Helsinn Healthcare Exhibit 2026
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`Page 1 of 21
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`I, David G. Frame, have been retained by Defendants Dr. Reddy’s Laboratories Ltd. and
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`Dr. Reddy’s Laboratories Inc. (“DRL”) in the above-captioned matter. If I am called at trial, I
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`expect to testify with regard to the opinions, and the bases and reasons therefore, expressed
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`below:
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`I.
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`INTRODUCTION
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`1.
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`I understand that this is a “Hatch-Waxman” patent-infringement action arising
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`from defendants’ filing of ANDAs seeking approval from FDA to market generic versions of
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`Helsinn Healthcare’s Aloxi® (palonosetron hydrochloride) intravenous product.
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`2.
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`Aloxi® is indicated for the prevention of: (1) acute and delayed nausea and
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`vomiting associated with initial and repeat courses of moderately emetogenic cancer
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`chemotherapy; (2) acute nausea and vomiting associated with initial and repeat courses of highly
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`emetogenic cancer chemotherapy; and (3) postoperative nausea and vomiting for up to 24 hours
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`following surgery. (Ex. Al.) Aloxi® is available in two dosage strengths: 0.25 mg/5 ml and
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`0.075 mg/1.5 ml. (Id.)
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`3.
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`I understand that the patents at issue in this case are United States Patent Nos.
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`7,947,724 (Ex. B, “the ‘724 patent”), 7,947,725 (Ex. C, “the‘725 patent”), and 7,960,424 (Ex. D,
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`“the ‘424 patent”) (collectively, “the patents-in-suit"), and that plaintiffs have asserted claims 2
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`and 9 of the ‘724 patent; claim 2 of the ‘725 patent; and claims 2, 5 and 6 of the ‘424 patent
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`against DRL. The patents-in-suit concern intravenous solutions of palonosetron for treating
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`nausea and vomiting.2 More specifically, the patents-in-suit claim intravenous solutions
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`containing palonosetron at specified concentrations, buffered at specific pH ranges, and
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`,1
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`' Exhibits hereto are referred to as “Ex. _.
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`2 The patents-in-suit also use the term “emesis," which is a medical term for vomiting.
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`Page 2 of 21
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`Page 2 of 21
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`containing cxcipicnts including a tonicifying agent (e.g., mannitol) and a chelating agent (e.g.,
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`EDTA) at certain concentrations.
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`4.
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`I have been asked by counsel for DRL to opine based on my knowledge, skill,
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`education, training and experience with 5-HT3 receptor antagonist drugs to treat nausea and
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`vomiting, on the obviousness of the palonosetron concentrations in the asserted claims.
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`I
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`understand that DRL also retained Dr. Patrick P. DeLuca, an expert in the field of
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`pharmaceutical formulation, to opine on the obviousness of the formulations set forth in the
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`asserted claims.
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`5.
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`I am being compensated for my work in connection with this matter at the rate of
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`. per hour. No part of my compensation is dependent in any way on the outcome of this
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`6.
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`I have not testified as an expert witness at trial or by deposition within the
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`previous four years.
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`7.
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`I expect to rely on various exhibits at trial, including demonstratives, but I have
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`not prepared any such exhibit yet.
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`II.
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`SUMMARY OF OPINIONS
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`8.
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`The prior art taught that palonoseuon was a much more potent anti-emetic agent
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`than previous commercially-available setron drugs such as ondansetron and granisetron. Given
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`the high potency of palonosetron, a person of ordinary skill in the art would have estimated that
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`the effective dose of palonosetron to treat emesis would be low; falling approximately in the
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`range of 0.04 4 mg.
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`9.
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`Based on practical considerations as well as prior art teachings, the person of
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`ordinary skill would have selected a low concentration of palonosetron for an intravenous
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`solution approximately in the range of 0.004-0.8 mg/ml. Indeed, the prior art taught that low
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`palonosctron concentrations, c.g., 0.14, 0.1 and 0.03 mg/ml, in intravenous solutions were
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`effective in clinical and animal anti—cmctic studies. Thus, a person of ordinary skill in the art
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`would have had a reasonable expectation of success that low palonosctron concentrations would
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`10.
