`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`ITM Isotope Technologies Munich SE
`Petitioner
`
`v.
`
`The Johns Hopkins University
`Patent Owner
`
`_____________________
`
`Case PGR2025-00012
`Patent No. 11,938,201
`______________________
`
`EXPERT DECLARATION OF STEPHEN F. MARTIN, PH.D.
`
`
`
`
`I declare that all statements made herein of my knowledge are true, that all
`statements made herein on information and belief are believed to be true, and that
`these statements were made with the knowledge that willful false statements and the
`like so made are punishable by fine or imprisonment, or both, under Section 1001 of
`Title 18 of the United States Code.
`
`
`By: _______________________
`
`
`
`Date:__December 24, 2024__
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`I.
`
`INTRODUCTION ....................................................................................... 1
`A.
`Experience and Qualifications ........................................................... 1
`B.
`Review and Use of Documents and Other Materials .......................... 4
`SUMMARY OF MY OPINIONS ................................................................ 5
`II.
`III. LEGAL PRINCIPLES ................................................................................. 6
`IV. TECHNOLOGY BACKGROUND.............................................................. 9
`A.
`FAP Inhibitors ................................................................................... 9
`B. Optical and Radioimaging Agents.....................................................12
`C.
`Prior Art References .........................................................................16
`1.
`Dvořáková ..............................................................................16
`2.
`Jansen I ...................................................................................19
`3.
`Zimmerman ............................................................................22
`4.
`Jansen II ..................................................................................26
`5.
`Pomper ...................................................................................27
`V. U.S. PATENT NO. 11,938,201 ...................................................................29
`A.
`Specification .....................................................................................29
`B.
`Prosecution History...........................................................................37
`C.
`Claims of the ’201 Patent ..................................................................49
`VI. PERSON OF ORDINARY SKILL IN THE ART .......................................51
`VII. CLAIM CONSTRUCTION ........................................................................52
`A.
`“Low molecular weight” ...................................................................53
`B.
`“C(O)Alkyl” / “Aryl” ........................................................................57
`
`
`
`i
`
`

`

`VIII. INVALIDITY .............................................................................................59
`A. Ground I: Claims 1-3 Would Have Been Obvious to a POSA In
`View of Jansen I and/or Jansen II, Taken in View of
`Zimmerman and Pomper ...................................................................59
`1.
`Claim 1 ...................................................................................60
`2.
`Claim 2 ...................................................................................70
`3.
`Claim 3 ...................................................................................70
`4.
`No Secondary Indicia ..............................................................71
`B. Ground II: Claims 1-3 Would Have Been Obvious to a POSA
`In View of Dvořáková and Pomper ...................................................73
`1.
`Claim 1 ...................................................................................75
`[1a] “A low molecular weight compound of
`a.
`Formula (I): B-L-A (I) wherein:” ..................................75
`[1b] “A is a targeting moiety for FAP-α, wherein
`A has the structure of . . .”.............................................75
`[1c] “B is any optical or radiolabeled functional
`group suitable for optical imaging, positron-
`emission tomography (PET) imaging, single-
`photon emission computed tomography (SPECT)
`imaging, or radiotherapy” .............................................79
`[1d] “L is a linker having bi-functionalization
`adapted to form a chemical bond with B and A” ...........81
`[1e] “or a stereoisomer, tautomer, racemate, salt,
`hydrate, or solvate thereof” ...........................................82
`Claim 2 ...................................................................................82
`2.
`Claim 3 ...................................................................................83
`3.
`C. Ground III: Claims 1-3 Lack of Enablement .....................................84
`1.
`Scope of the Claimed Invention ..............................................84
`ii
`
`b.
`
`c.
`
`d.
`
`e.
`
`
`
`

