`Patent No. 9,173,942
`Petition for Post Grant Review
`Attorney Docket No. REDDY 7.2R-022
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________
`
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORIES, INC.,
`Petitioners
`
`v.
`
`HELSINN HEALTHCARE S.A. and ROCHE PALO ALTO LLC,
`Patent Owners.
`
`
`
`U.S. Patent No. 9,173,942 to Giorgio Calderari et al.
`Issue Date: November 3, 2015
`Title: LIQUID PHARMACEUTICAL FORMULATIONS OF PALONOSETRON
`____________________________
`
`Post Grant Review No. PGR2016
`__________________________________________________________________
`EXHIBIT 1038
`
`DECLARATION OF DR. CHRISTOPHER A. FAUSEL
`IN SUPPORT OF PETITION FOR POST GRANT REVIEW
`OF CLAIMS 1-19 OF U.S. PATENT NO. 9,173,942
`UNDER 35 U.S.C. §§ 321-329 AND 37 C.F.R. § 42.200 ET SEQ.
`
`
`
`4392305_1.docx
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`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1038
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`Exh. 1038
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`I, DR. CHRISTOPHER A. FAUSEL, declare and state as follows:
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`1.
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`I am a citizen of the United States of America and reside at 5411
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`North Capitol Avenue Indianapolis, Indiana.
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`2.
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`I have been retained by Dr. Reddy’s Laboratories, Ltd. and
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`Dr. Reddy’s Laboratories, Inc. (collectively “DRL,” Petitioner,” or “Requestor”) to
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`consider issues relating to the validity of claims 1-19 of U.S. Patent No. 9,173,942
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`(“the ‘942 Patent”). I understand that Helsinn Healthcare S.A. and Roche Palo Alto
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`LLC (collectively “Helsinn”) are the Patent Owners.
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`3.
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`I am being compensated at my normal rate for time spent working on
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`this matter, which includes my time for preparing this declaration. My
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`compensation is not dependent on the outcome of this case.
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`4.
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`I am presently a clinical pharmacist practicing at the Indiana
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`University Simon Cancer Center in Indianapolis, Indiana charged with managing
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`the operations and clinical practice of the cancer service line pharmacies.
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`Accordingly, I have a great deal of experience with chemotherapeutic agents as
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`well as medications given to prevent or reduce the side effects of such treatments,
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`including the dosing, schedules, and interactions of these types of pharmaceuticals.
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`I have over 19 years of experience in practice as an oncology pharmacist at a
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`National Cancer Institute designated clinical cancer center. My employment
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`history, education, professional activities, patents, and other miscellaneous
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`4392305_1.docx
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`Exh. 1038
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`publications are set forth in my curriculum vitae, attached as Exhibit 1039.
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`Exhibit 1039 also includes a listing of publications, including books and patents.
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`5.
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`I have a Bachelor of Science degree (Albany College of Pharmacy,
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`1993) and a Doctor of Pharmacy degree (Albany College of Pharmacy, 1996). I
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`achieved Board Certification in Oncology Pharmacy (BCOP) in 1999 and have
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`maintained this designation with recertification every seven years.
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`6.
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`A Doctor of Pharmacy (Pharm.D.) is a somewhat unique individual
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`who can be involved in patient care in a number of different contexts. Often, they
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`have daily interactions with treating physicians consulting on drug selection, dose,
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`drug interactions, and treatment protocol selection, particularly in a clinical
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`oncology setting. A Pharm.D. who provides direct patient care to oncology patients
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`has particular expertise in the supportive care aspect of cancer care. Supportive
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`care with respect to drug therapy can encompass using medications to ameliorate
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`nausea and vomiting related to chemotherapy or surgery, appropriate use of
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`anti-infective drugs, pain management, and proper dosing of medications in
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`patients that have impaired liver or kidney function.
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`7.
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`Pharmacists specializing in oncology that work at large academic
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`medical centers actively participate
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`in
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`the
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`tripartite mission of
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`these
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`institutions: patient care, education, and research. Like physicians, we are very
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`well versed in pharmacokinetics, dosing, and administration issues, as well as
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`4392305_1.docx
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`2
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`Exh. 1038
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`practical issues relating to drug handling and storage. But we also understand a
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`number of issues that often fall into the realm of a drug formulator. A Pharm.D.
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`may be involved in formulating and compounding, and thus, they have more than a
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`basic understanding of common excipients, concepts like concentration, and
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`physical and chemical stability. While a formulator might be more interested in
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`how concentration can impact drug stability in the first instance, both a Pharm.D.