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`It would have been obvious to use low concentrations of palonosctron
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`including
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`the 0.05 mg/ml concentration recited in the asserted claims
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`in an intravenous solution of
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`palonosctron for treating emesis.
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`III.
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`PROFESSIONAL QUALIFICATIONS
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`1 1.
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`I received a B.S. in Chemistry from St. Louis University in 1986, and a B.S. in
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`Pharmacy and Pharm. D. in 1993 and 1994, respectively, from Wayne State University.
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`12.
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`I am presently Assistant Professor of Pharmacy at the University of Michigan and
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`Hernatology/Oncology/BMT Clinical Specialist with the University of Michigan Health System.
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`In my present positions, I teach therapeutics and pharmacology at the University of Michigan,
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`College of Pharmacy, and, in conjunction with physicians, I treat patients who are receiving
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`chemotherapy for hematologic malignancies and for those receiving a bone marrow transplant.
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`In my work ueating patients, I have established our antiemetic guidelines and do much of the
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`supportive care management of these patients.
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`I also do both clinical and translational research
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`in the fields of oncology and infectious diseases.
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`13.
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`Prior to joining the University of Michigan, I was Assistant Professor at Rush
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`University from 1995-2006. While working at Rush University, I chaired the Chemotherapy
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`Overview Committee at Rush Medical Center from 1995 to 2005.
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`I was Director of Clinical
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`Hernatology/Oncology Phamiacy Services and Research at Rush University Medical Center
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`from 1999 to 2005. In that role, I was responsible for overseeing all clinical pharmacy oncology
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`services and oncology patient outcomes monitoring. I was also director of the anticoagulation
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`program for hip and knee replacement where we were responsible for supportive care issues such
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`as nausea and vomiting post-operatively.
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`14.
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`I have taught graduate courses and have given frequent presentations on many
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`topics in oncology, including therapies for multiple disease conditions and lectures on supportive
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`care.
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`I have delivered over 50 professional presentations to clinicians on the treatment of both
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`chemotherapy-induced and post-operative nausea and vomiting.
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`15.
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`I have participated in designing clinical studies of 5-HT3 receptor antagonists for
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`treating both chemotherapy-induced nausea and vomiting and post-operative nausea and
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`vomiting. My role in the clinical studies has involved being a part of large multicenter trials as
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`well as designing and implementing my own randomized controlled trial for post-operative
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`nausea and vomiting, as well as several smaller trials in the oncology setting.
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`In my years of clinical practice I have had experience with all of the 5-HT;
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`antagonists approved in the U.S., including Aloxi® (palonosetron), Zofran® (ondansetron),
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`Kytril® (granisetron) and Anzemet® (dolasetron).
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`I have managed nausea and vomiting using
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`these agents in over 4,000 patients.
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`17.
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`Additional details of my education and experience are set forth in my curriculum
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`vitae, a copy of which is attached as Ex. E. Exhibit E also contains a partial listing of the
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`companies and conferences where I have been invited to speak, the lectures and short courses I
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`have given and the publications I have authored.
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`IV. METHODOLOGY APPLIED AND MATERIALS REVIEWED
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`18.
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`I understand that in determining whether a claimed invention is obvious, the
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`scope and content of the prior art must be determined, the differences between the prior art and
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`the claimed invention must be ascertained, and the obviousness of the claimed invention must be
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`judged from the viewpoint of a person of ordinary skill in the art at the time the claimed
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`invention was made, including the knowledge such a person could have gleaned from the
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`references available at that time.
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`I understand that the analysis should not be done using
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`hindsight, but that the determination of whether a claimed invention would have been obvious
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`must be based on a consideration of the prior art, and without knowledge of the teachings of the
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`19.
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`I understand that the ultimate determination of validity of a patent is a legal
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`question, which will be decided by the Court, but that it is within the scope of my role as an
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`expert to read the claims of a patent, understand what they would mean to a person of ordinary
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`skill in the art, review the prior art and opine on how the prior art relates to the claims of the
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`20.
