 1004, p. 18
`
`
`
`be made using phage display technology as is well known in the art.” (Ex. 1001,
`
`col. 21, lines 34-36)
`
`45.
`
`I understand that the ’603 patent also indicates that monoclonal or
`
`polyclonal antibodies are useful in the methods of the invention. (Ex. 1001, col. 20,
`
`lines 45-64) I understand that there is no indication either in the ’603 patent
`
`specification or its prosecution history that the term “IL-11R antibody” or “IL-11Rα
`
`antibody” is limited to monoclonal antibodies. Accordingly, I understand the scope
`
`of the term “antibody” includes both monoclonal and polyclonal antibodies,
`
`antibody fragments or synthetic antibody or a synthetic antibody fragment as set
`
`forth at col. 20, lines 39-41 (Ex. 1001).
`
`46. For purposes of this proceeding, I have used the following construction
`
`for “Interleukin 11 receptor α (IL-11Rα) antibody”: “any natural or synthetic,
`
`monoclonal or polyclonal antibody made using any animal system including phage,
`
`or fragment or derivative thereof, that binds to IL-11Rα of any species.”
`
`D.
`
`47.
`
`“capable of inhibiting Interleukin 11 (IL-11) mediated signaling”
`
`I understand that the ’603 patent indicates that antibodies that bind to
`
`an IL-11R “may inhibit IL-11 mediated signaling by blocking the binding of IL-11
`
`to an IL-11R or by preventing signal transduction via the gp130 co-receptors.” (Ex.
`
`1001, 17, lines 27-30). I understand that in “preferred embodiments the IL-11R is
`
`IL-11Rα and suitable binding agents may bind the IL-11Rα polypeptide and may be
`
`19
`
`Lassen - Exhibit 1004, p. 19
`
`
`
`inhibitors or antagonists of IL-11Rα.” (Id., col. 17, lines 31-34). Such antibodies
`
`may also “inhibit or prevent association of IL-11Rα with gp130 to form a functional
`
`receptor complex capable of productive signaling, e.g. in response to IL-11 binding.”
`
`(Id., col. 18, lines 29-32). It is unclear what the difference is between IL-11R and
`
`IL-11Rα. I understand that IL-11Rα is the receptor on the cell surface responsible
`
`for binding to IL-11 and involved with producing a signal in the cell downstream. I
`
`understand that there is an IL-11Rα2, which is produced by the proteolytic cleavage
`
`of IL-11Rα (also known as IL-11Rα1) from the surface of the cell. I also understand
`
`that the human form results from two different cDNAs produced by alternative
`
`splicing, which yields a 80 kD protein and a 82 kD protein. (Ex. 1067, 141).
`
`However, IL-11Rα2 can produce no signal as it is not on the cell surface. Given the
`
`discussion, I understand IL-11Rα to be the form that is on the cell’s surface and
`
`provides the signal.
`
`48. For purposes of this proceeding, I have used the following construction
`
`for “capable of inhibiting Interleukin 11 (IL-11) mediated signaling”: any antibody
`
`within the definition above that is “capable of blocking the binding of IL-11 to an
`
`IL-11Rα or preventing signal transduction via the gp130 co-receptors.”
`
`E.
`
`“wherein the fibrosis is fibrosis of the heart, liver, kidney, or eye”
`
`49. For purposes of this proceeding, I have construed the phrase to limit the
`
`fibrosis being treated to fibrosis in the heart, liver, kidney, or eye.
`
`20
`
`Lassen - Exhibit 1004, p. 20
`
`
`
`50.
`
`I understand from the ’603 patent that the fibrosis can be any of the
`
`following from col. 3, lines 46-56 (Ex. 1001):
`
`
`
`IV. THE LEVEL OF ORDINARY SKILL IN THE ART
`
`51.
`
`I have been informed that I must analyze the claims of the ’603 patent
`
`from the perspective of what someone of ordinary skill in the relevant field at the
`
`time of the claimed invention would have known or understood.
`
`52.
`
`I have been advised that there are multiple factors relevant to
`
`determining the level of ordinary skill in the pertinent art, including the educational
`
`level of active workers in the field at the time of the invention, the sophistication of
`
`the technology, the type of problems encountered in the art, and the prior art
`
`solutions to those problems. I have been informed that the level of skill in the art is
`
`evidenced in part by the prior art references.
`
`21
`
`Lassen - Exhibit 1004, p. 21
`
`
`
`53.
`
`In my opinion given the ’603 patent and the prior art existing prior to
`
`the earliest priority date of December 2015, a person of ordinary skill in the art at
`
`the time would typically have had a Ph.D. in immunology, molecular biology,
`
`cellular biology, or a similar field, or an M.D. with similar experience. In my
`
`opinion, a person of ordinary skill in the art would typically have had at least about
`
`five years of experience with antibodies and antibody engineering, or access to other
`
`individuals with that knowledge and experience. Likewise, a person of ordinary skill
`
`in the art would have had knowledge and experience in fibrosis, or access to a person
`
`with that knowledge and experience.
`
`V.
`
`THE PRIOR ART
`
`A. U.S. Application Publication No. 2014/0219919 to Edwards et al.
`(“Edwards”; Ex. 1008)
`
`54.
`
`I understand that the Edwards patent publication was published on
`
`August 7, 2014, which is more than one year before the earliest possible priority
`
`date on the face of the ’603 patent (December 16, 2015). I understand that
`
`Edwards is prior art to the ’603 patent under 35 U.S.C. § 102 (a).
`
`55.
`
`I understand that Edwards is listed in the file history of the ’603 patent
`
`as having been submitted and considered by the Examiner. However, I did not find
`
`any discussion of the Edwards reference with regard to the claims in the file history
`
`of the ’603 patent.
`
`22
`
`Lassen - Exhibit 1004, p. 22
`
`
`
`56.
`
`I understand that Edwards teaches reagents “that bind IL-11Rα and
`
`neutralize IL-11 signaling.” (Ex. 1008, para. [0013]).
`
`57.
`
`I understand
`
`that Edwards
`
`teaches numerous IL-11-mediated
`
`conditions at paragraphs [0159] to [0162] including inflammatory airway conditions
`
`(e.g., asthma, chronic obstructive airway disease (COPD), rhinitis or allergy) or
`
`inflammatory dermatitis (e.g., atopic dermatitis). (Ex. 1008, para. [0159]). I
`
`understand that Edwards exemplifies an “IL-11-mediated condition” to include an
`
`autoimmune condition, an inflammatory condition, a wasting condition, bone
`
`condition, or cancer. (Ex. 1008, para. [0160]).
`
`58.
`
`I understand that Edwards (Ex. 1008) states in the “BACKGROUND”
`
`section the fo
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