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`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 OF PETER BOWERS
`
`IN SUPPORT OF
`
`PETITION FOR POST GRANT REVIEW
`
`
`
`1
`
`Lassen - Exhibit 1003, p. 1
`
`
`
`I.
`
`BACKGROUND AND QUALIFICATIONS
`
`1.
`
`I, Peter Bowers, Ph.D., have been retained by Drinker Biddle & Reath
`
`LLP on behalf of Lassen Therapeutics 1, Inc. (“Lassen”) as an independent expert
`
`in the field of antibody design and engineering.
`
`2.
`
`I am currently Associate Professor at the David Geffen School of
`
`Medicine at UCLA where I also serve as Associate Director for Drug Development
`
`in the UCLA Clinical and Translational Science Institute (CTSI) and Director of the
`
`David Geffen School of Medicine (DGSOM) Therapeutic Antibody Laboratory at
`
`the University of California, Los Angeles. At UCLA, I work in part to guide the
`
`process of antibody project selection and therapeutic concept design, and oversee
`
`management of therapeutic project teams, all aspects of related project antibody
`
`discovery, engineering and lead candidate selection, including supervision of staff,
`
`data management and screening platforms.
`
`3.
`
`Prior to this position, I was Senior Director and scientific founder of
`
`AnaptysBio, a now publicly-traded therapeutic antibody product company
`
`[NASDQ; ANAB]. While with AnaptysBio, I worked to develop a new antibody
`
`discovery platform based on aspects of B cell adaptive immune response and somatic
`
`hypermutation for the generation of high-affinity therapeutic antibody discovery and
`
`optimization. I also oversaw antibody discovery, antibody humanization and
`
`analytics for two first-in-class clinical stage antibodies including Etokimab,
`
`2
`
`Lassen - Exhibit 1003, p. 2
`
`
`
`targeting interleukin-33 for the treatment of severe adult asthma and severe adult
`
`peanut allergy, and ANB019, an antibody blocking interleukin-36 receptor for the
`
`treatment of the rare inflammatory disease, generalized pustular psoriasis.
`
`4.
`
`In total, I oversaw antibody discovery and engineering activities for
`
`over 35 antibody therapeutic projects including 5 antibodies in clinical trials
`
`partnered with pharmaceutical companies targeting checkpoint inhibitors as
`
`antagonists and agonists.
`
`5.
`
`I obtained my Bachelor’s of Science degree in Biochemistry from the
`
`University of Iowa in 1992. I obtained my Doctoral degree in Biochemistry from
`
`the University of Washington in Seattle 1998 studying protein and protein/DNA
`
`structure and biophysics using nuclear magnetic resonance.
`
` I performed
`
`postdoctoral research in the laboratories of Dr. David Baker (University of
`
`Washington) and David Eisenberg (University of California, Los Angeles) focusing
`
`on protein engineering and design and functional genomics respectively.
`
`6.
`
`I have published or co-authored about 25 scholarly articles peer-
`
`reviewed journals such as the Proceedings of the National Academy of Sciences,
`
`Science, Nature Structural Biology, Journal of Biological Chemistry, and the Journal
`
`of the American Chemical Society. These papers address aspects of protein structure
`
`and function with half of the papers relating to antibody discovery and engineering
`
`specifically. I have also authored invited review papers, book chapters, and meeting
`
`3
`
`Lassen - Exhibit 1003, p. 3
`
`
`
`reports. Several of my publications focus on immunoglobulin crystal structures,
`
`binding properties, and therapeutic potential. I am the co-inventor on a dozen U.S.
`
`issued and patent applications covering both antibody discovery methods and
`
`therapeutic antibodies covering composition of matter.
`
`7.
`
`I have lectured, organized, and taught multiple courses at UCLA, on
`
`antibody structure, pharmacology and function, protein structure, molecular
`
`interactions, and structure-based drug design.
`
`8.
