IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Alexis Howerton et al.
`In re Patent of:
`12,115,166 Attorney Docket No.: 47291-0007PS1
`U.S. Patent No.:
`October 15, 2024
`Issue Date:
`Appl. Serial No.: 15/820,256
`April 26, 2023
`Filing Date:
`Title:
`CORTICOTROPIN RELEASING FACTOR RECEPTOR
`ANTAGONISTS
`
`DECLARATION OF DAVID E. BUGAY, PH.D.
`
`1
`
`NEUROCRINE-1004
`
`
`
`Alexis Howerton et al.
`In re Patent of:
`12,115,166 Attorney Docket No.: 47291-0007PS1
`U.S. Patent No.:
`October 15, 2024
`Issue Date:
`Appl. Serial No.: 15/820,256
`April 26, 2023
`Filing Date:
`Title:
`CORTICOTROPIN RELEASING FACTOR RECEPTOR
`ANTAGONISTS
`
`DECLARATION OF DAVID E. BUGAY, PH.D.
`
`1
`
`NEUROCRINE-1004
`
`
`
`I, David E. Bugay of Tavernier, FL, declare that:
`
`I.
`
`INTRODUCTION
`1.
`I have been retained by counsel for Petitioner Neurocrine Biosciences,
`
`Inc. to provide expert opinions in connection with a petition for post grant review
`
`of U.S. Patent No. 12,115,166 (the “’166 Patent”), assigned to Spruce Biosciences,
`
`Inc. (“Spruce”). Specifically, I have been asked to comment on issues related to
`
`stability as raised in Spruce’s ’166 Patent.
`
`2.
`
`The opinions set forth below are based on my nearly 35 years of
`
`experience as an expert in analytical and physical-analytical characterization of
`
`pharmaceutical entities and on the results of analyses discussed in this report.
`
`II. QUALIFICATIONS AND BACKGROUND INFORMATION
`3.
`I am an expert in the areas of analytical chemistry, physical chemistry,
`
`physical analytical chemistry, and the characterization and analysis of active
`
`pharmaceutical ingredients (“API”), excipients, pharmaceutical intermediates and
`
`formulations, and pharmaceutical dosage forms. My expertise includes designing
`
`and executing stability studies that comply with regulatory requirements and
`
`interpreting the data acquired from said studies. Stability studies use high
`
`performance liquid chromatography and other appropriate analytical techniques to
`
`assess APIs and drug products under real-time and accelerated conditions. The
`
`data collected from such stability studies allows me to draw conclusions regarding
`
`2
`
`
`
`the chemical and/or physical stability of a given API and drug product, including
`
`recommending an appropriate shelf life.
`
`4.
`
`I received my B.S. degree in Chemistry from Le Moyne College, in
`
`Syracuse, NY, in 1981. I then received my Ph.D. in Physical Chemistry at the
`
`University of Vermont in 1987.
`
`5.
`
`After obtaining my Ph.D., I accepted a position as a Research
`
`Investigator in the Department of Analytical Research and Development at the
`
`Squibb Institute for Medical Research. Between 1990 and 1998, I held the
`
`positions of Senior Research Investigator I, Senior Research Investigator II, and
`
`then Principal Scientist in the Department of Analytical Research and
`
`Development at the Bristol-Myers Squibb Pharmaceutical Research Institute
`
`(BMSPRI).
`
`6.
`
`From 1998 through May of 2008, I held senior positions within SSCI,
`
`Inc. which later became Aptuit, Inc. when Aptuit acquired SSCI in October 2006.
`
`SSCI/Aptuit is a contract research organization specializing in pharmaceutical
`
`development, including the characterization of various pharmaceutical entities
`
`(liquids, solids, gases, excipients, blends, formulated product, etc.). Initially, I was
`
`Vice President of Analytical Chemistry at SSCI and subsequently Senior Vice
`
`President of Analytical Chemistry. After Aptuit’s purchase of SSCI, I was
`
`Managing Director of Aptuit Consulting. During these ten years, I managed and
`
`3
`
`
`
`led the Analytical Research Department, Analytical Resources Department, and
`
`Consulting Group and interacted with numerous pharmaceutical companies
`
`providing them with analytical services and consulting.
