`Patent No. 9,173,942
`Petition for Post Grant Review
`Attorney Docket No. REDDY 7.2R-021
`
`
`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. xxxxx
`__________________________________________________________________
`
`Exhibit 1026
`DECLARATION OF DR. CHRISTOPHER A. FAUSEL IN
`SUPPORT OF PETITION FOR POST GRANT REVIEW
`OF CLAIMS 1-6, 10, AND 11 OF U.S. PATENT NO. 9,173,942
`UNDER 35 U.S.C. §§ 321-329 AND 37 C.F.R. § 42.200 ET SEQ.
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`4380159_1.docx
`
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,173,942
`Reddy Exhibit 1026
`
`Exh. 1026
`
`Helsinn Healthcare Exhibit 2077
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00008
`
`Page 1 of 31
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`
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`I, DR. CHRISTOPHER A. FAUSEL, declare and state as follows:
`
`1.
`
`I am a citizen of the United States of America and reside at 5411
`
`North Capitol Avenue Indianapolis, Indiana.
`
`2.
`
`I have been retained by Dr. Reddy’s Laboratories, Ltd. and
`
`Dr. Reddy’s Laboratories, Inc. (collectively “DRL,” Petitioner,” or “Requestor”) to
`
`consider issues relating to the validity of claims 1-6, 10, and 11 of U.S. Patent
`
`No. 9,173,942 (“the ‘942 Patent”). I have also been retained by DRL to provide my
`
`expert opinions in connection with two of this patent’s predecessors, U.S. Patent
`
`Nos. 9,066,980 and 8,729,094, which are the subject of litigation in the U.S.
`
`District Court for the District of New Jersey (Civil Action No. 12-2867). I
`
`provided an expert report in connection with that matter. I understand that Helsinn
`
`Healthcare S.A. and Roche Palo Alto LLC (collectively “Helsinn”) are the Patent
`
`Owners.
`
`3.
`
`I am being compensated at my normal rate for time spent working on
`
`this matter, which includes my time for preparing this declaration. My
`
`compensation is not dependent on the outcome of this case.
`
`4.
`
`I am presently a clinical pharmacist practicing at the Indiana
`
`University Simon Cancer Center in Indianapolis, Indiana charged with managing
`
`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
`
`4380159_1.docx
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`Exh. 1026
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`Page 2 of 31
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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
`
`National Cancer Institute designated clinical cancer center. My employment
`
`history, education, professional activities, patents, and other miscellaneous
`
`publications are set forth in my curriculum vitae, attached as Exhibit 1027.
`
`Exhibit 1027 also includes a listing of publications, including books and patents.
`
`5.
`
`I have a Bachelor of Science degree (Albany College of Pharmacy,
`
`1993) and a Doctor of Pharmacy degree (Albany College of Pharmacy, 1996). I
`
`achieved Board Certification in Oncology Pharmacy (BCOP) in 1999 and have
`
`maintained this designation with recertification every seven years.
`
`6.
`
`A Doctor of Pharmacy (Pharm.D.) is a somewhat unique individual
`
`who can be involved in patient care in a number of different contexts. Often, they
`
`have daily interactions with treating physicians consulting on drug selection, dose,
`
`drug interactions, and treatment protocol selection, particularly in a clinical
`
`oncology setting. A Pharm.D. who provides direct patient care to oncology patients
`
`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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`4380159_1.docx
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`2
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`Exh. 1026
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`Page 3 of 31
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`
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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.
`
`7.
`
`Pharmacists specializing in oncology that work at large academic
`
`medical centers actively participate
`
`in
`
`the
`
`tripartite mission of
`
`these
`
`institutions: patient care, education, and research. Like physicians, we are very
`
`well versed in pharmacokinetics, dosing, and administration issues, as well as
`
`practical issues relating to drug handling and storage. But we also understand a
`
`number of issues that often fall into the realm of a drug formulator. A Pharm.D.
`
`may be involved in formulating and compounding, and thus, they have more than a
`
`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
`
`how concentration can impact drug stability in the first instance, both a Pharm.D.
