`
`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`AZURITY PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`HELSINN HEALTHCARE S.A.,
`Patent Owner.
`
`
`Patent No. 9,943,515
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`
`
`
`DECLARATION OF RUDOLPH M. NAVARI, M.D., Ph.D., F.A.C.P.
`HELSINN EXHIBIT 2069
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
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`Table of Contents
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`I. INTRODUCTION ........................................................................................ 1
`II. BACKGROUND AND QUALIFICATIONS ............................................. 3
`III. MATERIALS REVIEWED ......................................................................... 6
`IV. LEVEL OF ORDINARY SKILL ................................................................ 6
`V. STATE OF THE ART AT THE TIME OF THE INVENTION.............. 8
`A. Chemotherapy-Induced Nausea and Vomiting .................................... 8
`B. As of November 2009, FDA-Approved CINV
`Treatments Did Not Allow for Adequate Control of Nausea ........... 13
`1. Corticosteroids ......................................................................... 15
`2. 5-HT3 Receptor Antagonists .................................................... 15
`3. Neurokinin-1 Receptor Antagonists ........................................ 16
`C. In 2009, Various Drug Candidates Showed
`Potential for Controlling Chemotherapy-Induced Nausea ................. 19
`1. Olanzapine ............................................................................... 21
`2. Gabapentin ............................................................................... 23
`3. Cannabinoids ............................................................................ 23
`D. The ’515 Patent Offered a Much-Needed
`CINV Treatment That Allowed for Control of Nausea ..................... 24
`VI. ANALYSIS OF CERTAIN
`LITERATURE REFERENCED BY DR. PEROUTKA .............................. 26
`
`A. Herrstedt (Ex. 1010) ........................................................................... 26
`B. Bös (Ex. 1014) .................................................................................... 28
`C. Herrington (Ex. 1016) ........................................................................ 31
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`VII. REBUTTAL TO DR. PEROUTKA’S OPINIONS ...................................... 32
`A. Dr. Peroutka’s Analysis Fails to Consider Several
`Factors That Would Have Been Pertinent to a POSA ....................... 34
`1. Dr. Peroutka Fails to Consider the Problem Facing a POSA .. 34
`2. Dr. Peroutka Fails To Analyze the Various
`Paths a POSA Could Have Taken in an
`Attempt to Solve the Problem They Faced .............................. 39
`B. Dr. Peroutka Fails to Show a POSA Would Have
`Been Motivated to Select Netupitant for Triple Therapy .................. 43
`C. Dr. Peroutka Fails to Show a POSA Would Have
`Used a Single Dose of Netupitant Based on Aprepitant Studies ....... 47
`D. Dr. Peroutka Fails to Demonstrate that a POSA
`Would Have Reasonably Expected that
`Substituting Netupitant for Aprepitant in Triple
`Therapy Would Have Treated Both Nausea and Vomiting ............... 52
`E. Helsinn Did Not Mischaracterize Any Data During Examination .... 53
`1. The Emend® Label and Other Art
`Show that Aprepitant Did Not Achieve a
`Statistically Significant Reduction Against Nausea ................ 53
`2. Combination of Palonosetron and
`Netupitant Provided a Statistically Significant
`Effect on Nausea, When Other Combinations Did Not ........... 61
`VIII. CONCLUSION ............................................................................................ 68
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`I, Rudolph M. Navari, M.D., Ph.D., F.A.C.P., declare as follows:
`I. INTRODUCTION
`1. I am hematologist oncologist and the Executive Director of the Cancer
`Care Program of Central and South America for the World Health Organization
`(“WHO”). The WHO program focuses on cancer prevention and control with
`implementation of evidence-based interventions for prevention, early detection
`diagnosis, treatment, and palliative care. I have practiced in the field of oncology
`for over 40 years. I still see patients five days a week and have treated over
`200,000 of patients throughout my career.
`2. I have been retained by counsel for Helsinn Healthcare S.A.
`(“Helsinn” or “Patent Owner”) in connection with this proceeding before the
`United States Patent and Trademark Office (“PTO”). I understand that this
`proceeding involves U.S. Patent No. 9,943,515 (“the ’515 patent”) (Ex. 1003).1 I
`understand that the ’515 patent is titled “Compositions and Methods for Treating
`Centrally Mediated Nausea and Vomiting” and is presently owned by Helsinn.