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`and a formulator are likely to be concerned about compatibility between different
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`drugs and diluents and drug stability issues. Thus, a Pharm.D.’s responsibilities
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`and interests can overlap with those of treating physicians and formulators alike,
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`making their input in drug design and analysis invaluable.
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`8. My specific experience in research has been in collaboration with
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`physician colleagues in the drafting and conducting of clinical trials in patients
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`with cancer, including studies that focus on the use of antiemetic drugs in cancer.
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`Additionally, I have served on Institutional Review Boards (IRB) for over 15 years
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`to assess the merit of clinical trial proposals with regard to the federal code of
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`regulations for protection of human subjects. For the last three years, I have served
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`in a volunteer capacity as the Chairman of the Board of a not-for-profit
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`organization called the Hoosier Cancer Research Network, which is dedicated to
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`doing high-quality investigator initiated trials in patients with cancer.
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`4392305_1.docx
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`3
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`Exh. 1038
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`9.
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`I actively teach at the Purdue School of Pharmacy and the Indiana
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`University School of Medicine for didactic classwork related to the therapeutic use
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`of drugs in patients with cancer. Further, I provide a number of certified
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`pharmacy/medical education lectures for pharmacists, nurses, and physicians at
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`conferences throughout the United States. Lastly, I have provided experiential
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`teaching at my clinical setting at Indiana University Simon Cancer Center for
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`Doctor of Pharmacy students and graduate pharmacist resident trainees.
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`I.
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`PERSON OF ORDINARY SKILL IN THE ART
`I understand that patents are read in light of the knowledge of a person
`10.
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`of ordinary skill in the art (“POSA”) as of the earliest effective filing date of the
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`patent. I have been told by counsel to assume that the earliest effective filing date
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`is January 30, 2003, for purposes of this proceeding.
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`11.
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`It has been explained to me that a POSA is a hypothetical person who
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`is deemed to be aware of all relevant prior art. A POSA is also a person of
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`ordinary creativity, not an automaton.
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`12.
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`I am further told by counsel that factors relevant to determining the
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`level of skill in the art include: the educational level of the inventors, the types of
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`problems encountered in the art, prior art solutions to those problems, the rapidity
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`with which innovations are made, the sophistication of the technology, and the
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`4392305_1.docx
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`4
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`Exh. 1038
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`educational level of active workers in the field. I understand from counsel that a
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`POSA may be a composite of different types of individuals.
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`13.
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`I understand from counsel that in a dispute between the Patent Owner
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`and Petitioner in connection with other family members of the ‘942 Patent in the
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`U.S. District Court for the District of New Jersey, Patent Owner took the position
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`that a POSA was “[s]omeone who is actively involved in the development of
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`pharmaceutical products which involves collaborative teamwork among persons
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`with relevant experience. This person would have a degree in chemistry,
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`pharmaceutical chemistry, pharmacy, medicine, clinical pharmacology, or another
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`pharmaceutical science-related field and experience in designing, developing,
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`evaluating, and/or testing pharmaceutical formulations with a B.S. or master’s
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`degree in, and two to three years’ experience, or a Ph.D. or M.D. degree and one to
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`two years of experience.” (Exh.1028.) I can accept this in the context of the claims
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`of the ‘942 Patent.
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`II. THE ‘942 PATENT
`14. The Abstract of the ‘942 Patent states that it is directed to shelf-stable
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`liquid formulations of palonosetron for reducing chemotherapy and radiotherapy
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`induced nausea and vomiting that can be used in the preparation of intravenous and
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`oral medicaments. (Exh.1001 Abstract.)
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`4392305_1.docx
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`5
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`Exh. 1038
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`15. The specification of the ‘942 Patent acknowledges that the active
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`compound palonosetron was already known, was disclosed in U.S. Patent
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`No. 5,202,333 (“the ‘333 Patent” or “Berger”) (Exh.1006) as a 5-HT3 receptor
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`antagonist, and is useful for the treatment of delayed emesis (Exh.1001,
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`at 1:56-62). However, according to the specification, formulating palonosetron in
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`liquid formulations was not an easy task, typically due to shelf-stability issues. (Id.
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`1:62-64.) The specification states that the intravenous palonosetron formulation in
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`Example 13 of Berger had a “shelf stability of less than the 1-2 year time period
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`required by health authorities in various countries.” (Id. 2:9-11.) It was an object of
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`the invention to provide a palonosetron hydrochloride formulation with increased
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`pharmaceutical stability. (Id. 2:44-60.)