`

`2.
`3.
`4.
`5.
`6.
`7.
`
`Existence of Specific Working Examples ...............................87
`Guidance in the Specification .................................................89
`Level of Ordinary Skill in the Art ...........................................90
`Nature and Predictability of the Art ........................................91
`Quantity of Experimentation Needed ......................................92
`How Routine Any Necessary Experimentation Is in the
`Relevant Field .........................................................................93
`8. Weighing the Wands Factors...................................................93
`D. Ground IV: Claims 1-3 Lack Written Description .............................94
`E.
`Ground V: Claims 1-3 are Indefinite .................................................95
`IX. CONCLUSION ........................................................................................ 100
`
`
`
`iii
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`

`

`
`
`
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by counsel for Petitioner ITM Isotope
`
`Technologies Munich SE (“Petitioner”) as an independent expert consultant in this
`
`proceeding before the U.S. Patent and Trademark Office (“USPTO”). I am being
`
`compensated for the time I spend on this matter, but no part of my compensation is
`
`dependent on the outcome of this proceeding.
`
`2.
`
`I understand that this proceeding involves U.S. Patent No. 11,938,201
`
`(“the ’201 patent”), issued on March 26, 2024. EX1001 at Cover. I understand that
`
`the application for the ’201 patent was filed on July 18, 2023, as U.S. Patent
`
`Application No. 18/354,282, and claims a priority date of October 23, 2017. Id.
`
`3.
`
`I submit this Declaration on behalf of Petitioner as an expert in the field
`
`of organic chemistry, including bioactive natural products and molecular probes, in
`
`the above-identified proceeding. My qualifications in these areas, as well as other
`
`areas, are established below and by my curriculum vitae (EX1003).
`
`A. Experience and Qualifications
`I received a B.S. degree in chemistry from the University of New
`4.
`
`Mexico in 1968 and a Ph.D. degree in chemistry from Princeton University in 1972.
`
`After postdoctoral years at the University of Munich and Massachusetts Institute of
`
`Technology, I joined the faculty at The University of Texas at Austin (UTA) in 1974
`
`
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`1
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`

`

`
`
`where I was a faculty member in the Department of Chemistry until my retirement
`
`in 2024; I held the M. June and J. Virgil Waggoner Regents Chair in Chemistry.
`
`5.
`
`At the UTA, I taught courses at the undergraduate and graduate levels
`
`in the general areas of organic chemistry, including advanced courses specializing
`
`in synthetic organic, natural product, heterocyclic, and bioorganic chemistry.
`
`6. My research interests lie broadly in organic and bioorganic chemistry
`
`and chemical biology. More specifically my research involved the synthesis of
`
`biologically active natural products, many of which were complex heterocycles, and
`
`the study of energetics and structure in protein-ligand interactions. My research also
`
`focused on the design and synthesis of nitrogen-containing heterocyclic compounds
`
`and other small molecules that may be used as molecular probes to study biological
`
`function and as potential leads to treat various diseases, including cancer,
`
`neurodegeneration, and neurological disorders by a fundamentally new approach.
`
`7.
`
`I supervised undergraduate and graduate students, postdoctoral
`
`associates and research scientists who prepared, purified, and characterized organic
`
`compounds. I also supervised studies in chemical biology and physical biochemistry,
`
`including molecular modeling, protein isolation and crystallography, mutagenesis,
`
`mechanistic enzymology, enzyme inhibitor design, medicinal chemistry, and
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`molecular caging. I have published approximately 360 scientific papers in primary
`
`
`
`2
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`