`3. I understand that Azurity Pharmaceuticals, Inc. (“Azurity” or
`“Petitioner”) is challenging the patentability of claims 1-23 of the ’515 patent
`
`
`1 I understand that the documents I identify herein have been labeled with
`exhibit numbers, and I include those exhibit numbers here for ease of reference.
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`(collectively, “the challenged claims”). I also understand that Petitioner has
`submitted a declaration from Dr. Stephen J. Peroutka (“Peroutka Declaration”)
`(Ex. 1009) in connection with Azurity’s assertions regarding the challenged claims.
`4. I have been asked to provide my opinions on, among other things,
`chemotherapy-induced nausea and vomiting (“CINV”), the ’515 patent, the state of
`the art, and issues raised by Dr. Peroutka. For purposes of my opinions in this
`proceeding, I understand from counsel that the relevant time frame is the late
`2000s, including the time leading up to November 18, 2009. This Declaration
`provides my opinions from the perspective of a person of ordinary skill in the art
`(“POSA”) during that time frame.
`5. Based on my review of the ’515 patent, the state of the art, and other
`materials identified in Appendix A, I have arrived at the opinions and conclusions
`that are set forth in this Declaration. In preparing this Declaration, I relied on my
`own expertise, clinical experience, and knowledge of the literature in the field,
`including my background knowledge of supportive oncology.2
`
`
`2 Supportive oncology (or supportive care in cancer) focuses on the
`prevention, control, and management of the adverse effects of cancer and its
`treatment to improve the quality of life for people living with cancer.
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`6. My opinions in this proceeding are based upon information currently
`known to me, and I may supplement or amend my opinions with respect to any
`additional information or opinions I become aware of after the date of the
`submission of this Declaration, including in response to any further declarations or
`opinions provided by Dr. Peroutka. As stated above, this Declaration contains
`responses to the statements, arguments, and conclusions contained in the Peroutka
`Declaration. It should also not be presumed that I agree with any specific
`statement, argument, or conclusion in the Peroutka Declaration unless I have
`addressed that conclusion or opinion herein.
`7. I am being compensated for my work in this proceeding at my
`standard rate of $500/hour. My compensation is in no way contingent on the
`nature of my findings, the presentation of my findings in testimony, or the outcome
`of this or any other proceeding. I have no other interest in this proceeding.
`II. BACKGROUND AND QUALIFICATIONS
`8. I have been a practicing medical oncologist and cancer supportive care
`specialist since 1977. My clinical practice focuses on caring for patients with
`cancer and managing their symptoms, as guided by rigorous, evidence-based,
`collaborative research. My own research focuses on discovery, validation, and
`accessibility of innovative approaches to improving the quality of life of people
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`with cancer. A significant goal of my practice and research is to improve treatment
`tolerance and quality of life of patients with symptomatic cancer, including CINV.
`9. I received an M.D. from the Medical College of Virginia in 1977.
`I also received a Ph.D. in Chemical Engineering from the University of Virginia in
`1970, a M.S. in Chemical Engineering from University of Virginia in 1968, and a
`B.S. in Chemical Engineering from University of Notre Dame in 1966.
`10. I completed my postdoctoral residency in internal medicine at the
`University of Alabama, Birmingham, where I was the Chief Resident (1977-1981).
`I completed a fellowship in medical oncology at the University of Washington and
`the Fred Hutchinson Cancer Research Center in Seattle Washington (1982-1983). I
`also later completed a fellowship in clinical medical ethics at the University of
`Chicago School of Medicine (1998-1999).
`11. I have held medical licenses in Alabama, Washington, Indiana,
`Mississippi, and Missouri. I have received certifications from the American Board
`of Internal Medicine (1981) and the American Board of Internal Medicine in the
`Subspecialty Board of Medical Oncology (1983).
`12. Throughout my work, I have been recognized as a key opinion leader
`in cancer supportive care research, including CINV. I have been involved in over
`100 clinical trials, both national and local, and I am an author of over 150
`published, peer-reviewed articles relating to symptom management and quality of
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`life for patients with cancer, including several specific to nausea and vomiting. I
`have also served in a consulting/advisory role for several pharmaceutical
`companies, including Merck, GSK, and Helsinn.