`
`Based in part on my research and publications over time, I have been
`
`awarded numerous funding grants from national and state scientific organizations
`
`(Defense Advanced Research Project Agency (DARPA), Defense Threat Reduction
`
`Agency and The National Institutes of Health (NIH) National Heart, Lung, Blood
`
`Institute), in the amount of about $3.5M to investigate antibody assays, stability,
`
`structure and therapeutic applications in inflammation, MI (myocardial infarction),
`
`oncology, and immuno-oncology.
`
`9. My professional qualifications are described in further detail in my
`
`curriculum vitae, which is attached as Appendix A.
`
`10.
`
`I am being compensated for my work on this case at my customary rate
`
`of $450 per hour plus expenses. 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
`
`4
`
`Lassen - Exhibit 1003, p. 4
`
`
`
`financial ties with Lassen, nor with Drinker, Biddle, and Reath LLP outside of my
`
`engagement in this proceeding.
`
`11.
`
`I have not testified in a U.S. court or in any U.S. administrative
`
`proceeding over the past ten years.
`
`A.
`
`12.
`
`INFORMATION PROVIDED TO ME
`
`I have been informed by Drinker Biddle counsel (“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 from Counsel that “extrinsic evidence” – i.e., evidence other than the
`
`patent and prosecution history – can be relevant in determining how one of ordinary
`
`skill would understand terms of art used in the claims. I have been informed by
`
`Counsel, 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.
`
`13.
`
`In comparing the claims of the United States Patent No. 10,106,603
`
`(“the ’603 patent”) to Cook, et al. 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 (“POSITA”) using my experience and knowledge in the
`
`5
`
`Lassen - Exhibit 1003, p. 5
`
`
`
`relevant field given my understanding of extrinsic and intrinsic evidence as
`
`explained by Counsel.
`
`14.
`
`I am informed by Counsel that the application for the ’603 patent was
`
`filed on May 24, 2018, but that claims to be related to an application filed in Great
`
`Britain on December 16, 2015. For purposes of this declaration only, I have assumed
`
`a priority date of December 16, 2015, in determining whether a reference constitutes
`
`prior art to the ’603 patent.
`
`15.
`
`I have been informed by Counsel that a claim in a granted patent must
`
`be sufficiently supported by the disclosure in the patent’s specification, read in the
`
`context of what one of skill in the art would have known at the time of the claimed
`
`invention. I understand from Counsel that the basic inquiry for written description
`
`is whether the patentee conveys in its disclosure within the patent that it had
`
`possession of the subject matter as of the filing date. I also understand form Counsel
`
`that demonstrating possession requires a precise definition of the invention.
`
`16. The claims of the ’603 patent recite a method of treating fibrosis in a
`
`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 a fibrosis of the heart, liver, kidney, or eye.
`
`6
`
`Lassen - Exhibit 1003, p. 6
`
`
`
`17. To satisfy the written description requirement for such claims, I have
`
`been informed by Counsel that the specification must disclose either a representative
`
`number of species of IL-11Rα antibodies falling within the scope of the claimed
`
`genus or the structural features common to the members of the genus such that one
`
`skilled in the art can “visualize or recognize” the members of the claimed genus. I
`
`have been informed by Counsel that this written description requirement applies
`
`whether a compound is claimed per se or a method is claimed that entails the use of
`
`the compound.
`
`18.
`
`I have been informed by Counsel that in addition to written description,
`
`a patent specification must also enable a person of ordinary skill in the art to make
`
`and use the full scope of the claimed invention without undue experimentation as of
`
`its effective filing date. I understand from Counsel that the following factors should
`
`be considered when making this determination: (1) the breadth of the claims, (2) the
`
`nature of the claimed invention, (3) the state of the prior art and the level of
`
`predictability in the art, (4) the knowledge of one of ordinary skill in the art, (5) the
`
`amount of direction provided by the named inventor(s), (6) the presence or absence
`
`of working examples, and (7) the quantity of experimentation needed to make or use
`
`the claimed invention based on the content of the disclosure.