`

`
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`journals together with several patents, reviews, and book articles. Details may be
`
`found in many of my peer-reviewed publications listed in my CV. EX1003.
`
`8.
`
`In recognition of my achievements, I have received a number of awards,
`
`including the NIH Career Development Award; the American Cyanamid Academic
`
`Award; the Alexander von Humboldt Prize; the Arthur C. Cope Scholar Award; the
`
`Japanese Society for the Promotion of Science Award; the Wyeth Research Award;
`
`the International Society of Heterocyclic Chemistry Senior Award; the Ernest
`
`Guenther Award in the Chemistry of Natural Products (ACS); and the Gund-
`
`Harrington Scholar Award.
`
`9.
`
`I am a fellow of the American Association for the Advancement of
`
`Science and of the American Chemical Society. I have also served as the regional
`
`editor of Tetrahedron for the Americas and Chairman of the Executive Board of
`
`Editors of Tetrahedron Publications.
`
`10. Since 1999, I have acted as a member of the Advisory Board of the
`
`scientific book series Organic Synthesis, which publishes checked procedures for
`
`the synthesis of organic compounds. From 1991-1999, I served as a member of the
`
`Board of Editors of that publication. In that capacity, I was responsible for evaluating
`
`and checking synthetic procedures that had been submitted by other chemists.
`
`
`
`3
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`

`

`
`
`11.
`
`I have served as a consultant in medicinal and process chemistry for a
`
`number of pharmaceutical companies, including Procter and Gamble, Athena
`
`Neuroscience, Elan Pharmaceutical, ICOS Corporation, and Abbott Laboratories.
`
`12.
`
`I
`
`am
`
`co-author of
`
`the popular undergraduate
`
`laboratory
`
`book Experimental Organic Chemistry: A Miniscale and Microscale Approach.
`
`This text generally describes the basic techniques of experimental organic chemistry
`
`as well as the practical aspects of performing many standard reactions in the
`
`laboratory. It is used in our first-year organic chemistry laboratory class at UTA, as
`
`well as at other institutions.
`
`13. As the president of NuvoNuro and principal investigator on a major
`
`NIH HEAL grant, I currently supervise all activities related to early drug discovery
`
`and development, including molecular modeling, ligand design and synthesis, and
`
`interpretation of in vitro and in vivo experimental data.
`
`14.
`
`I am being compensated for my time working on this matter at my
`
`customary rate of $800 per hour. No part of my compensation is contingent upon
`
`my opinions, my performance, or the outcome of this matter or any issue in it.
`
`B. Review and Use of Documents and Other Materials
`In forming my opinions, I have considered the documents and materials
`15.
`
`cited herein. I additionally have based my opinions on my professional and academic
`
`experience in the broad areas of organic chemistry and chemical biology.
`
`
`
`4
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`

`

`
`
`II. SUMMARY OF MY OPINIONS
`It is my opinion, based on my review of the prior art, that it would have
`16.
`
`been obvious to a POSA as of October 23, 2017, to combine the teachings of Jansen
`
`I, Jansen II, Zimmerman, and Pomper in order to arrive at the claimed subject matter
`
`and that the alleged unexpected results provided by Patent Owner during prosecution
`
`are not commensurate in scope with the ’201 patent claims.
`
`17. Further, based on my review of the prior art, it is my opinion that it
`
`would have also been obvious to a POSA to combine the teachings of Dvořáková
`
`and Pomper in order to arrive at the ’201 patent claimed subject matter.
`
`18.
`
`It is also my opinion that the ’201 patent claims do not satisfy the
`
`written description or enablement requirements. Given the breadth of the ’201 patent
`
`claims and the functional language recited therein, the disclosure of the ’201 patent
`
`does not provide adequate written description for its claims, and it would require
`
`undue experimentation to make and use the full scope of the claims.
`
`19. Finally, in my opinion, the term “low molecular weight” in the ’201
`
`patent claims is indefinite. The ’201 patent and its file history does not provide
`
`numerical boundaries for the term “low molecular weight” and, based on my
`
`experience, knowledge, and review of the materials in this case, it is my opinion that
`
`the claims fail to inform those skilled in the art about the scope of the claims with
`
`reasonable certainty.
`
`
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`5
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`