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`Since a patent is to be understood from the perspective of a person of ordinary
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`skill in the art to which it pertains, I have considered who such a hypothetical person might be.
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`In my opinion, a person of ordinary skill in the art to which the patents-in-suit pertain would
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`have had at least formal education or training in pharmaceutical science or a related area and
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`experience in pharmaceutical formulation development, including experience in intravenous
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`solution formulation development.
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`21.
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`I understand that the original patent application that ultimately issued as the
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`patents-in-suit was filed on January 30, 2003.
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`I understand that the “prior art” in this matter
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`includes references published prior to January 30, 2002.
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`I understand that a person ofordinary
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`skill in the art is presumed to have knowledge of the art available to the public as of January 30,
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`2002.
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`22.
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`In providing my opinions, I rely on my education and experience as a clinical
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`pharmacist over the last 17 years and my review of the materials listed in Ex. F.
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`IV.
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`BACKGROUND ON EMESIS, CINV, PONV AND 5-I-[T3 RECEPTOR
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`ANTAGONISTS
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`23.
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`Nausea and vomiting are common undesirable side-effects of cancer
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`chemotherapy and other medical procedures that involve the administration of anesthesia.
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`Emesis is a medical term for vomiting.
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`24.
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`The mechanisms that lead to both chemotherapy-induced nausea and vomiting
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`(CINV) and post-operative nausea and vomiting (PONV) are similar. One of the main chemicals
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`in the body that is responsible for emesis is called serotonin. During an emetic episode,
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`serotonin, which is primarily released from the stomach area, binds to receptors called serotonin
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`type-3 receptors. This binding activates neurons which send signals to the brain to cause a
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`person to have emesis (vomit) or to become nauseated. These serotonin type-3 receptors are
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`called 5-HT; receptors, as serotonin is chemically known as 5-hydroxytryptamine (5-HT).
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`25.
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`In addition to serotonin, it is well-understood that approximately twenty other
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`chemicals in the body are also responsible for causing nausea and vomiting. Nevertheless, in
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`most individuals it is the acute release of serotonin within several hours of receiving
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`chemotherapy or anesthesia that is primarily responsible for the initial vomiting that patients
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`experience. It is for this reason that the development and clinical use of drugs to treat emesis has
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`focused on blocking or antagonizing the 5-HT3 receptor. These drugs are generally referred to as
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`5-HT3 antagonists, and may be identified by the suffix “-setron” in the drugs name (c.g.,
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`palonosetron, ondansetron, granisetron) .
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`26.
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`Chemotherapy-induced nausea and vomiting is classified as acute or delayed.
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`Acute CINV is defined as occurring and resolving within 24 hours of chemotherapy. Delayed
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`CINV, on the other hand, is defined as occurring more than 24 hours after chemotherapy
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`administration. (See Ex. G, “Kris 1985”, M.G. Kris et al., Incidence, Course, and Severity of
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`Delayed Nausea and Vomiting Following the Administration of High-Dose Cisplatin, J. Clin.
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`Oneol., 1985, 3(10), 1379-1384). This classification was developed simply as a tool for
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`purposes of defining outcomes for anticmetic trials. The 24-hour mark is not a magic number
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`that neatly delineates acute and delayed physiologic responses that cause nausea and vomiting.
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`Post-operative nausea and vomiting does not generally use the 24-hour time period to define a
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`late period of emesis. While the same terminology is not generally used in PONV, it is generally
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`accepted that nausea and vomiting happening later than 6 hours after the end of an operative
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`procedure is considered a delayed process.
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`27.
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`Chemotherapy-induced nausea and vomiting is a very common side-effect of
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`many cancer treatments. In 1983 (before the development of the 5-HT3 antagonists), it was
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`found that patients receiving chemotherapy ranked nausea and vomiting as the first and second
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`most severe side effects, respectively. (See Ex. H, “de Boer-Dennert 1997”, M. de Boer-
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`Dennert et al., Patient Perceptions of the Side-Effects of Chemotherapy: the Influence of SHT3
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`Antagonists, British J. Cancer”, 1997, 76(8), 1055-1061; Ex. I, “Oates 1983", A. Coates et aI.,
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`On the Receiving End- Patient Perception of the Side-effects of Cancer Chemotherapy, Eur. J.