`
`7.
`
`In June 2008, I founded my own consulting firm, PharmAnalysis,
`
`Inc., and in May 2009, I opened an accompanying laboratory, Triclinic Labs., Inc.
`
`8.
`
`Triclinic Labs is a contract research company that provides a wide
`
`range of research and analytical services focusing on pharmaceutical entities.
`
`Services provided include solid form screening (including polymorphs, salts, co-
`
`crystals, and amorphous materials), solid form selection, crystallization method
`
`development, compendial testing, analytical method development, chemical and
`
`physical stability testing, solid-state characterization, problem solving, counterfeit
`
`analysis, containment analysis and identification, regulatory consulting, and other
`
`related consulting services.
`
`9.
`
`Based on my experience, and in particular my experience relating to
`
`instrumental analysis, I have developed considerable expertise in analyzing and
`
`evaluating APIs, excipients, physical blends, intermediates isolated from
`
`manufacturing, formulated granules, and various types of drug products, including
`
`tablets, capsules, microspheres, suspensions, liquid formulations, and specialized
`
`formulations.
`
`4
`
`
`
`10. During my nearly 38 years working for BMSPRI, SSCI/Aptuit, and
`
`Triclinic Labs, I conducted analytical techniques on many different drug product
`
`formulations, API systems, formulation blends, intermediates, and excipients to
`
`understand the properties and stability of the API and finish dosage form.
`
`11. While working at both SSCI/Aptuit and Triclinic Labs, I have assisted
`
`a large number of drug companies in analytical characterization, problem solving,
`
`stability testing, and regulatory issues relating to pharmaceutical drug
`
`development. In addition, I have assisted various pharmaceutical companies in
`
`legal matters relating to analytical, physical, and physical-analytical chemistry as a
`
`consultant or expert witness.
`
`12. Throughout my career, I have been invited by numerous universities
`
`and institutions around the world to present lectures on various areas of my
`
`expertise in analytical, physical, and physical-analytical chemistry as applied to
`
`pharmaceutical development. I have authored or co-authored over 40 scientific
`
`publications, including seminar presentations, a textbook, book chapters, and
`
`papers. I am also a manuscript reviewer for several journals, including
`
`Pharmaceutical Research, Journal of Pharmaceutical Sciences, Applied
`
`Spectroscopy, Journal of Pharmaceutical and Biomedical Analysis, Organic
`
`Process Research and Development, and International Journal of Pharmaceuticals.
`
`In my capacity as a reviewer, I have refereed numerous manuscripts in the area of
`
`5
`
`
`
`pharmaceutical chemistry, including formulation design, analytical method
`
`development and validation, stability testing, characterization of APIs and
`
`formulations, formulation performance, and solid-state attributes of pharmaceutical
`
`entities.
`
`13. From September 1998 to December 2009, I was an Adjunct Professor
`
`in the Department of Industrial and Physical Pharmacy at Purdue University in
`
`West Lafayette, Indiana. I taught a course to both undergraduate and graduate
`
`students entitled “Pharmaceutical Solids,” which relates to the identification and
`
`characterization of solid-state forms of pharmaceutical compounds.
`
`14.
`
`I have taught numerous other courses relating to the chemical and
`
`physical characterizations of pharmaceutical materials. Examples of such courses
`
`include the annual SSCI short course for pharmaceutical scientists entitled
`
`“Pharmaceutical Solids,” an American Association of Pharmaceutical Scientists
`
`(AAPS) short course entitled “Characterization of Drug Substances—A Holistic
`
`Approach,” and in-house courses to at least twenty different pharmaceutical
`
`companies located around the world. All of the courses presented include lectures
`
`on the use of various instrumental and chemical analysis techniques for the
`
`physical and chemical characterizations and stability of pharmaceutical materials.
`
`15.