`

`
`
`III. LEGAL PRINCIPLES
`I have no formal legal training, and I have relied on the lawyers
`20.
`
`representing Petitioner in this case for the applicable legal standards governing my
`
`analyses and opinions. I have applied those standards in providing my opinions
`
`regarding validity. The legal standards that were provided to me are set forth below.
`
`21.
`
`I understand that patentability must be analyzed from the perspective
`
`of “a person of ordinary skill in the art” (POSA) in the same field as the challenged
`
`patent as of the “effective filing date” of the claims. I understand that a POSA is a
`
`hypothetical individual presumed to know the relevant art as of the “effective filing
`
`date” and has the same level of skill as the ordinary practitioner of the art at issue.
`
`22.
`
`I understand that the meaning of a particular claim term is to be viewed
`
`from the perspective of one of ordinary skill in the art at the time of the invention,
`
`and my opinions below are offered from this perspective. I also understand that
`
`patent claims must be read in view of the patent’s written description, drawings, and
`
`prosecution history. My opinions are offered from this perspective.
`
`23.
`
`I understand that a patent claim is unpatentable for obviousness if any
`
`subject matter within the scope of the claim would have been obvious to a POSA,
`
`considering (1) the scope and content of the prior art, (2) the differences between the
`
`prior art and the claimed invention, and (3) the level of ordinary skill in the art, and
`
`(4) any secondary considerations of non-obviousness, including unexpected results,
`
`
`
`6
`
`

`

`
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`commercial success of products or processes using the invention, long-felt need for
`
`the invention, failure of others to make the invention, industry acceptance of the
`
`invention, and copying of the invention by others.
`
`24.
`
`I further understand that a claim may be obvious based on multiple
`
`references combined with one another, or pursuant to the knowledge and skill of a
`
`POSA. I also understand there must have been a reason that would have prompted a
`
`POSA to combine the features of the prior art in the way the claimed invention does.
`
`25.
`
`I also understand that a person skilled in the art must have reasonably
`
`expected that the combination will work. That is, obviousness requires a “reasonable
`
`expectation of success” in achieving the claimed subject matter.
`
`26.
`
`I understand that the specification must include a written description of
`
`the claimed subject matter. It is my understanding that the patent statute imposes a
`
`written description requirement that is met if the patent specification describes the
`
`claimed invention in sufficient detail such that one skilled in the art can reasonably
`
`conclude that the inventor had possession of the full scope of the claimed subject
`
`matter at the time the application was filed.
`
`27.
`
`I also understand that the written description requirement requires the
`
`specification, when considered as a whole, to convey to a person of ordinary skill in
`
`the art, either explicitly or inherently, that the inventor invented the subject matter
`
`claimed in the patent. I further understand that the description requirement of the
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`
`
`7
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`

`

`
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`patent statute requires a description of an invention, not an indication of a result that
`
`one might achieve if one made that invention.
`
`28.
`
`I understand that the specification must also enable a person of ordinary
`
`skill in the art relevant to the patent to practice the claimed subject matter without
`
`undue experimentation. I also understand that the scope of support must be
`
`commensurate in scope with the claims. More specifically, I understand that the
`
`specification must “teach those skilled in the art how to make and use the full scope
`
`of the claimed invention without undue experimentation.”
`
`29.
`
`I understand that the following “Wands” factors may be considered to
`
`determine whether “undue experimentation” by a person of ordinary skill would be
`
`required:
`
`1) the breadth of the claims;
`
`2) the quantity of experimentation needed to make or use the invention;
`
`3) the nature of the invention;
`
`4) the existence of working examples;
`
`5) the amount of direction provided by the inventor;
`
`6) the state of the prior art;
`
`7) the level of predictability in the art;
`
`8) the level of skill in the art.
`
`
`
`8
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`