`
`and a formulator are likely to be concerned about compatibility between different
`
`drugs and diluents and drug stability issues. Thus, a Pharm.D.’s responsibilities
`
`and interests can overlap with those of treating physicians and formulators alike,
`
`making their input in drug design and analysis invaluable.
`
`8. My specific experience in research has been in collaboration with
`
`physician colleagues in the drafting and conducting of clinical trials in patients
`
`with cancer, including studies that focus on the use of antiemetic drugs in cancer.
`
`Additionally, I have served on Institutional Review Boards (IRB) for over 15 years
`
`4380159_1.docx
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`3
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`Exh. 1026
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`Page 4 of 31
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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
`
`organization called the Hoosier Cancer Research Network, which is dedicated to
`
`doing high-quality investigator initiated trials in patients with cancer.
`
`9.
`
`I actively teach at the Purdue School of Pharmacy and the Indiana
`
`University School of Medicine for didactic classwork related to the therapeutic use
`
`of drugs in patients with cancer. Further, I provide a number of certified
`
`pharmacy/medical education lectures for pharmacists, nurses, and physicians at
`
`conferences throughout the United States. Lastly, I have provided experiential
`
`teaching at my clinical setting at Indiana University Simon Cancer Center for
`
`Doctor of Pharmacy students and graduate pharmacist resident trainees.
`
`I.
`
`PERSON OF ORDINARY SKILL IN THE ART
`I understand that patents are read in light of the knowledge of a person
`10.
`
`of ordinary skill in the art (“POSA”) as of the earliest effective filing date of the
`
`patent. I have been told by counsel to assume that the earliest effective filing date
`
`is January 30, 2003, for purposes of this proceeding. All of the prior art relied on in
`
`my declaration was published more than a year before the earliest effective filing
`
`date.
`
`4380159_1.docx
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`4
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`Exh. 1026
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`Page 5 of 31
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`11.
`
`It has been explained to me that a POSA is a hypothetical person who
`
`is deemed to be aware of all relevant prior art. A POSA is also a person of
`
`ordinary creativity, not an automaton.
`
`12.
`
`I am further told by counsel that factors relevant to determining the
`
`level of skill in the art include: the educational level of the inventors, the types of
`
`problems encountered in the art, prior art solutions to those problems, the rapidity
`
`with which innovations are made, the sophistication of the technology, and the
`
`educational level of active workers in the field. I understand from counsel that a
`
`POSA may be a composite of different types of individuals.
`
`13.
`
`I understand from counsel that in a dispute between the Patent Owner
`
`and Petitioner in connection with other family members of the ‘942 Patent in the
`
`U.S. District Court for the District of New Jersey, Patent Owner took the position
`
`that a POSA was “[s]omeone who is actively involved in the development of
`
`pharmaceutical products which involves collaborative teamwork among persons
`
`with relevant experience. This person would have a degree in chemistry,
`
`pharmaceutical chemistry, pharmacy, medicine, clinical pharmacology, or another
`
`pharmaceutical science-related field and experience in designing, developing,
`
`evaluating, and/or testing pharmaceutical formulations with a B.S. or master’s
`
`degree in, and two to three years experience, or a Ph.D. or M.D. degree and one to
`
`4380159_1.docx
`
`5
`
`Exh. 1026
`
`Page 6 of 31
`
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`
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`two years of experience.” (Exh.1028.) I can accept this given the claims of the
`
`‘942 Patent.
`
`II. THE ‘942 PATENT
`14. The ‘942 Patent states that it is directed to shelf-stable liquid
`
`formulations of palonosetron for reducing chemotherapy and radiotherapy induced
`
`nausea and vomiting that can be used in the preparation of intravenous and oral
`
`medicaments. (Exh. 1001 Abstract.) As the patent states in the “Background of the
`
`Invention,” palonosetron is a 5-HT3 receptor antagonist, a known class of drugs at
`
`the time of the alleged invention. They treat emesis by antagonizing cerebral
`
`functions associated with the 5-HT3 receptor. (Id. 1:28-33.) Drugs within this class
`
`include ondansetron, granisetron, alosetron, tropisetron, and dolasetron, which
`
`were all commercially available at the time of the alleged invention. (Id. 1:33-35,
`
`2:12-43.) I understand that these drugs are often administered intravenously shortly
`
`before the initiation of chemotherapy or radiotherapy, and are effective in
`
`controlling acute emesis. (Id. 1:35-38, 47-53.)