`
`In 2003, in recognition of my contributions to the field of
`
`pharmaceutical chemistry, I was elected as a Fellow of the American Association
`
`6
`
`
`
`of Pharmaceutical Scientists. Additionally, I was elected to the United States
`
`Pharmacopeia (USP) General Chapters Expert Committee for the term for 2005-
`
`2010. The General Chapters Expert Committee is responsible for reviewing,
`
`revising, generating, and updating chapters on analytical, physical, and physical-
`
`analytical technologies which are incorporated into the USP and utilized by the
`
`pharmaceutical community. During my term, the USP awarded the General
`
`Chapters Expert Committee the “USP Award for an Outstanding Contribution to
`
`the Standards-Setting Process.” Additionally, I was appointed to the USP
`
`Spectroscopy Advisory Committee and the USP NMR Advisory Committee,
`
`which received a letter of merit for our contribution to the activities of USP.
`
`Finally, I was selected by USP to represent the United States at the World Health
`
`Organization’s (WHO) meeting on counterfeit drugs and their impact on patient
`
`safety.
`
`16. A copy of my curriculum vitae is provided (as Appendix A to this
`
`Declaration). This contains a list of my publications for at least the last ten years.
`
`17.
`
`I am being compensated at my usual and customary rate of $1,050 per
`
`hour in addition to reimbursement of reasonable business expenses such as
`
`materials for experiments, instrument time, travel, and photocopying. My
`
`compensation is in no way based on the outcome of this matter and has not
`
`influenced my views in this matter.
`
`7
`
`
`
`III. ANALYSIS PERFORMED AND MATERIALS CONSIDERED
`
`18.
`
`In forming my opinions set forth in this Declaration, I rely upon my
`
`knowledge and professional experience in the field of pharmaceutical chemistry,
`
`drug development, and drug characterization, as discussed above. In addition, I
`
`have considered in whole or in part the materials listed below:
`
`Exhibit
`Number
`
`1001
`
`1002
`
`1032
`
`1038
`
`1050
`
`1051
`
`Citation
`
`U.S. Patent No. 12,115,166 to Alexis Howerton, et al. (“the
`’166 patent”).
`U.S. Prosecution History of the ’166 Patent.
`Part 1, 1-624
`Part 2, 625-1248
`Part 3, 1249-1872
`Part 4, 1873-2182
`Part 5, 2183-2495
`Part 6, 2496-3119
`Deore et al., “The Stages of Drug Discovery and Development
`Process,” Asian J. of Pharm. R. & D. 7(6): 62-67 (2019)
`(“Deore”).
`Yamaguchi et al., “Approval success rates of drug candidates
`based on target, action, modality, application, and their
`combinations,” Clin. Transl. Sci. 14:1113-22 (2021)
`(“Yamaguchi”).
` “Guidance for Industry, Q1A(R2) Stability Testing of New
`Drug Substances and Products,” U.S. Department of Health and
`Human Services, Food and Drug Administration (November
`2003).
` “Guidance for Industry, Q1E Evaluation of Stability Data,”
`U.S. Department of Health and Human Services, Food and Drug
`Administration (June 2004).
`
`8
`
`
`
`IV.
`
`INTERPRETATION OF THE ’166 PATENT CLAIMS AT ISSUE
`19.
`I understand that, for purposes of my analysis in this post grant
`
`review proceeding, the terms appearing in the ’166 Patent claims should be
`
`interpreted according their ordinary and customary meaning as understood by a
`
`person of ordinary skill in this art (“POSA”), as discussed in Section VI, in view of
`
`the patent’s disclosure and prosecution history. In that regard, I understand that the
`
`best indicator of a claim term’s meaning is its usage in the context of the patent
`
`specification as understood by a POSA. I further understand that the words of the
`
`claims should be given their plain meaning unless that meaning is inconsistent with
`
`the patent specification or the patent’s history of examination before the Patent
`
`Office. I also understand that the words of the claims should be interpreted as they
`
`would have been interpreted by a POSA at the time the invention was made (not
`
`today). Because I do not know at what date the invention as claimed was made, I
`
`have used the earliest priority date of U.S. Patent No. 12,115,166 as the point in
`
`time for claim interpretation purposes. That date is August 14, 2017, the date the
`
`first provisional application in this patent family was filed. I currently have not
`
`been asked to provide opinions on the interpretation of particular terms and phrases
`
`of the ’166 Patent but reserve the right to do so if asked or in response to any
`
`arguments or opinions set forth by Spruce and its expert(s).