`

`
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`30.
`
`I also understand that although they are two separate requirements,
`
`written description and enablement may rely on the same facts and have overlapping
`
`analyses.
`
`31.
`
`I understand that patent claims must “particularly point out and
`
`distinctly claim” the subject matter the inventor regards as his invention. More
`
`specifically, I understand that patent claims are invalid as indefinite when, read in
`
`light of the specification delineating the patent, and the prosecution history, they
`
`“fail to inform, with reasonable certainty, those skilled in the art about the scope of
`
`the invention.” I have also been informed that an underlying principle is that without
`
`sufficient precision, there would be “[a] zone of uncertainty which enterprise and
`
`experimentation may enter only at the risk of infringement claims.”
`
`IV. TECHNOLOGY BACKGROUND
`FAP Inhibitors
`A.
`32. Fibroblast-activation protein (FAP, FAP-α, seprase, alpha2 antiplasmin
`
`converting enzyme) is a type II transmembrane serine protease and a member of the
`
`prolyl oligopeptidase subfamily S9b. EX1007 at 1:16-19. This family of serine
`
`proteases, which preferentially cleaves peptides after proline residues, also includes
`
`prolyl oligopeptidase (PREP) and the dipeptidyl peptidases (DPPs) DPPIV, DPPII,
`
`and DPP8/9.1. EX1010 at 491.
`
`
`
`9
`
`

`

`
`
`33.
`
`In over 90% of human epithelial tumors, FAP expression is associated
`
`with activated stromal fibroblasts and pericytes, and FAP is generally not expressed
`
`in healthy tissues. Id. Studies have shown that FAP expression promotes
`
`tumorigenesis, while FAP inhibition can mediate tumor growth. Id. Thus, research
`
`has focused on developing a map of the physiological substrate spectrum to develop
`
`FAP inhibitors. Improved FAP inhibitors should have combined low nanomolar
`
`FAP inhibition and high selectivity for FAP over related proteases, including DPPs
`
`and PREP. Id.
`
`34.
`
`Initial development of FAP inhibitors focused on compounds including
`
`pyrrolidine-2-boronic acid derivatives, such as the structure below:
`
`
`
`Id. at Figure 1. However, the pyrrolidine-2-boronic acid derivatives were shown to
`
`not be sufficiently selective, leading to safety concerns. Id. at 491.
`
`35. Further research, as disclosed in Jansen I and Jansen II, focused on the
`
`development of FAP inhibitors with high selectivity. Exemplary embodiments of
`
`Jansen I include the following:
`
`
`
`10
`
`

`

`
`
`with specific focus on varying the substituent:
`
`
`
`EX1007 at 98:50-59, Table 4. The selectivity of most of the compounds for FAP
`
`over PREP was reported as 50x higher than the reference compounds. Id. at 95:47-
`
`
`
`50.
`
`36. However, Jansen I points to the position of the nitrogen atom in the
`
`substituent as having “pivotal importance”, stating that “the 4-quinolinoyl ring
`
`clearly displays the best results.” EX1007 at 78:24-31.
`
`
`
`
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`11
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`

`

`
`
`
`
`4-quinolinoyl ring
`
`37. This is further affirmed by the findings of Jansen II, which concluded
`
`that the presence of a 4-quinolinoyl ring resulted in higher selectivity as shown in
`
`the Abstract Figure of Jansen II, reproduced below.
`
`38.
`
` Therefore, as of October 23, 2017, FAP inhibitors, including the
`
`structures taught by Jansen I and Jansen II, were known to have high selectivity and
`
`performance compared to earlier FAP inhibitors, such as pyrrolidine-2-boronic acid
`
`
`
`derivatives.
`
`B. Optical and Radioimaging Agents
`39. The expression of distinct proteins, such as FAP, on the surface of
`
`tumor cells of many cancer
`
`types allows
`
`the possibility of diagnosing,
`
`
`
`12
`
`