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`16. The Summary of Invention in the specification of the ‘942 Patent
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`further iterates that the core objective of the invention is to shelf-stable
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`formulations. The specification of the ‘942 Patent discloses the following with
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`respect to shelf-stable formulations:
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`• “These formulations are shelf stable for periods greater than 24
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`months at room temperature, and thus can be stored without
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`refrigeration,
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`and manufactured using non-aseptic,
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`terminal
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`sterilization processes.” (Id. 2:67-3:3(emphasis added).)
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`4392305_1.docx
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`6
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`Exh. 1038
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`• “Thus, in one embodiment the invention provides a pharmaceutically
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`stable solution for preventing or reducing emesis comprising (a) from
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`about 0.01 mg/mL
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`to about 5 mg/mL palonosetron or a
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`pharmaceutically acceptable salt thereof; and (b) a pharmaceutically
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`acceptable carrier.” (Id. 3:9-15 (emphasis added).)
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`• “The inventors have further discovered that by adjusting the
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`formulation's pH and/or excipient concentrations it is possible to
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`increase the stability of palonosetron formulations.” (Id. 3:16-18
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`(emphasis added).)
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`• “Therefore,
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`in another embodiment,
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`the
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`invention provides a
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`pharmaceutically stable solution for preventing or reducing emesis
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`comprising (a) palonosetron or a pharmaceutically acceptable salt
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`thereof; and (b) a pharmaceutically acceptable carrier, at a pH from
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`about 4.0
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`to about 6.0.” (Exh.1001, at 3:19-23.) “In another
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`embodiment the invention provides a pharmaceutically stable solution
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`for preventing or reducing emesis comprising from about 0.01 to
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`about 5.0 mg/ml palonosetron or a pharmaceutically acceptable salt
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`thereof; from about 10 to about 100 millimoles citrate buffer; and
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`from about 0.005 to about 1.0 mg/ml EDTA.” (Id. 3:23-30 (emphasis
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`added).)
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`4392305_1.docx
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`7
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`Exh. 1038
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`• “The inventors have further discovered that the addition of mannitol
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`and a chelating agent can increase the stability of palonosetron
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`formulations. Therefore, in still another embodiment the invention
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`provides a pharmaceutically
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`stable
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`solution . . . wherein
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`the
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`pharmaceutically acceptable carrier comprises a chelating agent and
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`mannitol.” (Id. 3:31-40 (emphasis added).)
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`17. The specification of ‘942 Patent also discloses in the Detailed
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`Description of the Invention a pharmaceutically stable solution comprising
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`palonosetron and a carrier, wherein the pH is “from about 4.0 to about 6.0.” (Id.
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`5:27-28.) Other suitable ranges include “from about 4.5 to 5.5.” (Id. 5:28-29.) A
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`solution pH value of 5.0 allegedly imparts the greatest stability. (Id. 5:30, 7:25-26.)
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`18. The specification further states that a solution of palonosetron
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`including a citrate buffer and EDTA can be stable. (Id. 3:24-29, 5:35-48.) Such a
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`formulation can include about 0.01 to about 5.0mg/ml palonosetron, about 10 to
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`about 100 millimoles citrate buffer and about 0.005 to about 1.0mg/ml EDTA. (Id.)
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`The patent concludes that an optimal formulation includes EDTA 0.05% and
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`20mM citrate buffer, with a pH of 5. (Id. 7:37-40.)
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`19. The specification further states that the addition of mannitol, which
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`can be accompanied by a chelating agent, can increase the stability of palonosetron
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`formulations. (Id. 3:31-33, 5:63-6:10.) The chelating agent is preferably EDTA.
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`4392305_1.docx
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`8
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`Exh. 1038
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`(Id. 6:10.) The suitable concentration range of EDTA is from about 0.005mg/mL to
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`about 1.0mg/mL, with 0.5mg/mL disclosed as the optimal value. (Id. 6:11-14.)
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`Likewise, the concentration of mannitol ranges from about 10.0mg/mL to about
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`80.0mg/mL. (Id. 6:16-18.) The level of mannitol in a palonosetron formulation
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`containing citrate buffer is said to be 4.15%. (Id. 7:52-54, Example 3.)
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`20. The specification does not say which of the foregoing features, or
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`combination of features, of a palonosetron formulation produces a particular level
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`of stability (such as 24-month stability at room temperature) or which formulations
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`are considered “stable”. However, it discloses a representative formulation
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`including palonosetron hydrochloride at a concentration of 0.05mg/ml, 41.5mg/ml
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`of mannitol (a tonicifying agent), 0.5mg/ml of EDTA (a chelating agent), citrate
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`buffer, a pH adjusting agent (i.e., NaOH/HCl) and water. This formulation is said
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`to be useful for intravenous administration. (Id. 7:55-8:10, Example 4.)