`
`
`
`9
`
`
`
`V.
`
`LEGAL STANDARDS
`A. Written Description
`20.
`I understand that the specification must contain a “written
`
`description” of the claimed invention that allows a person of ordinary skill in the
`
`art to recognize that the inventor invented what is claimed. I understand that the
`
`test for written description is whether the disclosure in the specification reasonably
`
`conveys to a POSA that the inventor had possession of the full scope of the
`
`claimed invention as of the filing date. I understand that the written description
`
`requirement is applied in the context of the state of knowledge in the art at the time
`
`the patent application was filed.
`
`21.
`
`The level of detail required to satisfy the written description
`
`requirement varies depending on the nature and scope of the claims and on the
`
`complexity and predictability of the relevant technology. I understand that factors
`
`used to evaluate the sufficiency of a disclosure include: 1) the existing knowledge
`
`in the particular field; 2) the extent and content of the prior art; 3) the maturity of
`
`the science or technology; and 4) the predictability of the claimed method or
`
`invention.
`
`22.
`
`I understand that when a claim recites a genus of compounds using
`
`functional language to define a claimed result, the specification must disclose
`
`either a representative number of compounds falling within the scope of the genus
`
`10
`
`
`
`that achieve the claimed result, or structural features common to the members of
`
`the family that achieve the claimed result, so that a POSA can visualize or
`
`recognize the members of the family.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`23.
`I understand the POSA as relevant to the ’166 Patent has already been
`
`defined by Neurocrine’s experts, including by Dr. Maya Lodish. I agree with this
`
`definition, which is reproduced below.
`
`24. A POSA would have a medical degree or a Ph.D. in a field related to
`
`endocrinology, and would have knowledge of hormone regulation and disorders,
`
`and knowledge of the treatment regimens employed to treat such disorders. The
`
`POSA would also have at least three years of experience conducting research
`
`concerning endocrine disorders, including CAH and other adrenal disorders. A
`
`POSA may have also worked as part of a multi-disciplinary team and drawn upon
`
`not only his or her own skills, but also consulted with others on the team having
`
`specialized skills to solve a problem, including analytical chemistry and
`
`pharmaceutical formulation.
`
`25.
`
`I consider myself as someone who the POSA would have consulted
`
`with, at least as of the earliest relevant timeframe, 2017.
`
`11
`
`
`
`VII. TECHNOLOGY BACKGROUND
`A. Drug Discovery Process
`26. Discovery of new drug compounds for therapeutic uses is a long,
`
`expensive, and labor-intensive process. Typically, from the drug discovery phase
`
`to FDA approval, it may take 12-15 years of work and hundreds of millions of
`
`dollars of investment. See EX1032, 62. The drug development process can be
`
`thought of in several steps—discovery and development, preclinical research,
`
`clinical research, FDA review, and FDA post-market safety monitoring. Id., 63-
`
`65.
`
`27. The drug discovery phase generally entails scientists identifying a
`
`target for a drug to act on and then screening different molecular compounds to
`
`find the best compound that provides beneficial effects against the target. This
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`process entails trial and error. At this stage, tens of thousands of compounds are
`
`evaluated in laboratory tests over the course of several years before only a handful
`
`are advanced to preclinical testing and development. Id., 63-65; see also EX1038,
`
`1114.
`
`28. Once candidates are advanced to the preclinical testing and
`
`development stage, their properties are thoroughly evaluated to understand
`
`potential efficacy and safety risks before use in any human clinical trial.