`13. I have served as a member of every major guideline committee for
`antiemetics as well as for the treatment of solid tumors and hematological
`malignancies. The guidelines that I have helped develop include those provided by
`the National Comprehensive Care Network (“NCCN”), the Multinational
`Association of Supportive Care in Cancer (“MASCC”), and the American Society
`of Clinical Oncology (“ASCO”). These guidelines provide a consensus of expert
`views on currently accepted approaches to treating CINV. The creation of these
`guidelines and recommendations requires a comprehensive evaluation of the
`current CINV treatments as well as any recent developments.
`14. I have also served as a member of various professional and honorary
`societies, as well as a reviewer on editorial boards. These include Current Drug
`Targets, Expert Review of Quality of Life in Cancer Care, and Cancer
`Management and Research.
`15. My qualifications, professional experience, education, patents, and
`publications are set forth in my curriculum vitae, which is being submitted as Ex.
`2044.
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`III. MATERIALS REVIEWED
`16. In forming my opinions expressed in this Declaration, I reviewed and
`considered the materials cited in this Declaration as well as the materials listed in
`Appendix A. All of the opinions contained in this Declaration are based on the
`documents I reviewed, as well as my professional judgment, education, and
`knowledge and experience regarding oncology and supportive cancer care
`medications.
`17. My opinions are also guided by my appreciation of what a POSA
`(as that term is defined below) would have understood about the state of the art
`during the relevant time period (late 2000s, including the time leading up to
`November 18, 2009). I understand that this time frame is based on the November
`18, 2009 filing date of U.S. Provisional Application No. 61/262,470, to which
`the ’515 patent claims priority.
`IV. LEVEL OF ORDINARY SKILL
`18. Counsel has asked me to provide my opinions in this Declaration from
`the perspective of a POSA with respect to the ’515 patent as of the relevant time
`period as defined above in Paragraph 4. I further understand that the POSA is
`presumed to be aware of all the pertinent prior art. In my opinion, the relevant
`field of invention is oncology and, more specifically, supportive cancer care.
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`Supportive cancer care is, in general, the prevention, control, and management of
`the adverse effects of cancer and its treatment.
`19. In my opinion, a POSA in November 2009 was actively involved in
`the field of oncology and, more specifically, supportive cancer care, which
`involves a number of disciplines and requires collaborative teamwork among
`persons with relevant experience. The POSA could have an advanced degree
`(e.g., Ph.D., M.D., M.S., MSN, DNP, or equivalent) in a relevant field
`(e.g., oncology) with at least three years of experience in oncology, including the
`treatment of nausea and vomiting with supportive cancer care medications in
`cancer patients undergoing chemotherapy. In this definition of a POSA, more
`education can substitute for less practical experience, and vice versa.
`20. I provide this definition of a POSA based on my review of the ’515
`patent, the technology, the educational level and experience of active workers in
`the field, the types of problems faced by workers in the field, the solutions found to
`those problems, the sophistication of the technology in the field, and drawing on
`my own experience.
`21. I understand that Dr. Peroutka proposes a different definition of a
`POSA. Under Dr. Peroutka’s definition, a POSA did not need to have experience
`in oncology. (Ex. 1009 at ¶¶ 59-60.) I disagree with Dr. Peroutka’s definition.
`Dr. Peroutka’s definition is not directed to the subject matter of the invention,
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`which is supportive care in oncology, particularly methods of treating or preventing
`both nausea and vomiting in patients undergoing chemotherapy. My opinions in
`this case, however, are the same regardless of which definition for a POSA is
`adopted.
`22. I believe I am an expert in the field of oncology and supportive cancer
`care. Over the course of my career, I have instructed numerous students and
`supervised many clinicians who were junior to me. My interactions with these
`individuals helped me to analyze the questions posed in this proceeding from the
`perspective of a hypothetical POSA, who would have had less experience than I.
`V. STATE OF THE ART AT THE TIME OF THE INVENTION
`A. Chemotherapy-Induced Nausea and Vomiting
`23. “Chemotherapy” is a systemic type of drug therapy that uses
`chemicals to kill fast-growing cells, like cancer. Despite often being referred to as
`a single adverse event associated with cancer treatment, the phrase
`“chemotherapy-induced nausea and vomiting” (or “CINV”) actually encompasses
`two separate adverse events that may be induced by chemotherapy: (1) nausea, and
`(2) vomiting. (See, e.g., Ex. 2036 at 517, 528; Ex. 1010 at 143 (“Nausea and
`vomiting are ranked by patients as two of the worst adverse effects of cancer
`chemotherapy.”).) “Nausea” is a difficult term to put into words but is usually
`considered a sick or queasy sensation that is perceived as being in the stomach, and
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`is sometimes followed by vomiting. (Ex. 2036 at 517.) “Vomiting” (also known
`as “emesis”)3 may consist of a pre-ejection phase (called “retching”) followed by
`ejection of stomach contents. (Ex. 2036 at 517.) The sensation of nausea and the
`act of vomiting are protective reflexes with overlapping but distinct physiological
`pathways that work together to rid the intestine and stomach of toxic substances.