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`III. CLAIM CONSTRUCTION
`I understand that the only claim terms to be construed for the purposes
`21.
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`of
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`this
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`proceeding
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`are
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`the
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`terms
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`“formulation”
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`and
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`“pharmaceutical/pharmaceutically.” The
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`term “formulation” as recited
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`in
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`claims 1-19 is not defined in the specification. To a formulator, this term means the
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`composition or “recipe” of a product. (Exh.1029, at 691 (Formulate/formulation
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`means “2. To prepare according to a specified formula.” Formula means “4a. A
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`4392305_1.docx
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`9
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`Exh. 1038
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`prescription of ingredients in fixed proportion; a recipe.”).) “Formulation,” per se,
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`is not limited to “stable” formulations. “Formulation” is not limited to a single-use,
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`unit dose, or indeed a dose at all. Nor does it imply sterility. “Formulation” is not
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`limited to any intended use and certainly not reducing the likelihood of cancer
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`chemotherapy-induced nausea and vomiting.
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`22. The terms “pharmaceutical” and “pharmaceutically” are also not
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`defined in the specification. However, the term “pharmaceutically acceptable” is
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`defined as “that which is useful in preparing a pharmaceutical composition that is
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`generally safe, non-toxic and neither biologically nor otherwise undesirable and
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`includes that which is acceptable for veterinary use as well as human
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`pharmaceutical use.” (Exh.1001, at 4:19-23.) From the specification and claims of
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`the ‘942 Patent, it is clear that these pharmaceutical formulations are intended for
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`injection or infusion. A dictionary definition of “pharmaceutical” is that it is a drug
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`or medicine. (Exh.1030, at 1316 (The term pharmaceutical means “adj. Of or
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`relating to pharmacy or pharmacists. n. A pharmaceutical product or preparation.”
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`The term pharmacy means “The art of preparing and dispensing drugs.” The term
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`pharmaceutics means “The science of preparing and dispensing drugs.”).) I think a
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`POSA would
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`therefore understand
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`that
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`the
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`terms “pharmaceutical” and
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`“pharmaceutically” mean that the claimed formulation is an injectable drug or
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`medicine for humans or animals. But, that does not mean that the pharmaceutical
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`4392305_1.docx
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`10
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`Exh. 1038
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`formulation needs to be capable of providing any particular level of efficacy. These
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`terms also do not mean that the formulation is administered as a single-use, unit
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`dose, or that the pharmaceutical formulation constitutes a dose per se. These terms
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`do not mean that the pharmaceutical formulation is limited to any intended use and
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`certainly not to reducing the likelihood of cancer chemotherapy-induced nausea
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`and vomiting. These terms also do not impart a requirement for any particular level
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`or duration of storage or shelf stability. U.S. Patent Nos. 9,066,980 and 8,729,094,
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`which I understand are related to the ‘942 Patent, both expressly recite 18- or
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`24-month storage stability. No such term appears in the claims of the ‘942 Patent. I
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`must conclude from this that the claims of the ‘942 Patent were not intended to be
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`limited to any particular level or duration of storage stability.
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`IV. WRITTEN DESCRIPTION
` I read the specification of the ‘942 Patent as I believe a POSA would
`23.
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`read it and I understand that its disclosure and clear objective is for shelf-stable
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`formulations of palonosetron. I believe that a POSA reading the specification of
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`the ‘942 Patent with its repetitive references to shelf-stability of palonosetron
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`formulations would not read it as discussing or even hinting at a non-storage stable
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`palonosetron formulation.
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`24.
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` I understand patents need to contain a written description of the entire
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`invention within the four corners of the document. I do not believe there is written
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`4392305_1.docx
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`11
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`Exh. 1038
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`description support in the specification of the '942 Patent for non-storage stable
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`formulations of palonosetron.
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`I hereby declare under penalty of perjury under the laws of the United States
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`of America that the foregoing is true and correct, and that all statements made of
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`my own knowledge are true and that all statements made on information and belief
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`are believed to be true. I understand that willful false statements and the like are
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`punishable by fine or imprisonment, or both (18 U.S.C. § 1001).
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`Dr. hristopher A. Pause
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`4392305 _l.docx
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`12
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`Exh. 1038