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`Cancer Clin. Oneol., 1983, 19(2), 203-208). CINV significantly affects the quality of life for
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`cancer patients. Before the development of the 5-HT; antagonists, a significant number of
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`patients having CINV during the chemotherapy treatment cycle postponed or refilsed further
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`potentially curative treatment because of the severity of this adverse reaction to chemotherapy.
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`28.
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`Several variables play a significant role in the risk of CINV with the largest being
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`the inherent antiemetic potential of the chemotherapy agents the patient receives. The other
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`variables include a history of nausea and vomiting, female sex, obesity, and age. The risk based
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`on the chemotherapy agent is generally classified as high, moderate, or low ernetogenicity. (Ex.
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`J, “Gralla 1999”, R. Gralla, et al., Clinical practice guidelines for the use of antiemetics:
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`Evidence-based report by the American Society of Clinical Oncology. J Clin. Oncol., 1999, 17,
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`2971-2994).
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`29.
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`The risk of PONV has been shown to be based on four primary factors in patients
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`receiving balanced inhaled anesthesia: female sex, nonsmoking status, history of PONV, and
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`opioid use. The incidence of PONV with the presence of none, one, two, three, or all four of
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`these risk factors has been shown to be approximately 10%, 20%, 40%, 60%, and 80%,
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`respectively. (See Ex. K, “Apfel 1999", C. Apfel et al., A Simplified Risk Score for Predicting
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`Postoperative Nausea and Vomiting: Conclusions from Cross-validations Between Two Centers,
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`Anesthesiology, 1999, 91: 693-700).
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`30.
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`One of the first therapies used to treat nausea and vomiting were the
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`phenothiazines. The phenothiazines, however, were inadequate because they only caused a
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`complete block of nausea and vomiting in approximately 20% of patients. (Ex. L, “Chen 1998”,
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`J. Chen et aI., Efficacy of ondansetron and prochlorperazine for the management of
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`postoperative nausea and vomiting: a doubleblind, comparative study, Arch. Intern. Med., 1998,
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`158, 2124-2128). By the early 1980s, high-dose metoclopramide was shown to be more
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`effective for CINV than the phenothiazines, but due to its many side efi'ects was also not an ideal
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`Page 9 of 21
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`Page 9 of 21
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`therapy. The biggest single improvement in the treatment of CINV was the development of the
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`5-HT; antagonists in the 1990s.
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`31.
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`In 1991, a landmark trial showed that the selective 5-HT; antagonist ondansetron
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`increased response rates over high dose metoclopramide by 25-30% without the latter’s
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`significant side effects. As a result of this study, it became clear that the 5-HT; antagonists
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`would assume an important role in the treatment of chemotherapy-induced nausea and vomiting.
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`32.
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`The first 5-HT3 antagonist approved in the United States was ondansetron under
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`the brand name Zofran® in 1991. Soon to follow were granisetron (Kytril®) in 1994 and
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`dolasetron (Anzemet®) in 1997. Tropisetron (Navoban®) was also commonly used outside of the
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`United States during the 1990s. All of these drugs were available as injectable solutions.
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`33.
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`By 2001, selective 5-HT3 receptor antagonists had become the standard first line
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`drug therapy for treating CINV. Indeed, the American Society of Clinical Oncology Antiemetic
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`Guidelines developed in 1999 listed the serotonin antagonists in the highest therapeutic index
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`category and described them as “largely responsible for the ease of use and high effectiveness of
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`antiernetics in clinical practice.” (See Gralla 1999).
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`34.
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`Palonosetron was developed by Syntex (now Roche) as one of the
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`conformationally restricted analogs of granisetron and tropisetron (Ex. M, “Graul 1996", A.