`
`Preclinical development testing may include experiments to understand how the
`
`12
`
`
`
`drug candidates are absorbed, distributed, metabolized, or excreted, their
`
`mechanism of action, potential efficacy, and stability, the best dosages, preferred
`
`routes of administration (e.g., oral versus injectable), potential side effects
`
`(toxicity), and whether such candidates interact with other drugs. EX1032, 64-65.
`
`29. Once a lead candidate is further assessed and characterized through
`
`the preclinical development stage, that candidate is evaluated in multiple clinical
`
`studies in humans to evaluate safety and efficacy. Most clinical programs will
`
`evaluate drug candidates in phase 1, phase 2, and phase 3 trials that will run over
`
`the course of several years. The likelihood of drug candidates successfully
`
`proceeding through phase 1 all the way through phase 3 clinical trials and
`
`marketing approval is low—10-20%. EX1038, 1114.
`
`B.
`30.
`
`Overview of Stability for Drug Products
`The Food and Drug Administration (FDA) is the public health agency
`
`charged with, among other things, approving new or generic drugs to enter the
`
`market and monitoring the safety and efficacy of existing drugs. When approving
`
`a new drug or a generic version of an existing drug, the FDA generally does not
`
`conduct its own testing. Rather, the FDA analyzes the testing performed by the
`
`manufacturer to determine if the newly submitted drug is safe and effective for
`
`human use.
`
`13
`
`
`
`31. The FDA provides guidelines for how manufacturers can perform
`
`drug testing and what data may be included in a new or abbreviated drug
`
`application. For example, the FDA provides guidelines on how a manufacturer can
`
`perform stability testing and what stability data is required for approval.
`
`32. The FDA has adopted guidance from the International Council for
`
`Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
`
`(ICH) on, among other things, stability testing for new drugs. See EX1050;
`
`EX1051.
`
`33. The purpose of stability testing is to show the stability characteristics
`
`of a drug substance (also known as the API) and/or drug product over various time
`
`periods and once exposed to various environmental factors, like temperature,
`
`humidity, and/or light. EX1050, 1.3. Stability testing provides a stability profile
`
`eventually leading to the establishment of an estimated shelf life and recommended
`
`storage conditions for a drug. Id. Under FDA guidelines, stability studies should
`
`test any attribute of the drug that is susceptible to change or likely to influence
`
`qualify, safety, or efficacy. Id., 2.2.5. Thus, the specific stability tests that are
`
`performed for a given drug will vary based on, among other things, the physical
`
`and chemical properties of the drug. Id. Stability testing on both the drug
`
`substance (unformulated) and drug product (in final dosage form) is required in
`
`new and abbreviated drug applications.
`
`14
`
`
`
`34. The FDA provides specific guidance on how the API and final dosage
`
`form (drug product) should be tested based on the storage conditions and shelf life
`
`proposed by the drug’s manufacturer. For example, an aqueous-based product in a
`
`semipermeable container should be tested for water loss, and a product to be stored
`
`in a refrigerator should be tested at refrigerator temperatures. Id., 2.2.7.3, 2.2.7.4.
`
`The proposed shelf life and length of a stability study should be sufficient to cover
`
`storage, shipment, and subsequent use. Id., 2.2.7.
`
`35. Generally, for a drug that is to be stored at room temperature, stability
`
`testing is performed under the following conditions. See id., 2.2.7.1.
`
`36. For a drug that is to be stored in refrigeration, stability testing is
`
`performed under the following conditions. See id., 2.2.7.4.
`
`
`
`
`
`15
`
`
`
`VIII. U.S. PATENT NO. 12,115,166
`37. The ’166 Patent is generally directed to a pharmaceutical composition
`
`comprising 3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(l-ethylpropyl)-2,5-
`
`dimethylpyrazolo(l ,5-a)pyrimidine (“Compound 1”) and methods of using the
`
`same for the treatment of congenital adrenal hyperplasia (CAH). EX1001,
`
`Abstract. I understand that Compound 1 as described in the ’166 Patent is the
`
`compound known as tildacerfont.