`
`15. The specification of the ‘942 Patent acknowledges that the active
`
`compound palonosetron was already known, was disclosed in U.S. Patent
`
`No. 5,202,333 (“the ‘333 Patent” or “Berger”) (Exh. 1006) as a 5-HT3 receptor
`
`antagonist, and is useful for the treatment of delayed emesis (Exh. 1001, 1:56-62).
`
`However, according to the patent, formulating palonosetron in liquid formulations
`
`4380159_1.docx
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`6
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`Exh. 1026
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`Page 7 of 31
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`was not an easy task, typically due to shelf-stability issues. (Id. 1:62-64.) The
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`patent states that the intravenous palonosetron formulation in Example 13 of
`
`Berger had a “shelf stability of less than the 1-2 year time period required by health
`
`authorities in various countries.” (Id. 2:9-11.) It was an object of the invention to
`
`provide a palonosetron hydrochloride formulation with increased pharmaceutical
`
`stability. (Id. 2:44-60.)
`
`16. The ‘942 Patent then describes the alleged invention. The inventors
`
`allegedly discovered that palonosetron could be formulated at concentrations of
`
`only about one tenth the amounts of other previously known compounds for
`
`treating emesis. (Id. 3:4-10.) The specification discloses various concentration
`
`ranges of palonosetron in formulations. The broadest disclosed range is from about
`
`0.01mg/mL to about 5mg/mL palonosetron. (Id. 3:9-15.) Other disclosed
`
`palonosetron concentration ranges include from about 0.03mg/mL to about
`
`0.2mg/mL, with 0.05mg/mL touted as the optimal concentration. (Id. 5:3-6.)
`
`17. An advantage purportedly associated with
`
`lower dosages of
`
`intravenous palonosetron was the ability to administer the drug in a single
`
`intravenous bolus over a short, discrete time period. (Id. 5:7-12.) The patent also
`
`states that palonosetron concentration impacts stability, and the greatest stability
`
`was seen at the lowest palonosetron concentrations. (Id. 7:40-43.)
`
`4380159_1.docx
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`7
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`Exh. 1026
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`Page 8 of 31
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`18. The specification offers the alleged discovery that by adjusting pH
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`and/or excipient concentrations, it is possible to increase the stability of
`
`palonosetron formulations. (Id. 3:15-17.) The specification provides three instances
`
`in which this purportedly is the case.
`
`19. For example,
`
`the specification discloses
`
`that adjusting
`
`the
`
`formulation’s pH can increase the stability of the formulation. (Id. 3:19-23.) The
`
`specification discloses a pharmaceutically stable solution comprising palonosetron
`
`and a carrier, wherein the pH is “from about 4.0 to about 6.0.” (Id. 5:27-28.) Other
`
`suitable ranges include “from about 4.5 to 5.5.” (Id. 5:28-29.) A solution pH value
`
`of 5.0 allegedly imparts the greatest stability. (Id. 5: 30, 7:25-26.)
`
`20. The specification further states that a solution of palonosetron
`
`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
`
`about 100 millimoles citrate buffer and about 0.005 to about 1.0mg/ml EDTA. (Id.)
`
`The patent concludes that an optimal formulation includes EDTA 0.05% and
`
`20mM citrate buffer, with a pH of 5. (Id. 7:37-40.)
`
`21. The specification further states that the addition of mannitol, which
`
`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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`(Id. 6:10.) The suitable concentration range of EDTA is from about 0.005mg/mL to
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`4380159_1.docx
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`8
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`Exh. 1026
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`Page 9 of 31
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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
`
`80.0mg/mL. (Id. 6:16-18.) The level of mannitol in a palonosetron formulation
`
`containing citrate buffer is said to be 4.15%. (Id. 7:52-54, Example 3.)
