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
`
`
`
`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
`
`
`
`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
`
`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
`
`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
`
`Cellular Biology, in 1980 with my dissertation on “Deposition of Extracellular
`
`Matrix by Cultured Corneal Endothelial Cells.” I performed post-doctoral training
`
`in ophthalmology research at the Medical College of Wisconsin and in the
`
`Laboratory of Developmental Biology and Anomalies at the National Institutes of
`
`Health (“NIH”) in Bethesda Maryland. At the NIH, my research focused on the
`
`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
`
`Research Scientist at the Upjohn Company, Kalamazoo, Michigan. I continued my
`
`2
`
`Lassen - Exhibit 1004, p. 2
`
`
`
`research on basement membrane structure and function at Upjohn where I also
`
`established a laboratory focused on diabetic nephropathy. During my 12 years at
`
`Upjohn, my research efforts expanded to include studies in epithelial and hair
`
`follicle regeneration, and the role of matrix metalloproteinases as regulators of
`
`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
`
`responsibilities in those roles included establishing a research laboratory focused
`
`on the role of TGFβ in chronic tissue injury and fibrosis. In collaboration with
`
`Cambridge Antibody Technology (Cambridge, UK), I and my team identified and
`
`characterized a novel, pan-neutralizing, human antibody against TGFβ. This
`
`antibody was studied in three phase 1 clinical trials for idiopathic pulmonary
`
`fibrosis, metastatic melanoma and focal segmental glomerulosclerosis (FSGS).
`
`Additional investigator studies with this antibody were also conducted in
`
`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
`
`was Renal Portfolio Director and Senior Director of Cell Biology in 2002, became
`
`Vice-President for the Renal and Fibrotic Diseases Research in 2003, and then
`
`3
`
`Lassen - Exhibit 1004, p. 3
`
`
`
`Group Vice-President responsible for renal, cardiovascular and bone and joint
`
`diseases in 2008. The acquisition of Genzyme by Sanofi in 2010 expanded my
`
`responsibilities to further include allied research efforts based in Paris and the
`
`newly created Tissue Injury and Fibrosis portfolio, containing 135 research
`
`personnel, and was closely aligned with a dedicated clinical development team. I
`
`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
`
`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
`
`of normal tissue homeostasis and in pathologic fibrosis. Beginning in 1984, my
`
`activities were focused entirely on the functional and physiologic impact of
`
`maladaptive tissue remodeling (fibrosis) and exploration of potential therapeutic
`
`approaches for the treatment of fibrotic diseases with principal focus in heart, lung,
`
`kidney, liver, skin and bone diseases.
`
`9.
`
`I have published or co-authored more than 80 journal publications,
`
`conference proceedings, technical reports, and technical presentations, and have
`
`been named as an inventor on numerous U.S. patents and patent applications. A
`
`4
`
`Lassen - Exhibit 1004, p. 4
`
`
`
`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
`
`international meetings. Recent examples include co-organizer of the 2014
`
`Keystone Symposium on Fibrosis, 2014 International Society of Nephrology
`
`meeting on novel renal therapeutics (co-organizer and speaker) and scientific
`
`advisor to the EU program on systemic kidney diseases (SysKid).
`
`11. My professional qualifications are described in further detail in my
`
`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
`
`with Drinker, Biddle, and Reath LLP outside of my engagement in this proceeding.
`
`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
`
`Lassen - Exhibit 1004, p. 5
`
`
`
`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
`
`meaning of the claims as described in the intrinsic evidence – i.e., evidence in the
`
`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
`
`
`
`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
`
`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
`
`
`
`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
`
`
`
`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
`
`
`
`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
`
`Lassen - Exhibit 1004, p. 10
`
`
`
`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
`
`Lassen - Exhibit 1004, p. 11
`
`
`
`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
`
`
`
`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
`
`
`
`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
`
`Lassen - Exhibit 1004, p. 14
`
`
`
`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
`
`
`
`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
`
`
`
`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
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