`

`
`
`characterizing, and treating the disease by probing the phenotypic identity,
`
`biochemical composition, and activity of the tumor. EX1009 at ¶ 5. The association
`
`and expression of FAP on tumors makes it a desirable candidate to exploit for
`
`noninvasive imaging. Id. Examples of diagnostic approaches for targeting FAP
`
`include in vivo optical imaging and radioimaging.
`
`40.
`
`In vivo optical imaging is a non-invasive imaging technique that uses
`
`visible or near-infrared light to visualize biological processes within a living
`
`organism by detecting photons emitted from optically active probes administered
`
`into the body. EX1017 at Introduction. In other words, optical probes, such as dyes,
`
`can be administered to a patient and following excitation with a light source, the
`
`light emitted by the optical probes can be monitored to provide insight related to
`
`diagnostics and/or treatment. Id. Most commonly, near-infrared (NIR) fluorescent
`
`probes are employed because biological tissues show very low absorption and auto-
`
`fluorescence in the NIR spectrum window. Id. The use of this approach in diagnostic
`
`and intraoperative imaging and in the monitoring of treatment response has been
`
`demonstrated for many diseases. Id.
`
`41. Thus, molecular imaging probes which target FAP would enable
`
`classification of cancer patients for FAP-targeted therapy. For example, Rüger
`
`provides anti-FAP-IL, which is a fluorescence-activatable liposome (fluorescence-
`
`quenched during circulation and fluorescence activation upon cellular uptake),
`
`
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`13
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`

`
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`bearing specific single-chain fragments directed against FAP. Id. at Abstract. Only
`
`FAP-expressing cells were able to take up and activate fluorescence of the anti-FAP-
`
`IL, and therefore the fluorescence of the probe could be used to monitor cancerous
`
`cells. Id.
`
`42.
`
`In addition, Dvořáková developed a polymer conjugate including a
`
`FAP targeting moiety and an optical dye (ATTO488). EX1008 at 8389. By including
`
`the FAP targeting moiety, the polymer conjugate directly targeted and bound
`
`selectively to only FAP expressing cells. Id. at 8390. The FAP expressing cells
`
`internalized the polymer conjugate, and the presence of the optical dye was utilized
`
`for imaging purposes. Id. at 8390-91. Thus, the FAP expressing cells produced a
`
`fluorescence signal from the optical dye, which allowed visualization of the tumors.
`
`Id. at 8391.
`
`43. Therefore, as of October 23, 2017, it was known to combine optical
`
`probes with FAP inhibitors that target FAP expressing cells to selectively visualize
`
`FAP-expressing cells.
`
`44. Radioimaging is another non-invasive imaging technique that employs
`
`radioactive substances rather than optical dyes. Examples of radioimaging
`
`techniques include positron-emission tomography (PET) imaging and single-photon
`
`emission computed tomography (SPECT) imaging. These techniques are some of
`
`
`
`14
`
`

`

`
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`the earliest and most mature molecular imaging techniques having high sensitivity
`
`and quantifiability. EX1018 at 1-2.
`
`45.
`
`In PET, a radioactive substance that emits positrons is injected into the
`
`patient, and positron emission is subsequently detected. Id. Examples of positron
`
`emitting isotopes are 11C, 15O, 18F, and 131I. Id. SPECT imaging occurs in a similar
`
`manner; however, the radioactive substance emits gamma radiation rather than
`
`positrons. Id. Examples of gamma emitting isotopes include 99mTc, 111In, 123I,
`
`and 177Lu. Id. Another approach is the use of these small molecules as carriers of
`
`radioactivity into the tumor for both radioimaging and radiotherapy. Id.
`
`46. Furthermore, molecules that include radioactive or radiolabeled
`
`moieties and can selectively bind to specific tumor cell surface proteins allow for
`
`the use of noninvasive imaging techniques for detecting the presence and quantity
`
`of tumor associated proteins. EX1009 at ¶ 5. This selective binding can provide
`
`information related to the diagnosis and extent of disease as well as prognosis and
`
`therapeutic management options, while minimally affecting other areas of the
`
`patient. Id. Thus, radiopharmaceuticals are not only capable of imaging the disease
`
`but also of delivering a therapeutic radionucleotide to the diseased tissue for
`
`treatment. Id.
`
`47. Again, as the expression of FAP is associated with tumors, research has
`
`focused on the development of radioimaging and radiotherapy agents which
`
`
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`15
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`