`
`22. The specification does not say which of the foregoing features, or
`
`combination of features, of a palonosetron formulation produces a particular level
`
`of stability (such as 24-month stability at room temperature). However, it discloses
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`a
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`representative
`
`formulation
`
`including palonosetron hydrochloride at a
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`concentration of 0.05mg/ml, 41.5mg/ml of mannitol (a tonicifying agent),
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`0.5mg/ml of EDTA (a chelating agent), citrate buffer, a pH adjusting agent (i.e.,
`
`NaOH/HCl) and water. This formulation is said to be useful for intravenous
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`administration. (Id. 7:55-8:10, Example 4.)
`
`23. The specification does not disclose any tonicity agents other than
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`sodium chloride and mannitol, does not mention a buffer other than citrate, and
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`does not mention any chelating agents other than EDTA and citrate.
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`III. CLAIM CONSTRUCTION
`I understand that the only claim terms to be construed for the purposes
`24.
`
`of
`
`this
`
`proceeding
`
`are
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`the
`
`terms
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`“formulation”
`
`and
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`“pharmaceutical/pharmaceutically.” The
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`term “formulation” as recited
`
`in
`
`claims 1-6, 10, and 11 is not defined in the specification. To a formulator, this term
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`4380159_1.docx
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`9
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`Exh. 1026
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`Page 10 of 31
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`
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`means,
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`the composition or “recipe” of a product.
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`(Exh.1029, at 691
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`(Formulate/formulation means “2. To prepare according to a specified formula.”
`
`Formula means “4a. A prescription of ingredients in fixed proportion; a recipe.”).)
`
`“Formulation,” per se, is not limited to “stable” formulations. “Formulation” is not
`
`limited to a single-use, unit dose, or indeed a dose at all. nor does it imply sterility.
`
`“Formulation” is not limited to any intended use and certainly not reducing the
`
`likelihood of cancer chemotherapy-induced nausea and vomiting.
`
`25. The terms “pharmaceutical” and “pharmaceutically” are also not
`
`defined in the specification. However, the term “pharmaceutically acceptable” is
`
`defined as “that which is useful in preparing a pharmaceutical composition that is
`
`generally safe, non-toxic and neither biologically nor otherwise undesirable and
`
`includes that which is acceptable for veterinary use as well as human
`
`pharmaceutical use.” (Exh.1001, at 4:19-23.) From the specification and claims of
`
`the ‘942 Patent, it is clear that these pharmaceutical formulations are intended for
`
`injection or infusion. A dictionary definition of “pharmaceutical” is that it is a drug
`
`or medicine. (Exh.1030, at 1316 (The term pharmaceutical means “adj. Of or
`
`relating to pharmacy or pharmacists. n. A pharmaceutical product or preparation.”
`
`The term pharmacy means “The art of preparing and dispensing drugs.” The term
`
`pharmaceutics means “The science of preparing and dispensing drugs.”).) I think a
`
`POSA would
`
`therefore understand
`
`that
`
`the
`
`terms “pharmaceutical” and
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`4380159_1.docx
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`10
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`Exh. 1026
`
`Page 11 of 31
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`
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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
`
`formulation needs to be capable of providing any particular level of efficacy. These
`
`terms also do not mean that the formulation is administered as a single-use, unit
`
`dose, or that the pharmaceutical formulation constitutes a dose per se. These terms
`
`do not mean that the pharmaceutical formulation is limited to any intended use and
`
`certainly not to reducing the likelihood of cancer chemotherapy-induced nausea
`
`and vomiting. These terms also do not impart a requirement for any particular level
`
`or duration of storage or shelf stability. The ‘094 and ‘980 Patents, which I
`
`understand are related to the ‘942 Patent, both expressly recite 18- or 24-month
`
`storage stability. No such term appears in the claims of the ‘942 Patent. I must
`
`conclude from this that the claims of the ‘942 Patent were not intended to be
`
`limited to any particular level or duration of storage stability.
