throbber
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
`
`DECLARATION STEPHEN LEDBETTER, PH.D.
`
`IN SUPPORT OF
`
`PETITION FOR POST GRANT REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`Lassen - Exhibit 1004, p. 1
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`

`

`I, Steven Ledbetter, declare as follows:
`
`I.
`
`BACKGROUND AND QUALIFICATIONS
`
`1.
`
`I, Steven Ledbetter, Ph.D., have been retained by Drinker Biddle &
`
`Reath, LLP (“Counsel”) on behalf of Lassen Therapeutics 1, Inc. (“Lassen”) as an
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`independent expert in the field of fibrosis.
`
`2.
`
`I am currently a consultant at BioRepair Consulting, LLC, which I
`
`founded in 2015. As a consultant, I provide my scientific expertise to the
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`biotechnology industry.
`
`3.
`
`I obtained my Bachelor of Science degree in Biology from the Alma
`
`College, Alma, Michigan in 1974. I obtained my Doctoral degree in Cell Biology
`
`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
`
`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
`
`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
`
`heparan sulfate proteoglycan (Perlecan).
`
`4.
`
`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
`
`2
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`Lassen - Exhibit 1004, p. 2
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`

`

`research on basement membrane structure and function at Upjohn where I also
`
`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.
`
`5.
`
`In 1996, I joined Genzyme Corporation as a Principal Scientist and in
`
`2000, I became the Director of Genzyme’s Cell Biology department and a Project
`
`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
`
`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).
`
`Additional investigator studies with this antibody were also conducted in
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`scleroderma, pulmonary radiation fibrosis, osteogenesis imperfecta, and metastatic
`
`breast cancer. A phase 2 study in FSGS was completed in 2015.
`
`6.
`
`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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`

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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.
`
`7.
`
`In 2016, I co-founded Omdana Therapeutics and served as Chief
`
`Development Officer until April 2017.
`
`8.
`
`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
`
`consulting activities. My experience, as indicated in my attached curriculum vitae,
`
`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
`
`approaches for the treatment of fibrotic diseases with principal focus in heart, lung,
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`kidney, liver, skin and bone diseases.
`
`9.
`
`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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`

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`complete list of my publications is also contained in my curriculum vitae attached
`
`as Appendix A.
`
`10.
`
`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).
`
`11. My professional qualifications are described in further detail in my
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`curriculum vitae, which is attached as Appendix A.
`
`12.
`
`I am being compensated at my usual rate of $300 per hour for work on
`
`this case. My compensation does not depend in any way on my opinions, my
`
`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.
`
`I am currently a paid consultant to Lassen separately from providing
`
`this Declaration. I own no Lassen stocks.
`
`14.
`
`I have not testified in a U.S. court or in any U.S. administrative
`
`proceeding in the past ten years.
`
`15.
`
`I have reviewed United States Patent No. 10,106,603 (“the ’603
`
`patent”) to Cook et al and its file history.
`
`
`
`5
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`Lassen - Exhibit 1004, p. 5
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`

`

`II.
`
`INFORMATION PROVIDED TO ME
`
`16.
`
`I understand from Counsel that the meaning of the claims of a patent
`
`are to be construed in accordance with the federal court claim construction
`
`standard that is used to construe a claim in a civil action under 35 U.S.C. § 282(b).
`
`I have been informed by Counsel that the Patent Trial and Appeal Board (“PTAB”)
`
`applies the same construction standard used in district courts, where the claims are
`
`given their ordinary meaning as understood by one skilled in the art at the time of
`
`the invention, informed by the claim language itself, the specification, and the
`
`prosecution history. I also understand that “extrinsic evidence” – i.e., evidence
`
`other than the patent and prosecution history – can be relevant in determining how
`
`a skilled artisan would understand terms of art used in the claims. I have been
`
`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
`
`the claims of the ’603 patent to the known prior art, I have carefully considered the
`
`’603 patent and the ’603 patent’s file history from the perspective of a person of
`
`ordinary skill in the art using my experience and knowledge in the relevant field.
`
`17.
`
`I am informed that the application for the ’603 patent was filed on
`
`May 24, 2018, but that it claims to be related to an application dated December 16,
`
`6
`
`Lassen - Exhibit 1004, p. 6
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`