`
`38. The ’166 Patent contains only 1 independent claim. Claim 1,
`
`reproduced below for ease of reference, recites:
`
`[a] method for treating congenital adrenal hyperplasia (CAH) in a
`human comprising:
`
`administering to said human a therapeutically-effective amount of a
`CRF1 receptor antagonist or a pharmaceutically acceptable salt
`thereof,
`
`wherein said human has received or has been previously determined
`to receive a first dose of a glucocorticoid, and administering to said
`human a second dose of a glucocorticoid,
`
`wherein said second dose of a glucocorticoid is reduced compared to
`said first dose of a glucocorticoid,
`
`wherein an androstenedione (A4) level in said human is reduced from
`baseline, or
`
`wherein an adrenocorticotropic hormone (ACTH) level in said human
`is reduced from baseline, or
`
`wherein a 17-hydroxyprogesterone (17-OHP) level in said human is
`reduced from baseline,
`
`16
`
`
`
`
`wherein said CRF1 receptor antagonist or a pharmaceutically
`acceptable salt thereof is administered at a dose between about 50
`mg/day and about 200 mg/day, and wherein said CRF1 receptor
`antagonist is stable for storage for a minimum of six months.
`
`
`39. As I discuss above, my opinions relate to chemistry, manufacturing,
`
`and controls (CMC) aspects of Spruce’s alleged invention claimed in the ’166
`
`Patent. Thus, I also have reproduced below for ease of reference, Claim 21 which
`
`recites:
`
`[t]he method of claim 1, wherein said CRF1 receptor antagonist is
`stable between about 25℃ and about 40 ℃.
`
`40. The specification of the ’166 Patent provides certain limited teachings
`
`regarding stability. The specification describes “stable” as “pharmaceutical
`
`compositions having about 95% or greater of the initial Compound 1 amount and
`
`about 5% w/w or less total impurities or related substances at the end of a given
`
`storage period.” EX1001, 25:21-26. The specification goes on to describe the
`
`allowed amounts of impurities for embodiments of pharmaceutical compositions
`
`containing Compound 1. For example, the specification states “[i]n some
`
`embodiments, the stable pharmaceutical compositions have about 5% w/w, about
`
`4% w/w, about 3% w/w, about 2.5% w/w, about 2% w/w, 1.5% w/w, about 1%
`
`w/w or about 0.5% w/w total impurities or related substances.” Id., 25:29-34.
`
`17
`
`
`
`41. The specification describes the stability at refrigerated, ambient, and
`
`accelerated conditions. For example, “[a]t refrigerated condition, the
`
`pharmaceutical compositions described herein are stable for at least 1 month, at
`
`least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12
`
`months, at least 15 months, at least 18 months, at least 24 months, at least 30
`
`months, at least 36 months.” Id., 25:46-51. The ’166 Patent further specifies that
`
`for some embodiments, “refrigerated conditions” is 5±5℃. Id., 25:51-53.
`
`42. Similarly, the ’166 Patent describes the stability of pharmaceutical
`
`compositions of Compound 1 at accelerated conditions. For example, the
`
`specification states “[a]t accelerated conditions, the pharmaceutical compositions
`
`described herein are stable for at least 1 month, at least 2 months, at least 3 months,
`
`at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8
`
`months, at least 9 months, at least 10 months, at least 11 months, at least 12
`
`months, at least 18 months, or at least 24 months.” Id., 26:15-21. “Accelerated
`
`conditions” include temperatures that are at or above ambient level, ranging from
`
`20℃ to 60℃, and relative humidity that are at or above ambient levels, ranging
`
`from 45% RH to 80% RH. Id., 26:15-33.
`
`43. The specification further describes “[i]n some embodiments the
`
`pharmaceutical compositions are stable at about 5±5oC to about 25±5oC for at least
`
`12 months.” EX1001, 26:38-40; see also id., 26:40-48.