`
`IV. THE PRIOR ART
`A. Dose Conversion
`26. The prior art sometimes discusses drug doses and amounts in different
`
`units than the claims. For example, claim 2 of the ‘942 Patent requires an amount
`
`of 0.25mg of palonosetron hydrochloride or other salt based on the weight of free
`
`palonosetron. This is not a recitation of a dose. The claimed invention is merely a
`
`formulation. Nothing in the claims suggests how much of this formulation would
`
`be administered to a human or animal or for what purpose. It is just an aqueous
`
`4380159_1.docx
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`11
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`Exh. 1026
`
`Page 12 of 31
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`
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`solution containing a specified amount of palonosetron. Where the prior art reflects
`
`a dose, it often does so by reporting a number of micrograms per kilogram of body
`
`mass.
`
`27.
`
`I have converted all units to milligrams. The conversion process from
`
`doses in “µg/kg” (or other units) for either human or animal data to milligrams is
`
`as follows. To convert human data in µg/kg to mg, one converts to mg/kg and
`
`multiplies by a “standard” 70kg person. This is an approximation of average
`
`human weight (men and women). A dose of 1µg/kg would first be converted to
`
`0.001mg/kg and then multiplied by 70kg, resulting in 0.07mg.
`
`28.
`
`In the prosecution of the ‘219 Patent, which is the parent of the
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`‘942 Patent, the Examiner relied upon this same 70kg standard weight conversion
`
`in explaining their position. (See Exh.1031, at 8.) Berger, owned by Patent Owner,
`
`used this conversion as well. (See Exh.1001, at 12:16-18 (“Therefore, a
`
`therapeutically effective amount for a 70kg human may range from . . . .”).)
`
`29. For animals, there is an extra step. After converting from µg/kg to
`
`mg/kg, the number is divided by a known factor of 5.3 for ferrets or 1.8 for dogs.
`
`This estimates equivalent doses in humans from animal doses. That result is then
`
`multiplied by a 70kg person. References in this report to doses in [square brackets]
`
`refers to the dose in humans in milligrams.
`
`4380159_1.docx
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`12
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`Exh. 1026
`
`Page 13 of 31
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`30. Animal doses are adjusted based on body surface area normalization
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`using a common conversion factor as described by FDA in the December 2002
`
`draft guidance entitled “Guidance for Industry and Reviewers: Estimating the Safe
`
`Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers”
`
`(Exh.1038). The extrapolation of the animal dose to human dose is calculated by
`
`dividing the dose in each of the animal species studied by the appropriate body
`
`surface area conversion factor (BSA-CF). The conversion factor is a unitless
`
`number that converts a mg/kg dose for each animal species to the mg/kg dose in
`
`humans. For ferrets, the animal dose is divided by a factor of 5.3. (See Exh.1038,
`
`at 6-7, Table 1.) The conversion factor for dogs is 1.8. (See id.)
`
`31. The Table 1 below reflects conversions of, as appropriate, µg/kg to
`
`mg fixed doses and animal doses to human doses in Eglen (Exh.1025) and Tang
`
`(Exh.1008).
`
`TABLE 1
`
`Amount in
`µg/kg
`0.1
`0.3
`1
`3
`10
`30
`100
`300
`
`Eglen
`(Human/Ferret)
`
`
`0.013mg
`0.04mg
`0.13mg
`0.4mg
`1.3mg
`
`
`Eglen
`(Human/Dog)
`
`0.012mg
`0.04mg
`0.12mg
`0.4mg
`1.2mg
`4.0mg
`12.0mg
`
`
`Tang (Human)
`0.007mg
`0.021mg
`0.07mg
`0.21mg
` n/a
`2.1mg
`
`
`
`4380159_1.docx
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`13
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`Exh. 1026
`
`Page 14 of 31
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`
`
`
`
`Berger
`B.