`

`2016. For purposes of this declaration only, I have assumed a priority date of
`
`December 16, 2016, in determining whether a reference constitutes prior art.
`
`18.
`
`19.
`
`I have been informed that the ’603 patent has not expired.
`
`In comparing the claims of the ’603 patent to the known prior art, I
`
`have carefully considered the ’603 patent and the ’603 patent’s file history from
`
`the perspective of a person of ordinary skill in the art using my experience and
`
`knowledge in the relevant field.
`
`20.
`
`I understand from Counsel that a patent claim is unpatentable if its
`
`subject matter is anticipated and obvious over one reference. I further understand
`
`from Counsel that anticipation of a claim requires that every element of a claim be
`
`disclosed expressly or inherently in a single prior art referenced, as claimed. I
`
`understand that a document can inherently teach a claim as follows. I understand
`
`that for example, if a method was used to treat a condition and that condition
`
`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
`
`mechanism, but the publication fails to describe the condition, then the publication
`
`would inherently teach the undescribed condition, because by the publication by
`
`treating such a disorder would in effect treat the condition.
`
`21.
`
`I further understand from Counsel that the obviousness of a patent
`
`claim requires that the claim be obvious from the perspective of a person of
`
`7
`
`Lassen - Exhibit 1004, p. 7
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`

`

`ordinary skill in the art at the time the ’603 patent was filed. I further understand
`
`that a patent claim can be found unpatentable as obvious where the differences
`
`between the subject matter sought to be patented and the prior art are such that the
`
`subject matter as a whole would have been obvious to a person of ordinary skill in
`
`the art at the time of the invention. I understand that an obviousness analysis
`
`requires a consideration of (1) the scope and content of the prior art, (2) the
`
`differences between the claimed invention and the prior art, and (3) the level of
`
`ordinary skill in the pertinent field.
`
`22.
`
`I further understand that certain factors, that I understand may be
`
`referred to as secondary considerations, may support or rebut the obviousness of a
`
`patent claim. I understand that such secondary considerations may include, among
`
`other things, the commercial success of the patented invention, any skepticism of
`
`those having ordinary skill in the art at the time of invention, unexpected results
`
`obtained during the process of claiming the invention, any long-felt but unsolved
`
`need in the art that was satisfied by the alleged invention, the failure of others to
`
`make the alleged invention, praise of the alleged invention by those having
`
`ordinary skill in the art, and copying of the alleged invention by others in the field.
`
`I understand that there must be a nexus—a connection—between any such
`
`secondary considerations and the alleged invention. I also understand that
`
`8
`
`Lassen - Exhibit 1004, p. 8
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`

`

`contemporaneous and independent invention by others is a secondary consideration
`
`tending to show obviousness.
`
`23.
`
`I further understand from Counsel that a claim is obvious if it unites
`
`old elements with no change to their respective functions, or alters prior art by
`
`mere substitution of one element for another known in the field and that
`
`combination yields predictable results. While it may be helpful to identify a reason
`
`for this combination, common sense should guide and no rigid requirement a
`
`teaching, suggestion or motivation to combine is required. When a product is
`
`available, design incentives and other market forces can prompt variations of it,
`
`either in the same field or different one. If the POSITA can implement the claimed
`
`invention from the prior art with no or limited modification such that the result is
`
`predictable, then obviousness likely bars its patentability. I understand that a
`
`patent claim may be obvious if common sense directs a POSITA to combine
`
`multiple prior art references or add missing features to reproduce the alleged
`
`invention as recited in the claims, and that this can be done with a reasonable
`
`expectation of scientific predictability. I understand that a POSITA is a person of
`
`ordinary creativity, not an automaton.
`
`24.
`
`I have been asked to consider the following:
`
`a) U.S. Application Publication No. 2014/0219919 to Edwards et al.
`
`(“Edwards”) (Ex. 1008);
`
`9
`
`Lassen - Exhibit 1004, p. 9
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`

`

`b) U.S. Application Publication No. 2008/0300147 to Chegini et al.
`
`(“Chegini”) (Ex. 1065);
`
`c) T. A. Wynn, “Fibrotic Disease and the T(H)1/T(H)2 Paradigm,” 4
`
`Nat. Rev. Immunol. 583 (2004); “Wynn” (Ex. 1010);
`
`d) Kristin Reilly, “Cardiac Fibrosis: New Treatments in
`
`Cardiovascular Medicine,” 40 U.S. Pharmacist 32 (Feb. 18, 2015)
`
`“Reilly (Ex. 1054);
`
`e) T.A. Wynn, “Cellular and molecular mechanisms of fibrosis,” 214
`
`J. Pathology 199 (2008); “Wynn” (Ex. 1068);
`
`f) Benoît Lebeau et al., “Reconstitution of two isoforms of the human
`
`interleukin-11 receptor and comparison of their functional
`
`properties,” 407 FEBS Lett. 141 (1997); “Lebeau (Ex. 1067);
`
`g) Eleanor Minshall et al., “IL-11 expression is increased in severe
`
`asthma: Association with epithelial cells and eosinophils,” 105 J.
`
`Allergy Clin. Immunol 232 (2000); “Minshall” (Ex. 1069); and
`
`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,
`
`background, and experience, as well as the documents I have reviewed to date.
`
`Those documents, and the other materials cited in this declaration, are listed in
`
`Appendix B. To the extent I am provided with additional documents or
`
`10
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`Lassen - Exhibit 1004, p. 10
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`