`(Ex. 2036 at 517.) Notably, nausea and vomiting do not always coexist
`simultaneously, as one can experience nausea without vomiting, and one can also
`suddenly vomit without nausea. (Ex. 2036 at 517.)
`24. CINV results in significant morbidity and negatively affects the
`quality of life of cancer patients. (Ex. 2036 at 516; Ex. 2001 at 1856; Ex. 1019 at
`1144; Ex. 2037 at 572.) CINV can result in weakness, weight loss, electrolyte
`imbalance, dehydration, and anorexia, and is associated with a variety of other
`complications, including fractures, esophageal tears, decline in behavioral and
`mental status, and wound dehiscence. (Ex. 2036 at 516; Ex. 2001 at 1856; Ex.
`2037 at 572.) Consequently, CINV may result in non-adherence to, dose
`
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`3 W hen I use the term “emesis,” I am referring to the acts of retching
`(dry heaving) or vomiting (expulsion of stomach contents), which do not include
`nausea.
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`reductions in, or even withdrawal from chemotherapy treatments for treatable
`cancers with positive historical clinical outcomes. (Ex. 2036 at 516; Ex. 1019 at
`1144 (“Twenty years ago, nausea and vomiting were common adverse events of
`certain types of chemotherapy and forced up to 20% of patients to postpone or
`refuse potentially curative treatment.”); Ex. 2001 at 1856; Ex. 2037 at 572.) While
`approximately 70% to 80% of all patients undergoing chemotherapy experience
`nausea and/or vomiting, patients tend to experience nausea more frequently than
`vomiting. (Ex. 2037 at 573.)
`25. Historically, chemotherapeutic agents were believed to cause CINV
`by activating certain neuroreceptors located in the central nervous system, brain,
`and gastrointestinal tract. (Ex. 2037 at 573; Ex. 2036 at 517.) Various
`neuroreceptors have been identified as potentially being involved in CINV,
`including serotonin receptors, dopamine receptors, neurokinin-1 (NK-1) receptors,
`acetylcholine receptors, GABA receptors, histamine receptors, cannabinoid
`receptors, opiate receptors, endorphin receptors, and muscarinic receptors. (Ex.
`2036 at 517-18; Ex. 2037 at 573.) Some exemplary antiemetic agents include
`benzodiazepines, cannabinoids, corticosteroids, dopamine antagonists, neurokinin-
`1 receptor antagonists (“NK-1 receptor antagonists”), and serotonin 5-HT
`3 receptor
`antagonists (“5-HT3 receptor antagonists”). (Ex. 2001 at 1872 (Table XII).)
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`26. Chemotherapeutic agents are classified by their emetic risk, such as
`high emetogenic chemotherapy (“HEC”) with a >90% risk of emesis, moderate
`emetogenic chemotherapy (“MEC”) with a 30-90% risk of emesis, low emetogenic
`chemotherapy with a 10-30% risk of emesis, and minimal emetogenic
`chemotherapy with a 0-10% risk of emesis. (Ex. 2037 at 585; Ex. 1019 at 1144.)
`27. The drugs that are used to treat CINV are administered
`prophylactically, meaning they are given to patients in advance of chemotherapy in
`an effort to prevent chemotherapy-related adverse events. An antiemetic therapy’s
`control of CINV has typically been measured in three phases following the
`administration of chemotherapy: acute (0-24 hours), delayed (>24-120 hours), and
`overall (0-120 hours).4 (Ex. 2037 at 585-86; Ex. 2001 at 1860.) Antiemetic
`
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`4 If despite prophylactic treatment, patients still experience vomiting and/or
`nausea within five days after chemotherapy administration, this condition is
`referred to as “breakthrough” CINV and would require “rescue therapy” treatment
`with additional antiemetics. (Ex. 2037 at 585.) Because “[i]t is very unlikely that
`established nausea and vomiting will respond to an agent in the same drug class
`after unsuccessful prophylaxis with an agent with the same mechanism of action,”
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`combinations are specifically chosen depending on their efficacy during these
`different time periods. (Ex. 2037 at 585-86; Ex. 2036 at 525-26.)