`
`18
`
`
`
`44. The specification provides a summary of limited stability data in
`
`Example 2. See id., 34:58-36:57. Table 1 (column 35) provides a summary of the
`
`stability of three lots of Compound 1 neat-filled into size 0 capsules with no added
`
`excipients at different strengths—1 mg, 5 mg, and 50 mg—along with three lots of
`
`capsules containing 200 mg of Compound 1 in HDPE bottles, which I have
`
`reproduced below:
`
`
`45. The ’166 Patent concludes after Table 1 that “[u]nder long term and
`
`accelerated conditions, no significant trend was observed in the three lots for any
`
`of the attributes evaluated throughout the course of the stability study.” EX1001,
`
`35:1-4.
`
`46. Table 1 is accompanied by Tables 2-4, which also discuss stability,
`
`however, the disclosures in Tables 2-4 are limited to stability protocols. Tables 3-4
`
`19
`
`
`
`(columns 35-36), for example, show the stability protocols for 200-mg capsules in
`
`30 mL HDPE (high density polyethylene) bottles.
`
`IX. OPINION – THE ’166 PATENT DOES NOT PROVIDE SUPPORT
`FOR THE CLAIMED STABILITY LIMITATION
`47.
`I have reviewed the disclosures of the ’166 Patent in view of claims 1-
`
`10 and 12-21 (the “Challenged Claims”). In my opinion, the required stability
`
`limitation of Claim 1 (and its dependent claims)—“wherein said CRF1 receptor
`
`antagonist is stable for storage for a minimum of six months”—is not supported by
`
`the specification. A POSA viewing the specification would understand that it
`
`describes the stability of only one CRF1 receptor antagonist—Compound 1
`
`(tildacerfont). As I discuss in further detail below, a POSA would not understand
`
`Spruce to have sufficiently described the stability for the members of the claimed
`
`large genus of CRF1 receptor antagonists.
`
`48. A POSA reading the specification would immediately understand that
`
`the “present invention” is pharmaceutical compositions and methods using 3-(4-
`
`Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(l-ethylpropyl)-2,5-dimethylpyrazolo(l
`
`,5-a)pyrimidine, which is tildacerfont. See EX1001, Abstract. And while the term
`
`“pharmaceutical compositions” is used throughout the specification, a POSA
`
`would have no question that it means pharmaceutical compositions of Compound 1
`
`(tildacerfont). For example, under the heading “Pharmaceutical Compositions,”
`
`the specification states “[d]isclosed herein is a pharmaceutical composition
`
`20
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`
`
`comprising Compound 1, a pharmaceutically acceptable salt, and/or a solvate
`
`thereof.” EX1001, 15:1-4.
`
`49. With respect to stability, the specification states that “[s]table as used
`
`herein refers to pharmaceutical compositions having about 95% or greater of the
`
`initial Compound 1 amount and about 5% w/w or less total impurities or related
`
`substances at the end of the a given storage period.” Id., 25:22-26 (emphasis
`
`added). The specification goes on to make clear that the “percentage of impurities
`
`is calculated from the amount of impurities relative to the amount of Compound
`
`1.” Id. 25:26-28 (emphasis added). With that framework in mind, a POSA would
`
`understand that any stability disclosures in the ’166 Patent are limited to only
`
`tildacerfont. These stability disclosures include discussion of stability in various
`
`storage conditions, “including refrigerated, ambient, and accelerated conditions,”
`
`(id., 25:19-22) as well as lists of temperature and humidity parameters for those
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`conditions (id., 25:46-26:15; 26:22-48). They also include discussion of the
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`amount of impurities allowed for the pharmaceutical compositions comprising
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`tildacerfont (id., 25:29-45) and stability storage duration (id., 25:46-51, 26:15-21).
`
`50. There is only one example in the specification of the ’166 Patent
`
`regarding stability—Example 2. Example 2 provides a summary of a stability
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`study conducted on tildacerfont that was neat-filled in capsules and then blister
`
`packaged or bottled. See EX1001, 34:58-67. A summary of stability conditions
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`21
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`
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`for these neat-filled capsules is found in Table 1. The specification states with
`
`respect to the tildacerfont stability testing that “[u]nder long term and accelerated
`
`condition, no significant trend was observed in three lots for any of the attributes
`
`evaluated throughout the course of the stability study.” Id., 35:1-4. Example 2
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`also includes Tables 2-4, which set forth stability protocols, but do not include any
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`quantitative stability data for tildacerfont, nor any other CRF1 receptor antagonist.