`

`information, including any declarations in this proceeding, I reserve the right to
`
`modify or expand upon my opinions based on any new information that may arise
`
`and in response to any additional reports and testimony.
`
`26.
`
`I have also been asked to consider whether the techniques and
`
`procedures discussed in each of the aforementioned references, alone or in view of
`
`other cited prior art, read on each limitation of independent claim 1 and dependent
`
`claims 2-10 (collectively, the “Challenged Claims”) of the ’603 patent.
`
`27. For the reasons I set forth below, I conclude that all the Challenged
`
`Claims of the ’603 patent are unpatentable as anticipated by or rendered obvious
`
`over Edwards (Ex. 1008) alone or in combination with Chegini (Ex. 1065) and
`
`Wynn (Ex. 1010).
`
`III. THE ’603 PATENT (Ex. 1001)
`
`28. The claims (claims 1-10) of the ’603 patent recite a method of treating
`
`fibrosis in human subject comprising administering to a human subject in need of
`
`treatment a therapeutically effective amount of an Interleukin 11 receptor α (IL-
`
`11Rα) antibody, which is capable of inhibiting Interleukin 11 (IL-11) mediated
`
`signaling, wherein the fibrosis is fibrosis of the heart, liver, kidney, or eye.
`
`29.
`
`I understand that each of the claims requires an anti-IL-11Rα antibody
`
`defined only by its binding function rather than any sequence or structure. I
`
`understand that claim 1 recites a method of treatment for fibrosis by administering a
`
`11
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`Lassen - Exhibit 1004, p. 11
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`

`

`therapeutic amount of an anti-IL-11Rα antibody of a genus that includes any
`
`antibody that binds to IL-11Rα:
`
`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.
`
`30.
`
`I understand that claims 2 to 10 depend from claim 1 and state
`
`additional antibody functional features based on the antibodies’ mechanism of action
`
`and based on the application of the antibody to treat different fibrosis indications.
`
`31.
`
`I understand that for this proceeding, the claim terms are to be construed
`
`under the same claim construction standard as civil actions in federal district court.
`
`I understand that under this approach, the claims are generally given their ordinary
`
`and customary meaning as understood by a person of ordinary skill in the art at the
`
`time of the invention (“the POSITA”) in the context of the entire claim and in the
`
`context of the entire patent. However, I also understand that only terms subject to a
`
`legitimate dispute need to be construed. Therefore, below I have provided
`
`constructions for terms in legitimate dispute. In my analysis, I have used the plain
`
`and ordinary meaning for the remaining terms.
`
`12
`
`Lassen - Exhibit 1004, p. 12
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`

`

`A.
`
`32.
`
`“method of treating fibrosis”
`
`I understand that this phrase occurs in the preamble of the claims. I
`
`further understand that claim preambles do not always limit the meaning of the
`
`claim. However, I have been informed by Counsel that, for purposes of this
`
`proceeding, this claim preamble is to be construed as limiting. I understand that a
`
`method of treating fibrosis must be sufficiently described and enabled in order for
`
`the claims to be patentable.
`
`33.
`
`I understand that the ’603 patent specification broadly defines
`
`“fibrosis” as referring to “the formation of excess fibrous connective tissue as a result
`
`of the excess deposition of extracellular matrix components.” (Ex. 1001, col. 33,
`
`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
`
`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
`
`Lassen - Exhibit 1004, p. 13
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`