`32. The prior art Berger patent, U.S. Patent No. 5,202,333 (“Berger”),
`
`taught that palonosetron was 5-HT3 receptor antagonists, and could be used in
`
`methods of treating diseases involving, among other things, emesis. (See Exh.1006,
`
`at 1:9-16, 3:16-24, 10:6-9.) Berger taught that palonosetron could be administered
`
`to humans (id. 9:50-55) as a pharmaceutical composition by the intravenous route,
`
`preferably “in a single unit dosage form” (id. 12:25-29, 13:1-5), and that the drug
`
`could be administered to treat CINV (id. 10:6-9 (“Compounds of Formula I are of
`
`particular value
`
`in
`
`treating
`
`(especially preventing)
`
`the emesis
`
`induced
`
`by . . . treatment for cancer with . . . chemotherapy. . . .”).
`
`33. Palonosetron could be employed as a pharmaceutically acceptable
`
`salt.
`
`(Exh.1006, at 3:13-15, 4:66-5:2.) Berger specifically disclosed
`
`the
`
`hydrochloride salt among a list of “pharmaceutically acceptable salts,” and taught
`
`that the compounds of Formula I, which include palonosetron, may “be converted
`
`to the corresponding acid addition salt with a pharmaceutically acceptable
`
`inorganic or organic acid.” (Id. 4:66-5:20, 19:30-33.)
`
`34. Berger identifies therapeutically effective amounts as including a
`
`range of 1.0ng/kg per day to 1.0mg/kg per day based on body weight, and a
`
`preferred range of 10ng/kg to 0.1mg/kg. (Id. 12:11-16.) As Berger explains, for a
`
`standard 70kg human, the preferred dose range is from 700ng/day to 7.0mg/day.
`
`4380159_1.docx
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`14
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`Exh. 1026
`
`Page 15 of 31
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`
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`(Id. 12:11-18; ¶¶ 26-31, supra.) Converted to milligrams, the unit of measurement
`
`utilized in claim 2 of the ‘942 Patent, this preferred range is 0.0007mg to 7.0mg.
`
`Berger taught that palonosetron could be provided in single unit doses. (Id. 13:2.)
`
`35. Berger notes the amount of palonosetron in final dosage forms
`
`preferably ranges from 0.00001% w to 1.0%w. (Exh.1006, at 12:66-67.) This is
`
`actually a way of expressing concentration. The claimed concentration of
`
`0.05mg/ml, when converted to this weight scale, would be 0.005% w. Thus, the
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`concentration claimed in claim 1 of the ‘942 Patent also falls within the
`
`concentration range described in Berger.
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`36. Berger also discloses the use of various amounts of palonosetron
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`(10mg-100mg) in Example 13. (Id. 29:6.) But this is clearly a reference to a
`
`concentration as opposed to a dose. The example does not specify how much of
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`this exemplified formulation is to be given to a patient. Indeed, a POSA would not
`
`likely think that this example was describing a dose per se because 10mg is outside
`
`of the preferred dose range described in Berger, and 100mg is outside of the entire
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`range described in Berger as being a therapeutically effective amount.
`
`37. Berger states: “[o]ne of ordinary skill in the art of treating such
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`diseases will be able, without undue experimentation and in reliance upon personal
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`knowledge and the disclosure of this application, to ascertain a therapeutically
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`effective amount of a compound of Formula I for a given disease.” (Id. 12:19-24.) I
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`agree.
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`38. More than a year before what I understand to be the earliest effective
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`filing date of the ‘942 Patent, there were publications of the results of Phase I
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`studies showing that administering palonosetron over a wide range of doses was
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`safe for humans. (Exhs.1046, 1047.) Eglen showed that various doses were safe
`
`and effective for animals as well. Knowing that palonosetron could be given over a
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`broad range of doses safely and that it was effective over a broad range as well, a
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`POSA would have been able to determine effective doses with nothing other than a
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`normal degree of effort and experimentation.
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`C. Eglen
`39. The Eglen paper also disclosed the use of intravenous solutions of
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`palonosetron hydrochloride for treating CINV in animal studies. (Exh.1025,
`
`at 860-61, Fig.1.) Eglen taught that ferrets and dogs, the species tested, were art
`
`recognized models for emesis in humans. (Id. at 861.) That said, I note that the
`
`disclosure of the ‘942 Patent seems to embrace treating animals as well as humans.