`28. As part of the process of developing potential treatments for CINV, a
`scientist will conduct clinical trials in humans to evaluate whether the test drug
`candidate shows efficacy in treating CINV. In these trials, control of vomiting and
`nausea must be measured independently across the acute period, the delayed
`period, and the overall period. (See Ex. 2001 at 1860, Table IV.) However, in
`November 2009, composite endpoints that represent various combinations of
`vomiting, nausea, both nausea and vomiting, or the use of rescue medications, were
`used to assess the efficacy of a given drug candidate, resulting in confusion about
`whether nausea and/or vomiting were being controlled. (See Ex. 2001 at 1860,
`Table IV.)
`29. In general, the use of composite endpoints in clinical studies attempts
`to summarize the patient’s experience of CINV as a single endpoint. The
`following composite endpoints are some examples that were used in clinical
`studies in November 2009 to assess the efficacy of a given drug candidate:
`
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`rescue therapy typically involves different drugs than were used prophylactically.
`(Ex. 2036 at 526.)
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`• Total Control = no vomiting, no use of rescue antiemetics, and no
`nausea
`• Complete Protection or Complete Control = no vomiting, no use of
`rescue antiemetics, and no significant nausea
`• Complete Response = no vomiting and no use of rescue antiemetics
`(See Ex. 1048 at 531; Ex. 2001 at 1860, Table IV; Ex. 1022 at 1442.)
`30. “Complete response” is the primary endpoint most often relied upon
`to demonstrate efficacy in clinical trials for CINV regimens, including by the FDA
`in connection with evaluating a drug product for potential approval. The
`“complete response” endpoint, however, excludes nausea as a parameter and only
`measures the ability to control vomiting. (Ex. 2036 at 521-22.) As a result, drugs
`or drug regimens that failed to adequately control nausea in a significant number of
`patients still received approval for indications for the prevention of CINV.
`(Ex. 2036 at 528; Ex. 1010 at 143.)
`B. As of November 2009, FDA-Approved CINV Treatments
`Did Not Allow for Adequate Control of Nausea
`31. Prior to the use of “triple therapy” (a term I explain below) in the
`treatment of CINV, clinicians used “standard therapy,” which was a two-drug
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`regimen involving dexamethasone and a 5-HT3 receptor antagonist.5 (Ex. 2036 at
`521.) By November 2009, the treatment guidelines for the prevention of CINV had
`evolved to recommend administration of a three-drug regimen that combined
`dexamethasone, a 5-HT3 receptor antagonist, and aprepitant. This combination
`was referred to as “triple therapy,” where each drug belongs to a different class and
`has a unique mechanism of action within that combination: (1) a corticosteroid
`(e.g., dexamethasone), (2) a 5-HT3 receptor antagonist (e.g., palonosetron), and (3)
`the NK-1 receptor antagonist aprepitant. (Ex. 2036 at 521.)
`32. Aprepitant’s inclusion in triple therapy improved the control of acute
`and delayed emesis compared to standard therapy (5-HT3 receptor antagonist and
`dexamethasone). (Ex. 2036 at 521.) However, despite being useful in the control
`of emesis, the “control of nausea was not improved with the use of aprepitant.”
`(Ex. 2036 at 522, 527 (“Aprepitant did not improve nausea in the study.”).)
`
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`5 An “antagonist” is a chemical compound administered to block other
`molecules from binding to their receptors. (Ex. 1010 at 144.) For example, a
`chemical compound that blocks or inhibits another molecule from binding to an
`NK-1 receptor is referred to as an “NK-1 receptor antagonist.”
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`33. Below, I briefly discuss what was known by November 2009 about
`each drug class that is included in “triple therapy” and its respective mechanism of
`action.
`1. Corticosteroids
`34. The first drug class in triple therapy to have been recognized as useful
`for treating CINV was corticosteroids. The recommended corticosteroid for use in
`triple therapy was dexamethasone, in large part due to its widespread use. (Ex.
`1010 at 145.)
`35. A number of studies had shown that for patients receiving moderately
`or highly emetogenic chemotherapy, dexamethasone prevented both acute and
`delayed vomiting. (Ex. 2036 at 524; Ex. 1010 at 145.) While studies had
`determined the optimal pre-chemotherapy dosages, the optimal dose for the control
`of delayed emesis had not been determined. (Ex. 2036 at 524.)