`
`B. Materials Considered
`
`7
`
`Lassen - Exhibit 1003, p. 7
`
`
`
`19.
`
`I have reviewed the ’603 patent. I have also reviewed and considered
`
`the documents cited in this declaration.
`
`20.
`
`I provide opinions in this declaration based on my education, training,
`
`background, and experience, and the indicated documents I have reviewed to date.
`
`To the extent I am provided with additional documents or 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.
`
`II.
`
`SUMMARY OF MY OPINIONS
`
`21.
`
`I have been asked to consider whether the disclosure in the ’603 patent
`
`demonstrates possession of the full scope of the invention recited in claims 1-10.
`
`The ’603 patent claims a method for treating human fibrosis of the heart, liver,
`
`kidney, or eye comprising administering antibodies capable of inhibiting an antigen.
`
`That inhibited antigen is an Interleukin 11 receptor α (“IL-11Rα”). The claims cover
`
`a diverse genus of antibodies having different amino acid sequences (the ’603 patent
`
`states that an “‘antibody’ includes a fragment or derivative of an antibody, or a
`
`synthetic antibody or synthetic antibody fragment.” A search of the term
`
`“derivative” provides no further use in the ’603 patent. The term “synthetic
`
`antibody” may encompass antibody mutations. Ex. 1001, col. 20, lines 39-41),
`
`associated higher order structures, and corresponding functions. Given my
`
`8
`
`Lassen - Exhibit 1003, p. 8
`
`
`
`understanding the ’603 patent claims, the antibody is not limited to a human antibody
`
`or human IL-11Rα antigen, but the antibody or antigen can be from any species.
`
`22.
`
`In my opinion, none of claims 1-10 in the ’603 patent is adequately
`
`described or supported. The ’603 patent fails to provide any representative working
`
`examples of antibodies that bind to an IL-11Rα to provide a therapeutic benefit in
`
`vivo, or guidance on how such an antibody would be administered therapeutically.
`
`In fact, I identified no IL-11Rα antibody sequences [or structures] in the ’603 patent,
`
`including for example 12, example 13 or example 14, which discuss that discovery,
`
`binding properties, specificity and functional characterization of novel anti-IL-11Rα
`
`antibodies has occurred. The data to support the binding affinity, specificity and
`
`functional activity of anti-IL-11Rα antibodies reported in examples 13 and 14, and
`
`presumably supporting Claims 1-10, are not disclosed within the ’603 patent. The
`
`only antibody listed in the examples supporting the anti-IL-11Rα antibody
`
`generation and characterization examples (Ex. 1001, 12-14) is an anti-IL-11
`
`antibody (not an anti-IL-11Rα antibody) obtained from a commercial source (Mouse
`
`IgG2A, Clone #22626; Catalog No. MAB218; R&D Systems, MN, USA). No
`
`sequence or epitope binding information is available for the R&D Systems antibody
`
`in the ’603 patent or the R&D Systems Product datasheet. The R&D Systems anti-
`
`IL-11 antibody is used as the sole support for the examples 9-11 supporting IL-11
`
`antibody discovery, binding and functional characterization. However, no evidence
`
`9
`
`Lassen - Exhibit 1003, p. 9
`
`
`
`is given in the ’603 patent that anti-IL-11 antibodies provide any guidance or
`
`expectation of success with regard to efficacy of IL-11Rα antibodies when
`
`administered to a subject to treat fibrosis. Furthermore, there is no demonstration in
`
`any in vivo model of fibrosis that anti-IL-11 antibodies have the same efficacy or
`
`effects as anti-IL-11Rα antibodies in treating fibrosis or the same efficacy or effects
`
`as knocking out or inhibiting the expression of the IL-11 or IL-11Rα gene.