`
`See id., 35:31-36:44. Based on this testing, the specification concludes that “[t]he
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`supportive data demonstrate that the pharmaceutical composition is stable for a
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`minimum of 6 months (end of study).” Id., 36:45-47.
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`51.
`
`In my opinion, a POSA reading the stability disclosures in the ’166
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`Patent would understand they are limited to tildacerfont alone. There is no
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`stability testing or data for any other CRF1 receptor antagonist nor would a POSA
`
`be able to predict the stability of any other CRF1 receptor antagonist in the
`
`sweeping genus of the Challenged Claims without testing for it. For example, a
`
`POSA would understand that stability can be affected by the dosage form of a
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`pharmaceutical. See supra, § VII.B. But the specification only discloses stability
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`information for Compound 1 (tildacerfont). See EX1001, Example 2. Spruce’s
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`own representations to the patent office are in agreement. I understand that in
`
`order to convince the patent office to allow the Challenged Claims, Spruce argued
`
`to the Examiner that the claimed dosages of Compound 1 tested in Example 2 were
`
`22
`
`
`
`special having “an unexpected benefit of being more stable for shelf storage.”
`
`EX1002, 2501. A POSA would understand from Spruce’s representations that
`
`Compound 1 (tildacerfont), purportedly, has unique stability properties and would
`
`not be able to extrapolate such properties to other members of the claimed CRF1
`
`receptor antagonist genus.
`
`52. Further, a POSA reading the Challenged Claims would understand
`
`that they are broad enough to encompass any type of dosage form for any one
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`CRF1 receptor antagonist in the sweeping claimed genus. As I discuss above,
`
`there are different criteria for determining stability for different pharmaceutical
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`dosage forms. See supra, § VII.B. Yet, the specification provides no data or other
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`disclosures, for the stability of any CRF1 receptor antagonists other than
`
`Compound 1 (tildacerfont). A POSA would find this lack of disclosure further
`
`compounds the deficiency of the specification in demonstrating the stability of any
`
`member of the claimed CFR1 receptor antagonist genus.
`
`53.
`
`In my opinion, the Challenged Claims of the ’166 Patent are not
`
`supported by the specification and lack the requisite written description for the
`
`stability limitation.
`
`23
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`
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`X.
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`RESERVATION OF RIGHTS
`54.
`This declaration sets forth my opinions to date. But my analysis may
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`continue, and I may acquire additional information and/or attain supplemental
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`insights that may result in added observations.
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`55.
`
`I hereby declare that all statements made of my own knowledge are
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`true and that all statements made on information and belief are believed to be true.
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`I further declare that these statements were made with the knowledge that willful
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`false statements and the like so made are punishable by fine or imprisonment, or
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`both, under Section 1001 of the Title 18 of the United States Code and that such
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`willful false statements may jeopardize the validity of the application or any
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`patents issued thereon.
`
`Dated: February 10, 2025
`
`By:
`
` David E. Bugay
`
`24
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`
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`APPENDIX A
`APPENDIX A
`
`25
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`EDUCATION
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`EMPLOYMENT
`EXPERIENCE
`
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`AWARDS
`
`US PATENTS
`
`
`DAVID E. BUGAY
`
`Ph.D., Physical Chemistry, May 1987
`University of Vermont, Burlington, VT 05405
`
`Research Advisors: Dr. Willem R. Leenstra and Dr. C. Hackett Bushweller
`Thesis Subject: Triplet state infrared vibrational studies involving polycyclic aromatic hydrocarbons,
`combined with the determination of extinction coefficients of cyclohexyl halides through equilibrium
`measurements by FTIR and FTNMR.
`
`B.S., Chemistry, May 1981
`Le Moyne College, Syracuse, NY 13214
`
`Chief Scientific Officer/Consultant, Triclinic Labs, Inc., Lafayette, IN, March 2009 to pr
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