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`Graul et al., RS-25259-197, Antiemetic 5-HT3 Receptor Antagonist, Drugs of the Future, 1996,
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`21(9): 906-910). Palonosetron differed from the other setron drugs then on the market in its
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`potency and selectivity as a 5-HT; antagonist. It was more potent and longer acting than either
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`ondansetron or granisetron, and its superior potency was attributed to its higher affinity for 5-
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`HT3 receptors. (Id at 907-910.) Generally, the higher the affinity of a drug for a receptor, the
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`longer it will stay at that receptor, and in turn the longer its duration of action will be. In the case
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`Page 10 of 21
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`of palonosetron, its high affinity meant that palonosetron had a longer duration of action than the
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`other setron drugs. Specifically, palonosetron had a duration of action 4-6 times longer than
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`granisetron and 8-10 times longer than ondansetron.3 In other words, palonosetron would have a
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`longer effect of about 3-4 days versus granisetron or ondanseuon at 12-24 hours.
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`35.
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`Palonosetron’s longer duration of action, however, did not necessarily add to its
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`clinical efficacy; it just meant that more doses of granisetron or ondansetron would need to be
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`administered to achieve the same effect as one dose of palonosetron. Indeed, given the fact that
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`it was known that the 5-HT; antagonists worked best during the first 24 hours afier a single day
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`of chemotherapy and their efficacy decreased significantly after that, palonosetron’s longer
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`duration of action did not necessarily add to its efficacy in all circumstances.
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`VI.
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`OPINIONS
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`36.
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`The patents-in-suit are directed to intravenous solution formulations of
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`palonosetron for treating emesis. Specifically, the asserted claims of the patents-in-suit claim
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`pharmaeeutically stable solutions containing “0.05 mg/ml" or “about 0.05 mg/ml” of
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`palonosetron or a pharmaceutically acceptable salt thereof (eg, palonosetron hydrochloride).
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`Further, the palonosetron solutions are buffered at a pH of “from 4.0 to 6.0” or more narrowly
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`“from 4.5 to 5.5." The solutions also contain excipients such as mannitol (a tonicifying agent)
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`and EDTA (a chelating agent), which are commonly used in many pharmaceutical preparations.
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`37.
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`For the reasons discussed below, it is my opinion that the concentration of
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`palonosetron in the asserted claims (i.e., “0.05 mg/ml" or “about 0.05 mg/ml") would have been
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`3 A drug’s duration of action is sometimes referred to in terms of its half-life, which is how long
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`it takes for 50% of the drug to leave the blood. Thus, here it could be said that palonosetron had
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`a longer half-life than either granisetron or ondansetron. Regardless of which term is used
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`(longer duration of action or half-life), the timing of these effects was very predictable based on
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`in vitro and animal studies.
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`obvious to a person of ordinary skill in the art in view of the prior art disclosure of palonosctron
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`as a much more potent antiemetic agent than the prior art 5-HT3 receptor antagonist drugs that
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`were known and commercially available at the time, as well as the prior art teaching of using low
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`concentrations of palonosctron in clinical and animal studies.
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`A.
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`Prior Art Teachings Concerning Palonosetron and Other Setron
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`Drugs and Their Effective Concentrations
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`38.
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`As discussed above, by January 30, 2002, there were several 5-HT3 receptor
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`antagonist drugs on the market for the treatment of chemotherapy-induced nausea and vomiting
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`and/or post-operative nausea and vomiting. The mechanism of action of these setron drugs was
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`well understood and the effectiveness of this class of drugs for the treatment of CINV and/or
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`PONV had been established.4 Palonosetron was n_ot the first in its class; ondansetron,
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`granisetron, tropisetron, and dolasetron preceded it. Palonosetron was just another in a class of
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`drugs that had been established as highly effective for the treatment of CINV and/or PONV.
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`39.
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`Palonosetron was disclosed in U.S. Patent No. 5,202,333 (Ex. N, “the ‘333
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`patent”), which issued on April 13, 1993. The ‘333 patent disclosed a genus of compounds
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`based on Formula I in the patent that were said to be 5-HT3 receptor antagonists. Palonosetron
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`was disclosed as one of the preferred compounds. (See id., col. 9, lines 23-26.)