`
`23. A single unidentified IL-11Rα antibody is used in the ’603 patent to
`
`support the efficacy of anti-IL-11Rα antibodies across many organ systems and
`
`therapeutic areas of fibrosis. The therapeutic potential of IL-11/IL-11Rα blockade
`
`is demonstrated in Example 6 by culturing in vitro human atrial fibroblasts cells in
`
`the presence/absence of an unknown neutralizing anti-IL-11Rα antibody. Results
`
`with the unknown neutralizing IL-11Rα are shown in Figure 24 with the abrogation
`
`of a TGFß1-mediated profibrotic response.
`
`24. Example 6 constitutes the single working example of the activity and
`
`therapeutic potential of anti-IL-11Rα antibodies. The anti-IL-11Rα antibody
`
`discussed in Example 6 lacks any sequence or structural description (other than its
`
`receptor neutralizing properties) in the ’603 patent. The in vitro result shows only
`
`that this anti-IL-11Rα antibody inhibits IL-11 mediated-signaling when using a
`
`single marker of fibrosis measured by only a single marker of fibrosis, αSMA, which
`
`is not a validated cause of fibrosis in humans nor is a therapeutic that reduces aSMA
`
`10
`
`Lassen - Exhibit 1003, p. 10
`
`
`
`proven to be efficacious to treat fibrosis (see Ex. 1001, Examples 10 and 11, col. 51-
`
`54). The ’603 patent does not demonstrate the therapeutic efficacy or in vivo activity
`
`of the unidentified IL-11Rα antibody, and no data is provided of potential IL-11RΑ
`
`antibody efficacy in treating in in vivo models of any fibrotic disease.
`
`25.
`
`I conclude based upon my review that the ’603 patent fails to provide
`
`sufficient representative examples across the claimed genus of antibodies that
`
`exhibit the function of inhibiting IL-11 mediated signaling.
`
`26.
`
`I conclude that the ’603 patent does not identify any L-11Rα antibody
`
`sequence, structural features, CDR composition, binding epitopes or paratopes that
`
`might correlate with the claimed function of inhibiting IL-11 mediated signaling,
`
`much less the therapeutic activity features for a group of anti-IL-11Rα antibody.
`
`27.
`
`In my opinion, based on the limited information in the ’603 patent, a
`
`person of ordinary skill in the art could not visualize what antibody sequences might
`
`provide the claimed ability to inhibit IL-11 mediated signaling by binding to the IL-
`
`11Rα antigen. Predicting the sequences of antibodies that bind to IL11Rα and
`
`provide this function of inhibiting IL-11 mediated signaling simply was not possible
`
`in 2015, which I understand is the priority date Patent Owner has asserted for the
`
`’603 patent, and it is still not practical today.
`
`28.
`
`I have also been asked to consider whether the disclosure in the ’603
`
`patent would enable a person of ordinary skill in the art to make and use or practice
`
`11
`
`Lassen - Exhibit 1003, p. 11
`
`
`
`the full scope of claims 1-10. For reasons similar to those discussed above, the
`
`person of ordinary skill in the art as of Patent Owner’s asserted priority date would
`
`not have had sufficient guidance provided to practice the full scope of the claimed
`
`method of treating fibrosis in human subjects in claims 1-10. The specification of
`
`the ’603 patent provides no example of a method of treatment of fibrosis with any
`
`IL-11Rα antibody.
`
`29. The specification of the ’603 patent offers Examples 12 and 13 in which
`
`allegedly 17 mouse monoclonal anti-human IL-11Rα antibody clones (for which no
`
`structure was provided for any of them) were generated and tested to determine if
`
`they inhibit IL-11 mediated signaling in in vitro cardiac atrial human fibroblasts.
