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Post Grant Review No. ________
`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
`
`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
`
`Exh. 1038
`
`

`
`
`
`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 1-19 of U.S. Patent No. 9,173,942
`
`(“the ‘942 Patent”). 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.
`
`Accordingly, I have a great deal of experience with chemotherapeutic agents as
`
`well as medications given to prevent or reduce the side effects of such treatments,
`
`including the dosing, schedules, and interactions of these types of pharmaceuticals.
`
`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
`
`4392305_1.docx
`
`Exh. 1038
`
`

`
`
`
`publications are set forth in my curriculum vitae, attached as Exhibit 1039.
`
`Exhibit 1039 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
`
`care with respect to drug therapy can encompass using medications to ameliorate
`
`nausea and vomiting related to chemotherapy or surgery, appropriate use of
`
`anti-infective drugs, pain management, and proper dosing of medications in
`
`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
`
`4392305_1.docx
`
`2
`
`Exh. 1038
`
`

`
`
`
`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
`
`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
`
`to assess the merit of clinical trial proposals with regard to the federal code of
`
`regulations for protection of human subjects. For the last three years, I have served
`
`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.
`
`4392305_1.docx
`
`3
`
`Exh. 1038
`
`

`
`
`
`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.
`
`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
`
`4392305_1.docx
`
`4
`
`Exh. 1038
`
`

`
`
`
`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
`
`two years of experience.” (Exh.1028.) I can accept this in the context of the claims
`
`of the ‘942 Patent.
`
`II. THE ‘942 PATENT
`14. The Abstract of 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.)
`
`4392305_1.docx
`
`5
`
`Exh. 1038
`
`

`
`
`
`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,
`
`at 1:56-62). However, according to the specification, formulating palonosetron in
`
`liquid formulations was not an easy task, typically due to shelf-stability issues. (Id.
`
`1:62-64.) The specification 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 Summary of Invention in the specification of the ‘942 Patent
`
`further iterates that the core objective of the invention is to shelf-stable
`
`formulations. The specification of the ‘942 Patent discloses the following with
`
`respect to shelf-stable formulations:
`
`• “These formulations are shelf stable for periods greater than 24
`
`months at room temperature, and thus can be stored without
`
`refrigeration,
`
`and manufactured using non-aseptic,
`
`terminal
`
`sterilization processes.” (Id. 2:67-3:3(emphasis added).)
`
`4392305_1.docx
`
`6
`
`Exh. 1038
`
`

`
`
`
`• “Thus, in one embodiment the invention provides a pharmaceutically
`
`stable solution for preventing or reducing emesis comprising (a) from
`
`about 0.01 mg/mL
`
`to about 5 mg/mL palonosetron or a
`
`pharmaceutically acceptable salt thereof; and (b) a pharmaceutically
`
`acceptable carrier.” (Id. 3:9-15 (emphasis added).)
`
`• “The inventors have further discovered that by adjusting the
`
`formulation's pH and/or excipient concentrations it is possible to
`
`increase the stability of palonosetron formulations.” (Id. 3:16-18
`
`(emphasis added).)
`
`• “Therefore,
`
`in another embodiment,
`
`the
`
`invention provides a
`
`pharmaceutically stable solution for preventing or reducing emesis
`
`comprising (a) palonosetron or a pharmaceutically acceptable salt
`
`thereof; and (b) a pharmaceutically acceptable carrier, at a pH from
`
`about 4.0
`
`to about 6.0.” (Exh.1001, at 3:19-23.) “In another
`
`embodiment the invention provides a pharmaceutically stable solution
`
`for preventing or reducing emesis comprising from about 0.01 to
`
`about 5.0 mg/ml palonosetron or a pharmaceutically acceptable salt
`
`thereof; from about 10 to about 100 millimoles citrate buffer; and
`
`from about 0.005 to about 1.0 mg/ml EDTA.” (Id. 3:23-30 (emphasis
`
`added).)
`
`4392305_1.docx
`
`7
`
`Exh. 1038
`
`

`
`
`
`• “The inventors have further discovered that the addition of mannitol
`
`and a chelating agent can increase the stability of palonosetron
`
`formulations. Therefore, in still another embodiment the invention
`
`provides a pharmaceutically
`
`stable
`
`solution . . . wherein
`
`the
`
`pharmaceutically acceptable carrier comprises a chelating agent and
`
`mannitol.” (Id. 3:31-40 (emphasis added).)
`
`17. The specification of ‘942 Patent also discloses in the Detailed
`
`Description of the Invention 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.)
`
`18. 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
`
`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.)
`
`19. The specification further states that the addition of mannitol, which
`
`can be accompanied by a chelating agent, can increase the stability of palonosetron
`
`formulations. (Id. 3:31-33, 5:63-6:10.) The chelating agent is preferably EDTA.
`
`4392305_1.docx
`
`8
`
`Exh. 1038
`
`

`
`
`
`(Id. 6:10.) The suitable concentration range of EDTA is from about 0.005mg/mL to
`
`about 1.0mg/mL, with 0.5mg/mL disclosed as the optimal value. (Id. 6:11-14.)
`
`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.)
`
`20. 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) or which formulations
`
`are considered “stable”. However, it discloses a representative formulation
`
`including palonosetron hydrochloride at a concentration of 0.05mg/ml, 41.5mg/ml
`
`of mannitol (a tonicifying agent), 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 administration. (Id. 7:55-8:10, Example 4.)
`
`III. CLAIM CONSTRUCTION
`I understand that the only claim terms to be construed for the purposes
`21.
`
`of
`
`this
`
`proceeding
`
`are
`
`the
`
`terms
`
`“formulation”
`
`and
`
`“pharmaceutical/pharmaceutically.” The
`
`term “formulation” as recited
`
`in
`
`claims 1-19 is not defined in the specification. To a formulator, this term means the
`
`composition or “recipe” of a product. (Exh.1029, at 691 (Formulate/formulation
`
`means “2. To prepare according to a specified formula.” Formula means “4a. A
`
`4392305_1.docx
`
`9
`
`Exh. 1038
`
`

`
`
`
`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.
`
`22. 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
`
`“pharmaceutically” mean that the claimed formulation is an injectable drug or
`
`medicine for humans or animals. But, that does not mean that the pharmaceutical
`
`4392305_1.docx
`
`10
`
`Exh. 1038
`
`

`
`
`
`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. U.S. Patent Nos. 9,066,980 and 8,729,094,
`
`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. WRITTEN DESCRIPTION
` I read the specification of the ‘942 Patent as I believe a POSA would
`23.
`
`read it and I understand that its disclosure and clear objective is for shelf-stable
`
`formulations of palonosetron. I believe that a POSA reading the specification of
`
`the ‘942 Patent with its repetitive references to shelf-stability of palonosetron
`
`formulations would not read it as discussing or even hinting at a non-storage stable
`
`palonosetron formulation.
`
`24.
`
` I understand patents need to contain a written description of the entire
`
`invention within the four corners of the document. I do not believe there is written
`
`4392305_1.docx
`
`11
`
`Exh. 1038
`
`

`
`description support in the specification of the '942 Patent for non-storage stable
`
`formulations of palonosetron.
`
`I hereby declare under penalty of perjury under the laws of the United States
`
`of America that the foregoing is true and correct, and that all statements made of
`
`my own knowledge are true and that all statements made on information and belief
`
`are believed to be true. I understand that willful false statements and the like are
`
`punishable by fine or imprisonment, or both (18 U.S.C. § 1001).
`
`Dr. hristopher A. Pause
`
`4392305 _l.docx
`
`12
`
`Exh. 1038

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