`

`
`
`specifically bind to FAP. For example, Zimmerman discloses “[s]mall molecule
`
`inhibitors of seprase [FAP] [] for use as
`
`therapeutic medicines or as
`
`radiopharmaceuticals useful in diagnostic imaging and in the therapeutic treatment
`
`of diseases characterized by overexpression of seprase [FAP].” Id. at ¶ 7. The FAP
`
`inhibitors are bound to a metal chelate including a radionucleotide. The
`
`radionucleotide is defined as a “molecule that is capable of generating a detectable
`
`image that can be detected either by the naked eye or using an appropriate
`
`instrument, e.g. positron emission tomography (PET) and single photon emission
`
`computed tomography (SPECT).” Id. at ¶ 49.
`
`48. Thus, as of October 23, 2017, it was known to combine radiolabeled
`
`functional groups with FAP inhibitors that target FAP expressing cells to visualize
`
`and/or treat FAP-related diseases.
`
`C.
`
`Prior Art References
`Dvořáková
`1.
`49. Dvořáková is a scientific paper entitled “Inhibitor-Decorated Polymer
`
`Conjugates Targeting Fibroblast Activation Protein” that was published in the
`
`Journal of Medicinal Chemistry on September 27, 2017. EX1008 at 8385. I
`
`understand that Dvořáková is therefore prior art to the ’201 patent.
`
`50. Dvořáková relates to developing polymer conjugates decorated with
`
`FAP inhibitors for application of imaging of FAP expressing cells. Id. at 8385, 8387.
`
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`16
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`

`
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`To target FAP, the conjugates therefore include “[s]pecific [i]nhibitors of FAP
`
`modified with PEG linkers” (Compounds 1-4) having the following structures:
`
`
`
`Id. at Scheme 1.
`
`51. As for the application of imaging, the FAP inhibitors (Compounds 1-4)
`
`are bound to an ATTO488 dye via a HPMA copolymer:
`
`
`
`17
`
`

`

`
`
`
`
`Id. at Figure 2b (emphasis added to the ATTO488 dye in red, the FAP inhibitor in
`
`blue, and the linker in green). ATTO488 dye is a fluorophore that contains a
`
`rhodamine-based structure and is known to be “highly suitable for single-molecule
`
`detection applications and high-resolution microscopy.” EX1011.
`
`52. The distance between the FAP inhibitor and the HPMA copolymer can
`
`be varied with the incorporation of a PEG linker as shown below:
`
`
`
`
`
`18
`
`

`

`
`
`EX1008 at Figure 2a.
`
`
`
`53. Dvořáková concludes that the inhibitor-decorated polymer conjugate
`
`can be used as a tool for the specific imaging of FAP-positive cells. Id. at 8387. The
`
`conjugate binds only to FAP-expressing cells and not to cells lacking FAP, and upon
`
`binding to FAP on the cell surface, the conjugate undergoes slow internalization
`
`resulting in a optical signal from the ATTO488 dye inside the cell. Id. Without the
`
`incorporation of the FAP inhibitor on the polymer conjugate, it does not bind to any
`
`cells. Id. Thus, Dvořáková concludes, “anti-FAP iBodies may represent an attractive
`
`theranostic tool for future in vivo imaging and selective drug delivery into the tumor
`
`microenvironment.” Id. at 8391.
`
`Jansen I
`2.
`Jansen I is U.S. Patent No. 9,346,814. Jansen I was issued on May 24,
`
`54.
`
`2016. EX1007 at Cover. I therefore understand that Jansen I is prior art to the ’201
`
`patent.
`
`55.
`
`Jansen I relates to the development of inhibitor compounds with high
`
`selectivity and specificity for FAP. Id. at Abstract. Exemplary embodiments of FAP
`
`inhibitors disclosed in Jansen I include the following structure:
`
`
`
`19
`
`