`
`However, Examples 12 and 13 of the ’603 patent fail to provide any sequences
`
`(structures) for the alleged 17 clones. The ’603 patent fails to indicate which of the
`
`alleged 17 clones were part of the majority that could bind to IL-11Rα let alone
`
`further structurally characterize the IL-11Rα binders. I also could not identify where
`
`the ’603 patent teaches the specific antibodies or the structures of the subset of the
`
`17 antibodies which could allegedly bind to IL-11Rα or how to obtain those
`
`antibodies that inhibited IL-11 mediated signaling to a greater extent than the mouse
`
`monoclonal anti-human IL-11 antibody clone #22626. Example 13 indicates that
`
`the antibodies with the collection of 17 anti-human IL-11Rα antibodies clone had
`
`variable function. The ’603 patent suggests that “a majority” of the subcloned
`
`12
`
`Lassen - Exhibit 1003, p. 12
`
`
`
`hybridomas bound to human IL-11Rα with high specificity, and only “several” of
`
`the antibodies had the ability to inhibit IL-11/IL-11R signaling to a greater extent
`
`than the monoclonal mouse anti-IL-11 antibody. (Ex. 1001, col. 55-57). The 17
`
`antibodies referenced do not constitute or teach a structure-function relationship and
`
`to the contrary, these antibodies as a subset of the genus claimed, demonstrate that
`
`different anti-IL-11Rα antibodies have different functions, including on in vitro
`
`measures of fibroblast activity.
`
`30. While the specification of the ’603 patent offers in vitro assays for
`
`testing antibodies for potential anti-fibrosis activity, it provides no guidance on
`
`suitable antibodies, their sequences, their binding epitopes and their resulting
`
`functional impact (for example blocking IL-11 binding, blocking IL-11Rα mediated
`
`signaling, or blocking association with the IL-11Rα co-receptor GP130), except
`
`through the blind screening of many sequences; however I did not identify the
`
`structure of even one antibody in this application. Given the itemized missing details
`
`in the ’603 patent, I would be unable to replicate the experiments to obtain anti-IL-
`
`11Rα antibodies with the activities as suggested in Examples 12 and 13. I would
`
`also be unable to compare an anti-IL-11Rα antibody I produced with their
`
`antibodies, because they do not provide a structure for their antibodies nor, as I
`
`understand, is did the inventors of the ’603 patent deposit their antibodies at a
`
`biological depository.
`
`13
`
`Lassen - Exhibit 1003, p. 13
`
`
`
`III. BACKGROUND AND STATE OF THE ART
`
`31. The IL-6 family of cytokines and receptors includes diverse members
`
`including IL-6, IL-27, IL-31, leukemia inhibitory factor (LIF), ciliary neurotrophic
`
`factor (CNTF), cardiotrophin 1 (CT-1), cardiotrophin-like, cytokine factor 1
`
`(CLCF1) and IL-11. (Ex. 1028, 10-17) Each of these cytokines, including IL-11,
`
`form a large 4 helical bundle that binds to the receptor complex. Each IL-6 family
`
`receptor heterodimeric complex contains a ‘generic’ GP130 receptor, common to all
`
`IL-6 receptors, and a ‘specific’ receptor responsible for binding to the cytokine in
`
`question, in this case IL-11 (Ex. 1019, 85-97; Ex. 1020, 773-89) In a structure likely
`
`similar to that of the IL-6/IL6R complex, the receptor, IL-11Rα, provides the
`
`majority of the specificity and for IL-11 affinity, while the associated co-receptor
`
`GP130 drives signal transduction, as evidenced by the absence of intracellular
`
`signaling motifs on IL-11R (Ex. 1006, 36197-203; Ex. 1022, 441-48).
`
`
`
`14
`
`Lassen - Exhibit 1003, p. 14
`
`
`
`Adapted from Ex. 1030, 1.