`
`(Exh.1001, at 4:19-23 (“’Pharmaceutically acceptable’ means . . . and includes that
`
`which is acceptable for veterinary use as well as human pharmaceutical use.”).)
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`40. Eglen showed effective dosages in ferrets in the range of 1-30µg/kg,
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`but it tested doses up to 100µg/kg. For the doses of 1, 3, 10, and 30µg/kg
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`Page 17 of 31
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`administered intravenously, an inhibitory effect against cisplatin induced emesis
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`(reduction in the number of emetic episodes) was observed in ferrets at all doses,
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`as illustrated in Eglen’s Fig. 5. (Exh.1025, at 863.) For a 70kg human subject (see
`
`¶¶ 26-31, supra), this dosage range corresponds to approximately 0.013 to 0.4mg
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`of palonosetron [0.013, 0.04, 0.13, and 0.4mg, respectively]. This means that for
`
`all four of the doses tested, palonosetron exhibited efficacy in reducing CINV. The
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`claimed amount of 0.25mg falls within this range of 0.013-0.4mg shown to be
`
`effective in Eglen.
`
`41. The data in dogs was similar and is illustrated in Eglen’s Fig. 6.
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`(Exh.1025, at 863, Fig.6.) While doses of 0.3-300µg/kg were formulated (id.
`
`at 861), an inhibitory effect was observed in dogs at doses of 1, 3, 10, 30,
`
`and 100µg/kg [0.04, 0.12, 0.4, 1.2, and 4.0mg]. (Id.) The claimed amount of
`
`0.25mg of palonosetron falls within this range as well.
`
`42.
`
`It would be readily apparent to a POSA to combine Berger and Eglen
`
`and, in particular to apply the ranges used in Eglen to narrow the dose and
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`concentration ranges described in Berger. Both tested (or suggested testing) in
`
`ferrets and dogs for efficacy in reducing the likelihood of CINV. (Exhs.1006
`
`Examples 16, 17; 1025, at 865.) Eglen was a later preclinical study published two
`
`years after Berger issued and more than five years after it originally was filed. And
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`Eglen included actual efficacy data, including comparative data against another
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`Exh. 1026
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`Page 18 of 31
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`setron, ondansetron. (Exh.1025, at 863.) No such data was presented in Berger.
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`This would motivate a POSA to use the doses disclosed in Eglen to further focus
`
`the work of Berger, which encompassed those dose ranges. And it would provide a
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`POSA with reasonable expectations of success in using those doses to produce
`
`formulations.
`
`D. Tang
`In 1998, Tang (Exh.1008) reported the preliminary efficacy results of
`43.
`
`palonosetron in a Phase II clinical study in women undergoing gynecological
`
`surgery; namely, hysterectomy. Palonosetron was administered to 218 patients to
`
`address postoperative nausea and vomiting (“PONV”), and was dosed at 0.1, 0.3,
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`1.0, 3.0, and 30µg/kg [0.007mg, 0.021mg, 0.07mg, 0.21mg, and 2.1mg] when
`
`multiplied by a standard 70kg human subject or placebo (Exh.1008, at 462)
`
`administered by IV over 30 seconds, 20-30 minutes before the end of surgery (id.
`
`at 463).
`
`44. All of the IV doses were administered in a total volume of 15ml in an
`
`isotonic sodium chloride solution. (Id.) Thus, at the dose of 0.007mg, the
`
`concentration used was 0.0005mg/ml. For the 0.021mg, the concentration was
`
`0.0014mg/ml. At a 0.07mg dose, the concentration was 0.005mg/ml. At a 0.21mg
`
`dose, the concentration was 0.014mg/ml, and at a dose of 2.1mg, the concentration
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`Exh. 1026
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`Page 19 of 31
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`was 0.14mg/ml. This range of concentrations encompasses
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`the claimed
`
`concentration of 0.05mg/ml. (See Table 2.)