`

`34.
`
`I understand that the ’603 patent describes Figure 3 as showing that
`
`“inhibition of IL-11 with a neutralizing antibody prevents TGFβ1-induced fibrosis.”
`
`(Ex. 1001, col. 7).
`
`35.
`
`I understand that the ’603 patent defines “fibrosis” as follows (Ex.
`
`1001, col. 33, lines 26-44):
`
`As used herein, “fibrosis” refers to the formation
`
`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”
`
`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.
`
`I also understand that the ’603 patent teaches “that inhibition of IL-11
`
`activity leads to a reduction in the molecular basis for fibrosis. Accordingly, in some
`
`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
`
`expression of IL-11 by cells of the subject, e.g. by fibroblasts or myofibroblasts.”
`
`(Ex. 1001, col. 19, lines 10-16.) I understand that the ’603 patent later states
`
`“[r]educing the amount of IL-11R available for binding to IL-11 and initiation of
`
`productive signalling provides an alternative means of reducing the level of IL-11
`
`stimulated signalling. Accordingly, in related 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 expression of IL-11R by cells of the
`
`subject, e.g. by fibroblasts or myofibroblasts.” (Id., at lines 60-67.)
`
`37. For purposes of this proceeding, therefore, I have used the following
`
`construction for “method of treating fibrosis”: “method of treating the formation of
`
`excess fibrous connective tissue as a result of the excess deposition of extracellular
`
`matrix components.”
`
`B.
`“administering to a human subject in need of treatment a
`therapeutically effective amount”
`
`38.
`
`I understand that the ’603 patent defines “therapeutically effective
`
`amount” as referring to “an amount sufficient to show benefit to the human subject.”
`
`(Ex. 1001, col. 33, lines 11-13)
`
`15
`
`Lassen - Exhibit 1004, p. 15
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`

`

`39. Because the phrase, “therapeutically effective amount”, is used in
`
`conjunction with a method of treating fibrosis, I understand that the therapeutic
`
`benefit to be shown must be related to treatment of fibrosis, which thereby limits the
`
`claims 1-10.
`
`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
`
`treating fibrosis” to which the “therapeutically effective amount” phrase is further
`
`defining.
`
`41. For purposes of this proceeding, I have used the following construction
`
`for the phrase “administering to a human subject in need of treatment a
`
`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.
`
`“Interleukin 11 receptor α (IL-11Rα) antibody”
`
`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-
`
`11Rα. (Ex. 1001, col. 17, lines 27-34.) The IL-11R binding agents can be an anti-
`
`ILR antibody (Id., line 35). The ’603 patent includes many different proteins in the
`
`definition of an “IL-11R antibody” which they set forth at col. 18 as follows:
`
`16
`
`Lassen - Exhibit 1004, p. 16
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`

`

`Suitable anti-IL-llR antibodies will preferably bind to
`IL-llR (the antigen), preferably human IL-llR, and may
`have a dissociation constant (KB) of one of 51 pM. 5100
`nM, 510 11M, 51 nM or 5100 pM. Binding aflinity of an
`antibody for its target is often described in terms of its
`dissociation constant (KD). Binding aflinity can be measured
`i by methods known in the art, such as by Surface Plasmon
`Resonance (SPR). or by a radiolabeled antigen binding
`assay (RIA) performed with the Fab version of the antibody
`and antigen molecule.
`Anti-IL-l 1 R antibodies may be antagonist antibodies that
`inhibit or reduce a biological activity of lL-llR. Anti-IL-
`11R antibodies may be antagonist antibodies that inhibit or
`reduce any function of IL-llR, in particular signalling. For
`example, antagonist IL-llR antibodies may inhibit or pre-
`vent binding of lL-ll to IL-llR, or may inhibit or prevent
`association of IL-llRa with gp130 to form a functional
`receptor complex capable of productive signalling, e.g. in
`response to IL-11 binding.
`Anti-IL-llR antibodies may be neutralising antibodies
`that neutralise the biological effect of IL-1 1R. e.g. its ability
`to initiate productive signalling mediated by binding of
`IL-ll.
`
`[J Ll
`'
`
`30
`
`4!]
`
`Neutralising activity may be measured by ability to neu-
`tralise lL-ll induced proliferation in the T11 mouse plas-
`macytoma cell line (Nordan, R. P. et al. (1987‘) J. Immunol.
`1392813).
`include
`Examples of known anti-IL-l 1R antibodies
`monoclonal antibody clone 025 (Sino Biological), clone
`EPR5446 (Abcam). clone 473143 (R & D Systems). clones
`8E2 and 8E4 described in US 2014/0219919 A1 and the
`
`monoclonal antibodies described in Blane et a] (J. Immunol
`Methods. 2000 Jul. 31: 241(1-2); 43-59»).
`
`
`
`17
`17
`
`Lassen - Exhibit 1004, p. 17
`
`Lassen - Exhibit 1004, p. 17
`
`

`

`From this description, I conclude that an “IL-11R antibody” may include any kind
`
`of antibody that binds to IL-11R and may be an antagonist antibody or a neutralizing
`
`antibody. (Ex. 1001, col. 18, lines 24-36). I also understand that an “IL-11R
`
`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”
`
`sect

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