`
`32. Around December 2015, I understand that it was thought that IL-11
`
`binds with low nanomolar affinity to IL-11Rα on the cell surface. The IL-11/ IL-
`
`11Rα complex is not competent for cell signaling, whereas heterodimerization IL-
`
`11/IL-11Rα with GP130 results in a higher affinity complex that is capable of
`
`intracellular signaling (Ex. 1017, 4403-12). This complex and temporal set changes
`
`involve transitions in receptor homo- and hetero-dimerization, conformational
`
`changes, interactions between IL-11 and IL-11Rα, interactions between IL-11 and
`
`GP130 and between IL-11Rα and GP130. Ex. 1006. The functional signaling
`
`complex of IL-11, IL-11Rα and gp130 contains two molecules of each of the three
`
`proteins. Ex.1006. IL-11Rα is an ~420 amino acid protein possessing multiple
`
`domains that have been shown to interact with IL-11. Likewise, GP130 is large
`
`multisubunit, ~870 amino acid protein containing multiple interaction domains that
`
`facilitate signaling with diverse binding partners across the IL-6 receptor family (Ex.
`
`1031).
`
`33.
`
`I understand that IL-6 family heterodimeric receptors drive signal
`
`transduction via receptor-associated Janus kinases (primarily JAK1 and JAK2)
`
`which phosphorylate conserved tyrosine residues in the cytoplasmic domains of
`
`signaling receptor subunits. I understand that downstream signaling pathways in the
`
`IL-6 family are activated in response, including signal transducer and activator of
`
`15
`
`Lassen - Exhibit 1003, p. 15
`
`
`
`transcription (STAT) proteins the mitogen-activated protein kinase (MAPK)
`
`cascade, the ERK (extracellular-regulated kinase) pathway, phosphatidylinositol-3-
`
`kinase (PI3K)/Akt pathway, and the SRC/YAP/NOTCH pathway. I understand that
`
`while signal transduction by individual IL-6 family members is broadly similar, the
`
`relative strength of activation of the specific pathways can differ depending on the
`
`cytokine, cytokine concentration and duration of cytokine stimulation, cell type and
`
`cell state, and physiological context.
`
`34. From the factors listed above, it is clear that antibodies against IL-11Rα
`
`could (i) inhibit IL-11Rα but not GP130 binding, (ii) inhibit IL-11Rα but not IL-11
`
`binding; (ii) inhibit heterodimerization of IL-11RΑ/GP130; (iii) drive IL-11Rα
`
`internalization of IL-11RΑ; and (iv) modulate expression of IL-11RΑ among other
`
`things. Therefore, characterizing the binding, structure and activity of an anti-IL-
`
`11Rα antibody in my opinion would be necessary to identify which anti-IL-11Rα
`
`antibody would also have the function of an anti-fibrotic effect.
`
`35.
`
`I understand the claims of the ’603 patent represent a method for the
`
`treatment of fibrosis that includes the use of any antibody made in any animal cell
`
`model that binds to any animal IL-11Rα (See, e.g., Ex. 1001, Claims 1-3 (“1. The
`
`method of treating fibrosis in the human subject, the method comprising
`
`administering to a human subject in need of treatment a therapeutically effective
`
`amount of an Interleukin 11 receptor alpha (IL-11Rα) antibody which is capable of
`
`16
`
`Lassen - Exhibit 1003, p. 16
`
`
`
`inhibiting Interleukin 11 (IL-11) mediated signaling, wherein the fibrosis is fibrosis
`
`of the heart, liver, kidney or eye. 2. The method of claim 1, wherein the antibody
`
`is capable of inhibiting or reducing the binding of IL-11 to an IL-11 receptor. 3.
`
`The method of claim 1, wherein the antibody is an IL-11Rα binding antibody.”).)
`
`Basically, claims 1-10 of the ’603 patent functionally characterize the antibody only
`
`by its ability to treat fibrosis in a human.
`
`36.
`
`I have been informed by Counsel that whether a compound is claimed
`
`per se or a method is claimed that entails the use of the compound, as in claims 1-
`
`10, the inventor has to provide a structural description of the compound. I have also
`
`been informed by Counsel that for a genus antibody claim, a written description
`
`requires either: 1) a representative number of species falling within the scope of the
`
`genus; or 2) the structural features common to the members of the genus so that one
`
`of skill in the art can ‘visualize or recognize’ the members of the genus.