`
`Average
`Dose In
`weight
`Methods
`(kg)
`Section
`70kg
`0.1mcg/kg
`70kg
`0.3mcg/kg
`70kg
`1mcg/kg
`70kg
`3mcg/kg
`70kg
`30mcg/kg
`* Isotonic sodium chloride
`
`TABLE 2
`Total Dose
`Total Dose
`(mcg)
`(mg)
`
`Dilution*
`(mL)
`
`Concentration
`(mg/mL)
`
`7mcg
`21mcg
`70mcg
`210mcg
`2100mcg
`
`0.007mg
`0.021mg
`0.07mg
`0.21mg
`2.1mg
`
`15mL
`15mL
`15mL
`15mL
`15mL
`
`0.00047mg/mL
`0.0014mg/mL
`0.0047mg/mL
`0.014mg/mL
`0.14mg/mL
`
`45. Tang also taught that the doses of 0.021mg and above exhibited at
`
`least some efficacy in preventing emesis demonstrating that these doses reduced
`
`the likelihood of PONV. That said, none of the doses in the study below 2.1mg
`
`produced a statistically significant decrease in the incidence of vomiting and the
`
`requirement for rescue antiemetics. But Tang teaches a POSA pharmaceutical
`
`formulations containing palonosetron or a salt thereof, which were isotonic
`
`(Exh. 1008 at 463.), and had a range of concentrations that encompass the claimed
`
`concentration.
`
`46. Given the foregoing, the Berger, Eglen, and Tang references each
`
`taught an aqueous solution of palonosetron hydrochloride having a range of
`
`concentrations that bracket 0.05mg/mL. The amount claimed in claim 2 is
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`Exh. 1026
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`Page 20 of 31
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`bracketed by the formulations disclosed in all three references as well. Berger and
`
`Tang made clear that their formulations were isotonic.
`
`V. THE ELEMENTS OF CLAIMS 1-6, 10, AND 11 OF
`THE ‘942 PATENT ARE KNOWN FROM THE PRIOR ART
`A. Pharmaceutically Sterile (All Claims Of The ‘942 Patent)
`47. Pharmacists have some experience with basic formulation and
`
`assessing pharmaceutical stability for injectable drugs. Pharmacists are charged
`
`with assessing active drug product and excipients in an intravenous drug
`
`formulation administered to patients so that they can consider things like allergic
`
`reactions, interactions between medications, and interactions between an active
`
`ingredient of one medication and an excipient of another. Further, often in
`
`hospitalized patients, multiple intravenous medications are being administered in
`
`time periods that may overlap. Pharmacists provide support to nursing in
`
`determining the optimal timing of medications such that drugs that are potentially
`
`incompatible are not administered concurrently. Alternatively, a pharmacist would
`
`discuss an alternative drug combination with the treating physician.
`
`48. Pharmacists also know the basic properties of the medications that
`
`they dispense. For example, I am unaware of any IV or injectable product that is
`
`not sterile. In my experience, and I believe a POSA would have the same
`
`experience, every commercial injectable or IV product is sterile. In my opinion,
`
`any POSA reading Berger, Eglen, or Tang, and knowing that these particular
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`formulations were intended for intravenous infusion into humans or animals,
`
`would understand them to be sterile, even if sterility was not mentioned, otherwise
`
`the drug product would not be safe for intravenous administration. A POSA’s
`
`expectations would be supported by the fact that the other setrons approved in the
`
`U.S. were all sterile. (Exhs.1009, at 1503 (“Sterile Injection for Intravenous (I.V.)
`
`or Intramuscular (I.M.) Administration”); 1010, at 3105 (“Kytril Injection is a
`
`clear, colorless, sterile, nonpyrogenic, aqueous solution
`
`for
`
`intravenous
`
`administration.”); 1011, at 680 (ANZEMET Injection is a clear, colorless,
`
`nonpyrogenic sterile solution for intravenous administration.” (Emphasis added).)
`
`B. Aqueous Intravenous Solution (All Claims Of The ‘942 Patent)
`49. A POSA would appreciate that the most common solvent used in
`
`parenteral products is