`

`
`
`with a specific focus on varying the following substituent:
`
`
`
`Id. at 98:50-59, Table 4. Jansen I further discloses that several different substituents
`
`can be featured at this position, including the following:
`
`
`
`
`
`20
`
`

`

`
`
`
`
`Id. at 100:26-60.
`
`56. While the selectivity of most of the compounds for FAP over PREP
`
`was reported as 50 times higher than the reference compounds, Jansen I points to the
`
`position of the nitrogen atom in the
`
`
`
`21
`
`

`

`
`
`substituent as being of “pivotal importance,” stating that “the 4-quinolinoyl ring
`
`clearly displays the best results.” Id. at 95:47-50.
`
`
`
`
`
`4-quinolinoyl ring
`
`Zimmerman
`3.
`57. Zimmerman is a U.S. Patent Publication No. 2010/009633 that was
`
`published on April 22, 2010. EX1009 at Cover. I therefore understand that
`
`Zimmerman is prior art to the ’201 patent.
`
`58. Zimmerman is directed to radiopharmaceuticals that are useful in
`
`diagnostic imaging and therapeutic treatment of FAP-related diseases, where the
`
`radiopharmaceuticals include complexes that contain a proline moiety as the
`
`targeting group and a radionuclide adapted for radioimaging and/or radiotherapy. Id.
`
`at Abstract.
`
`
`
`22
`
`

`

`
`
`59. Zimmerman teaches that there is a strong desire for the development of
`
`compounds specifically targeting FAP and having imaging or therapy capabilities.
`
`For example, Zimmerman states the following:
`
`“Radioactive molecules that selectively bind to specific
`tumor cell surface proteins allow for
`the use of
`noninvasive imaging techniques, such as molecular
`imaging or nuclear medicine, for detecting the presence
`and quantity of tumor associated proteins. Such methods
`may provide vital information related to the diagnosis and
`extent of disease, prognosis and therapeutic management
`options. For example, therapy may be realized through the
`use of radiopharmaceuticals that are not only capable of
`imaging disease, but also are capable of delivering a
`therapeutic radionuclide to the diseased tissue. The
`expression of seprase [FAP-α] on tumors makes it an
`attractive target to exploit for noninvasive imaging as
`well as targeted radiotherapy.”
`
`
`Id. at ¶ 5 (emphasis added).
`
`
`60. The compounds of Zimmerman have the following general structure:
`
`wherein:
`
`
`
`U is selected from the group consisting of —B(OH)2, —CN, —CO2H and
`
`P(O)(OPh)2;
`
`
`
`23
`
`

`

`
`
`G is selected from the group consisting of H, alkyl, substituted alkyl,
`
`carboxyalkyl, heteroalkyl, aryl, heteroaryl, heterocycle and arylalkyl;
`
`V is a bond, O, S, NH, (CH2—CH2-X)n or a group having the following
`
`structure:
`
`
`
`
`
`X is O, S, CH2, or NR;
`
`R is H, Me or CH2CO2H;
`
`W is H or NHR′;
`
`R′
`
`is hydrogen,
`
`acetyl,
`
`t-butyloxycarbonyl
`
`(Boc), 9H-fluoren-9-
`
`ylmethoxycarbonyl (Fmoc), trifluoroacetyl, benzoyl, benzyloxycarbonyl (Cbz) or
`
`substituted benzoyl;
`
`n is an integer ranging from 0 to 6;
`
`m is an integer ranging from 0 to 6;
`
`Metal represents a metallic moiety comprising a radionuclide; and
`
`Chelate represents a chelating moiety that chelates to said Metal.
`
`Id. at claim 1.
`
`61.
`
`In the general structure, the proline moiety shown below
`
`
`
`24
`
`

`

`
`
`
`
`is attached via a tether
`
` to a Metal-Chelate. Id. The proline moiety is capable of
`
`selectively inhibiting FAP, and the metal-chelate or radionuclide is adapted for
`
`radioimaging and/or radiotherapy. Id. at ¶ 7. The tether can be varied to “explore the
`
`effect of