`
`37. My review of the ’603 patent finds that the patent does not provide a
`
`representative number of species falling with the scope of the genus. I believe that
`
`the ’603 patent is not sufficient to guide a person of ordinary skill in the art to design,
`
`much less “visualize or recognize,” from the large number of antibodies falling
`
`within the claimed genus, sequences of antibodies that treat fibrosis of the heart,
`
`liver, kidney or eye; inhibits IL-11 mediated signaling; inhibits or reduces the
`
`binding of IL-11 to an IL-11 receptor; or binds to an IL-11 receptor. I believe a
`
`17
`
`Lassen - Exhibit 1003, p. 17
`
`
`
`person of ordinary skill in the art around December 2015 would have to test each
`
`and every sequence across a diverse pool of candidate antibodies to identify those
`
`that bind IL-11Rα and have the desired function given that no structural information
`
`or even mechanistic information is provided.
`
`A. Antibodies Must Be Screened
`
`38. To understand the unpredictability of antibody sequences that bind IL-
`
`11Rα and the vast pool of potential antibodies one of skill in the art would still have
`
`to screen them, to identify ones having the desired activity, and then would have to
`
`determine their structure and perhaps even mechanism of action.
`
`1.
`
`Primer on Antibody Structure
`
`39.
`
`I believe I need to provide background on the structure and biology of
`
`antibodies to explain the complexity of their diversity. An antibody (also called an
`
`immunoglobulin) is a protein that can recognize and bind to a target molecule (also
`
`referred to as an “antigen”). (Ex. 1038, 93). Intact antibodies typically contain four
`
`polypeptide chains, made up of two identical “heavy chains” and two identical “light
`
`chains” that pair to form two arms in a Y shape as illustrated in Figure 1 below. The
`
`“heavy” and “light” labels refer to the molecular weights of the two chains, with the
`
`heavy chain having additional amino acids at one end (green).
`
`18
`
`Lassen - Exhibit 1003, p. 18
`
`
`
`
`Figure 1. Exemplary antibody structure (taken from Ex. 1042, 1382 (Fig. 24-32).)
`
`40.
`
`In a typical antibody, the base of the “Y” shaped structure forms the
`
`constant region (c), which primarily regulates interaction of the antibody with
`
`cellular receptors in the body. (Ex. 1038, 96). The constant region comprises several
`
`domains that form the Fc portion of an antibody. (Ex. 1038, 96). Depending on the
`
`amino acid sequences included in the constant region on the heavy chain, human
`
`antibodies can be categorized into five different immunoglobulin classes, namely,
`
`IgM, IgD, IgG, IgA, and IgE. (Ex. 1038, 95). There are also subclasses within some
`
`of these. The human IgG class, for instance, can be further categorized into four
`
`subclasses, designated as IgG1, IgG2, IgG3, and IgG4. (Ex. 1038, 95). Likewise,
`
`light chains fall in one of two classes: lambda (λ) or kappa (κ). (Ex. 1038, 95).
`
`41. The regions on the two arms of the “Y” shaped structure in a typical
`
`antibody regulate binding to the targeted antigen. Because the amino acid sequences
`
`of these binding regions (arms) vary extensively from one antibody to another, they
`
`19
`
`Lassen - Exhibit 1003, p. 19
`
`
`
`are referred to as “variable regions.” (Ex. 1038, 93). The amino acid sequences in
`
`the variable regions determine which antigen an antibody will bind and how strongly
`
`it will bind to the antigen. (Ex. 1038, 93, 96). Even small changes in the sequence
`
`of the variable region can markedly alter antigen binding or eliminate binding
`
`altogether.
`
`42. Each variable region is formed from a pair of “variable domains”
`
`present on the heavy and light chains of the antibody. The light chain variable
`
`domain (“VL”) pairs with the heavy chain variable domain (“VH”) to form a specific
`
`three-dimensional structure capable of interacting with a target antigen. (Ex. 1038,
`
`96). A standard antibody has two identical sets of these VH-VL pairs, one on each
`
`arm of the “Y” shaped structure. Variants of this general structure are also well
`
`characterized in the literature.