`2. 5-HT3 Receptor Antagonists
`36. The second drug class in triple therapy to have been recognized as
`useful for treating CINV was 5-HT3 receptors antagonists. 5-HT3 receptors
`antagonists were believed to be effective in preventing acute vomiting because they
`blocked the serotonin receptors that typically react to serotonin rapidly released
`from the gut in response to the cytotoxic agents of chemotherapy. (Ex. 2036 at
`518-19; Ex. 1010 at 144.)
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`37. After the discovery of 5-HT3 receptors antagonists, but before NK-1
`receptor antagonists started being used to treat CINV, the published CINV
`treatment guidelines recommended the use of a 5-HT3 receptor antagonist and
`dexamethasone pre-chemotherapy (i.e., day 1) for the prevention of acute
`chemotherapy-induced vomiting, and the use of dexamethasone with or without a
`5-HT3 receptor antagonist following chemotherapy (days 2–4) for the prevention of
`delayed chemotherapy-induced vomiting. (Ex. 2036 at 518-19.)
`38. The guidelines recommend the following 5-HT3 receptor antagonists
`for use in triple therapy: dolasetron, granisetron, ondansetron, tropisetron,
`azasetron, ramosetron, and palonosetron. (Ex. 2036 at 519.)
`3. Neurokinin-1 Receptor Antagonists
`39. The third drug class in triple therapy was NK-1 receptor antagonists.
`The NK-1 receptor antagonist recommended by the guidelines was aprepitant.6
`
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`6 Aprepitant had two formulations, oral tablets of aprepitant marketed under
`the brand name Emend® and an injectable prodrug of aprepitant (fosaprepitant
`dimeglumine), which was marketed as Emend® for Injection (“Emend® IV”). (Ex.
`2002; Ex. 2004.) When fosaprepitant is administered intravenously, it is converted
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`40. As of 2009, clinical studies had demonstrated that for patients
`receiving MEC or HEC, NK-1 receptor antagonists improved the control of
`delayed emesis, but did not have a significant effect on the control of acute emesis
`or any phase of nausea. (Ex. 1034 at 2826 (“There were significant differences
`favoring aprepitant in the vomiting domain score (85.7% v 71.8%; P < .001) . . .
`but not in the nausea domain score (53.5% v 50.5%).”), 2827 (“There were no
`significant differences between the two treatment groups in reports of overall
`nausea (VAS < 5 mm; 33% for both) or significant nausea (VAS < 25 mm;
`aprepitant 61%, control 56%).”), 2828-29 (“In the present study, the most
`pronounced effect of aprepitant was seen in the prevention of vomiting, with an
`absolute difference of 17% between the aprepitant regimen and the control
`group. . . . There was no significant effect of aprepitant on nausea.”); Ex. 1048 at
`532-34.) For example, as of 2009, it was believed that “use of aprepitant-based
`anti-emetic regimen improves patients’ quality of life, especially on aspects of
`control of vomiting, while there was no difference in the nausea domain.” (Ex.
`1048 at 534.)
`
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`to aprepitant within 30 minutes after administration and provides a similar
`antiemetic effect. (Ex. 2036 at 522.)