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`4 It should be noted that the setron drugs then in use were not formally labeled for the treatment
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`of delayed nausea and vomiting, although they are routinely used for that purpose. The reason
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`for this is that none of the sellers of the other 5-HT3 antagonists did a fomial FDA approval trial
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`to seek labeling for this indication. Indeed, palonosctron’s indication for this purpose was based
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`on a comparison with one day of ondansetron or dolasetron, not multiple days. In other words,
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`the equivalent of 3-4 days of the 5-HT; antagonist palonosctron (because of its long duration of
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`action) was compared to just one day of ondanseuron or dolaseuron. Based on this comparison,
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`there was approximately a 10% increase of efficacy with palonosctron after the first 24 hours
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`versus no other drug. It was this small increase in efficacy that was basis for palonosctron
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`receiving FDA approval for use in both acute and delayed nausea and vomiting. (Ex. A, Aloxi,
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`Package Insert).
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`Page 12 of21
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`12
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`Page 12 of 21
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`40.
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`The ‘333 patent taught that the compounds of the invention could be used to treat
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`emesis.
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`(Id._, col. 9, line 56
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`col. 10, line 13.) Further, the ‘333 patent taught that the amount of
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`the compounds in a composition could vary widely depending upon the type of formulation, size
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`of a unit dosage, kind of excipients and other factors known to one skilled in the art of
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`pharmaceutical sciences. (Id., col. 12, lines 60-64.)
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`In this regard, the ‘333 patent stated that
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`“one of ordinary skill in the art of treating such diseases will be able, without undue
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`experimentation and in reliance upon personal knowledge and the disclosure of this application,
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`to ascertain a therapeutically effective amount of a compound of Formula I for a given disease.”
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`(Id., col. 12, lines 19-24.) The preferred concentration of the compounds of Formula I in
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`compositions was 0.0000l% to 1.0%, with the remainder being the excipients. (Id., col. 12, lines
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`64-67.)
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`41.
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`Several publications prior to January 30, 2002 specifically disclosed palonosetron
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`as a potent 5-HT3 receptor antagonist and an eflective anti-emetic agent in both animal studies
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`and clinical trials on human patients. These publications also disclosed that palonosetron was
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`much more potent than prior setron drugs.
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`42.
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`Specifically, a publication by Eglen et al. in 1995 (Ex. 0, “Eglen 1995”, R. M.
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`Eglen et al., Pharmacological characterization of RS 25259-1975, a novel and selective 5-HT3
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`receptor antagonist, in vivo, Br. J. Pharmacology, (1995) 114, 860-866) reported on the “in vivo
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`pharmacological effects [in animal studies] of [palonosenon hydrochloride] using ondansetron
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`and/or granisetron as reference compounds.” (Id. at 860.) The investigators concluded that
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`“[palonosetron hydrochloride] is a novel, highly potent [intravenous] and orally active 5-HT3
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`5 RS 25259 and RS 25259-197 are the internal designations for palonosetron and palonosetron
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`hydrochloride that were used by Syntex during development. (See, e.g., Ex. 0, Eglen 1995, at
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`86]; Ex. P, Tang 1998, at 462.)
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`receptor antagonist in viva. With respect to its anti-emetic activity, [palonosetron hydrochloride]
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`appears to be a significant improvement over ondansctron in terms of potency and duration of
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`action.” (Id. at 860, Abstract.)
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`43.
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`Palonosetron, ondanseuon and granisctron were administered both orally and
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`intravenously to ferrets and dogs to investigate palonosetron’s anti-emetic activity as compared
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`to ondansetron and granisctron. Ferrets and dogs were used in the study because “[t]he ferret
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`and the dog are well established animal models of emesis which respond to cancer
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`chemotherapeutic agents in a manner similar to that observed in man.” (Id. at 861.)
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`44.
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`In ferrets, palonosetron hydrochloride was administered intravenously at doses of
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`1-100 pg/kg. (Id. at 861.) Vehicle control was 1 ml/kg. (Id.) Thus, intravenous solutions
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`containing 0.001-0.1 mg/ml of palonosetron hydrochloride were administered.
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`45.
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`In ferrets, Eglen 1995 reported that palonosetron administered intravenously was
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`effective