`
`43. Antibody engineering techniques allow those skilled in the art to
`
`modify the standard antibody structures. (Ex. 1038, 97). For instance, researchers
`
`have prepared single-chain molecules containing a VH domain linked by a synthetic
`
`peptide to a VL domain. (Ex. 1038, 97). This single chain molecule often retains the
`
`three-dimensional structure of the traditional variable region and the associated
`
`ability to bind the target antigen. The resulting fragment is called a single-chain Fv,
`
`or scFv. (Ex. 1038, 97).
`
`20
`
`Lassen - Exhibit 1003, p. 20
`
`
`
`44. Other functional antibody binding fragments such as Fab, F(ab’)2, and
`
`Fv fragments have also been produced by researchers. (Ex. 1046, 129, 130 (Fig. 1);
`
`Ex. 1058, 342-44; Ex. 1038, 96-97). A Fab fragment comprises an antigen binding
`
`region made up of a complete light chain paired with the variable domain and one
`
`constant domain of the heavy chain. This corresponds to one arm of the “Y” shape
`
`in a standard antibody. (Ex. 1038, 96). A F(ab’)2 fragment contains both antigen-
`
`binding arms of the “Y” shape in an antibody linked by one or more disulfide bonds.
`
`(Ex. 1038, 97). An Fv fragment is a more truncated fragment that comprises only
`
`the variable domains of a heavy chain and a light chain. (Ex. 1038, 96-97; Ex. 1058,
`
`342-43 (Fig. 2)). The scFv, Fv, Fab fragments and full length antibodies often have
`
`different avid characteristics that can impact efficacy, apparent affinity, target
`
`internalization. Cell surface proteins are actively internalized and degraded as part
`
`of normal biological function and regulation. Antibody binding to a cell surface
`
`protein can affect the rate of antibody internalization, and different antibodies to the
`
`same cell surface protein can impact the rate of internalization differently. As such,
`
`antibodies that bind cell surface proteins are typically screened for this property via
`
`secondary antibody reagents and tags combined with flow cytometry, internalization
`
`should be screened in combination with identified variable domains (providing
`
`antigen binding specificity) to confirm desired activity.
`
`21
`
`Lassen - Exhibit 1003, p. 21
`
`
`
`2.
`
`Antibodies Exhibit Highly Diverse Sequences and that
`Variability Dictates Binding Affinity and Function
`
`45. The variable domains, which regulate interaction with antigens, exhibit
`
`extensive variability. One of the consequences of this structural diversity is that the
`
`immune response to a given antigen is also diverse. That variability allows different
`
`antibodies to bind to a wide range of different target molecules and to different sites,
`
`or epitopes within target molecules. Vastly different antibody sequences may bind
`
`to the same or similar antigens, while at the same time antibodies with quite similar
`
`sequences can form three-dimensional structures that bind entirely different
`
`antigens. (Table 3 infra in this declaration). Differences in sequence not only
`
`regulate antigen specificity (the antigen an antibody will bind) and affinity for that
`
`antigen, but they also dictate functional consequences in biologic systems (such as
`
`agonist or antagonist effects).
`
`46. Most antibody diversity occurs in the variable domains, which form the
`
`three-dimensional binding region responsible for interacting with a targeted antigen.
`
`While diversity occurs throughout the variable domains, there are three separate
`
`segments on each heavy chain and light chain that exhibit hypervariability in
`
`sequence. (Ex. 1038, 100-01). These regions of hypervariability are referred to as
`
`the complementarity determining regions (“CDRs”) because they directly interact
`
`with a target antigen by forming a complementary surface. (Ex. 1038, 101). As
`
`22
`
`Lassen - Exhibit 1003, p. 22
`
`
`
`discussed in detail below, even minute changes in the CDR sequences can drastically
`
`alter the antigen that will interact with the antibody.
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