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`41. In November 2009, numerous NK-1 receptor antagonists were under
`investigation or had been investigated, including but not limited to the following
`compounds:
`• ZD4974 (developed by AstraZeneca) (Ex. 2045)
`• CGP49823 (developed by Ciba-Geigy) (Ex. 2046)
`• Lanepitant (developed by Eli Lilly) (Ex. 2047)
`• LY686017 (developed by Eli Lilly) (Ex. 2048)
`• FK888 (developed by Fujisawa) (Ex. 2049)
`• Vofopitant (developed by GlaxoSmithKline) (Ex. 2050)
`• Vestipitant (developed by GlaxoSmithKline) (Ex. 2051)
`• Orvepitant (developed by GlaxoSmithKline) (Ex. 2057)
`• Befetupitant (developed by Hoffmann-La Roche) (Ex. 1011)
`• R116031 (developed by Janssen) (Ex. 2066)
`• L-733060 (developed by Merck) (Ex. 2052)
`• L-736281 (developed by Merck) (Ex. 2053)
`• TKA731 (developed by Novartis) (Ex. 2054)
`• NKP608 (developed by Novartis) (Ex. 2055)
`• CP-99994 (developed by Pfizer) (Ex. 2056)
`• CP-122721 (developed by Pfizer) (Ex. 2050)
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`• CJ-17493 (developed by Pfizer) (Ex. 2058)
`• CJ-11974 (developed by Pfizer) (Ex. 2050)
`• CJ-11972 (developed by Pfizer) (Ex. 2059)
`• RP67580 (developed by Rhone-Poulenc Rorer) (Ex. 2060)
`• Dapitant (developed by Rhone-Poulenc Rorer) (Ex. 2061)
`• SSR240600 (developed by Sanofi-Aventis) (Ex. 2062)
`• SCH388714 (developed by Schering-Plough) (Ex. 2063)
`• Rolapitant (developed by Schering-Plough) (Ex. 2051)
`• TAK637 (developed by Takeda) (Ex. 2061)
`• HSP117 (developed by Hisamitsu) (Ex. 2056)
`• KRP103 (developed by Kyorin Pharm) (Ex. 2064)
`• SLV317 (developed by Solvay) (Ex. 2065)
`(See Ex. 2045-Ex. 2066; see also Ex. 1001 at 3:24-43; Ex. 2001 at 1873; Ex. 2036
`at 519.)
`C. In 2009, Various Drug Candidates Showed
`Potential for Controlling Chemotherapy-Induced Nausea
`42. As of 2009, the gold-standard triple therapy had largely solved the
`problem chemotherapy-induced vomiting (emesis), but not chemotherapy-induced
`nausea, meaning that a majority of patients still experienced nausea following
`chemotherapy. (Ex. 1010 at 143, 148; Ex. 2036 at 528.) At that time, numerous
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`large clinical studies suggested that, while NK-1 receptor antagonists (e.g.,
`aprepitant) and 5-HT3 receptor antagonists (e.g., ondansetron, palonosetron) with
`dexamethasone significantly improved the prevention of vomiting, they had no
`significant effect on the control of nausea. (See, e.g., Ex. 2036 at 527-29; Ex. 1034
`at 2826-29; Ex. 1022 at 1444-46; Ex. 1048 at 531-34.) As a result, and unlike
`chemotherapy-induced vomiting, the control of nausea in patients receiving
`moderately and highly emetogenic chemotherapy remained a significant problem.
`(Ex. 2036 at 528; Ex. 1010 at 143 (“the majority of patients consider[ed] nausea as
`the main problem”), 148 (“Nausea and loss of appetite are the main problems for
`the majority of patients.”); Ex. 2037 at 573 (“patients often experience more nausea
`than vomiting”); Ex. 1034 at 2826-29; Ex. 1022 at 1444-46; Ex. 1048 at 531-34.).)
`43. Notwithstanding this, as of November 2009, numerous drug
`candidates had demonstrated promising antinausea efficacy in the treatment of
`CINV. Below, I discuss some exemplary compounds that were considered
`promising candidates at that time.
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`1. Olanzapine
`44. Olanzapine is an FDA-approved antipsychotic that received approval
`for schizophrenia in 1996. The structure of the compound is below:
`
`Olanzapine blocks multiple receptors including “dopamine at D1, D2, D3 and D4
`brain receptors, serotonin at 5-HT2a, 5-HT2c, 5-HT3 and 5-HT6 receptors,
`catecholamines at a1-adrenergic receptors, acetylcholine at muscarinic receptors
`and histamine at H1 receptors.” (Ex. 2036 at 524.)
`45. In 2009, a POSA would have understood that olanzapine in
`combination with a 5-HT3 receptor antagonist and dexamethasone “showed
`promise in controlling acute and delayed nausea in patients receiving moderately
`and highly emetogenic chemotherapy.” (Ex. 2036 at 528 (emphasis added); see
`also Ex. 1019 at 1149 (“Olanzapine, an atypical antipsychotic drug, has potential
`antiemetic properties because of its action at multiple receptor sites implicated in
`the control of nausea and vomiting.”); Ex. 1010 at 149 (“The most promising
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`seems to be olanzapine with very high complete response rates of both nausea and
`vomiting, when combined with a 5-HT3-receptor antagonist and a
`corticosteroid.”); Ex. 2037 at 588 (“studies have also shown the value of
`olanzapine for delayed and refractory emesis and nausea”).)
`46. In fact, subsequent further research that I conducted after 2009,
`including human clinical studies, confirmed that