Case IPR2015-
`Patent No. 8,729,094
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY'S LABORATORIES, LTD. and
`DR. REDDY'S LABORATORIES, INC.
`Requestors
`
`v.
`
`HELSINN HEALTHCARE S.A. and ROCHE PALO ALTO LLC
`Patent Owner
`
`Patent No. 8,729,094
`Issue Date: May 20, 2014
`Title: LIQUID PHARMACEUTICAL FORMULATIONS OF PALONOSETRON
`
`Inter Partes Review No. Unassigned
`
`(Exhibit 1040)
`
`DECLARATION OF PATRICK P. DELUCA, Ph.D.
`
`4122591_ 1.docx
`
`Dr. Reddy's Laboratories, Ltd., et al.
`V.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1040
`
`Exh. 1040
`
`
`Patent No. 8,729,094
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY'S LABORATORIES, LTD. and
`DR. REDDY'S LABORATORIES, INC.
`Requestors
`
`v.
`
`HELSINN HEALTHCARE S.A. and ROCHE PALO ALTO LLC
`Patent Owner
`
`Patent No. 8,729,094
`Issue Date: May 20, 2014
`Title: LIQUID PHARMACEUTICAL FORMULATIONS OF PALONOSETRON
`
`Inter Partes Review No. Unassigned
`
`(Exhibit 1040)
`
`DECLARATION OF PATRICK P. DELUCA, Ph.D.
`
`4122591_ 1.docx
`
`Dr. Reddy's Laboratories, Ltd., et al.
`V.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1040
`
`Exh. 1040
`
`
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`Case IPR20 15-
`Patent No. 8,729,094
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
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`I, PATRICK P. DELUCA, hereby declare as follows:
`
`1.
`
`2.
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`I am a US citizen and a resident of the state of Kentucky.
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`I am a Professor Emeritus in the Department of Pharmaceutical
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`Sciences, College of Pharmacy, University of Kentucky. I received a B.S. and M.S.
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`in Pharmacy from Temple University in 1957 and 1960, respectively. I received
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`my Ph.D. in Pharmaceutical Sciences from Temple University in 1963.
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`3.
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`During my career of over 50 years, my research and teaching interests
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`in pharmaceutical science and technology have been in various areas, including
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`parenteral and intravenous pharmaceutical formulations and drug product stability.
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`I have published over 225 research articles and authored or co-authored chapters in
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`several textbooks in the field, including a textbook on formulating small volume
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`parenteral drugs, such as the setrons. (Exh. 1 042.)
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`4.
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`I have received numerous awards and honors for my research and
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`teaching achievements. I am a founding member and Fellow of the American
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`Association of Pharmaceutical Scientists ("AAPS") and served as its President
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`between 2008 and 2009. I was the first Editor-in-Chief of the international journal
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`Pharmaceutical Development and Technology between 1995 and 1999, the first
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`4122591_ 1.docx
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`Exh. 1040
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`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
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`Editor-in-Chief of the AAPS online journal PharmSciTech between 2000 and
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`2007, and also served on the editorial boards of several other scientific journals in
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`the broad field of pharmaceutical sciences with special focus on pharmaceutical
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`technology and drug product development.
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`5.
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`In addition to my research and teaching, I have consulted over the
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`years for both brand and generic pharmaceutical companies on matters related to
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`pharmaceutical formulation and development. Additional details of my education,
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`experience, and credentials are set forth in my curriculum vitae. (Exh. 1041.)
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`6.
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`I was retained by Dr. Reddy's Laboratories, Ltd. and Dr. Reddy's
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`Laboratories, Inc. to serve as an expert m the litigation between Helsinn
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`Healthcare S.A. and Roche Palo Alto LLC v. Dr. Reddy's Laboratories, Ltd.,
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`Dr. Reddy's Laboratories, Inc., identified to the Patent Trial and Appeal Board in
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`the Notice of Related Matters in the Petition that this declaration supports.
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`7.
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`I have separately been retained by Lerner, David, Littenberg,
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`Krumholz & Mentlik, LLP ("counsel") to provide my opinions in the fields of
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`pharmaceutical formulation and stability for purposes of this IPR. I have read and
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`understood U.S. Patent No. 8,729,094 ("the '094 Patent") (Exh. 1001) as well as
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`all other references discussed in this declaration. I am being compensated for my
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`Attorney Docket No. REDDY 7.1R-012
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`time m an amount consistent with my customary consulting fee and my
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`compensation is not contingent on my opinion or the outcome of this proceeding.
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`I.
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`A PERSON OF ORDINARY SKILL IN THE ART
`8.
`I understand from counsel that patents such as the '094 Patent are
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`neither addressed to experts nor to laymen; rather they are addressed to persons of
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`ordinary skill in the relevant art at the time invention was made, which I have been
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`told by counsel to assume is January 29, 2003. I also understand from counsel that
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`factors relevant to the level of skill in the art include, without limitation: the
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`educational level of the inventor, the types of problems encountered in the relevant
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`area, prior art solutions to those problems, the rapidity with which innovations are
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`made, the sophistication of the technology, and the educational level of active
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`workers in the field
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`9.
`
`As noted previously, I was retained as an expert in connection with
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`other patents related to the '094 Patent. I did not, however, testify at Trial. I am not
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`an expert in patent law but, from my recollection, none of those patents involves
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`methods of treating CINV per se. That must be contrasted with claims 22-30 of the
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`'094 Patent, which appear on their face to relate to methods of treating CINV,
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`albeit by administering the types of formulation that are the focus of the
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`above-identified litigations.
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`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
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`10. Because of my involvement in the aforementioned litigations, I know
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`that Petitioner has taken the position that a person of ordinary skill in the art (a
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`"POSA") as to the patents at issue in those cases, would be a formulation scientist,
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`typically with a Ph.D. in pharmaceutics or a related field, and would have a couple
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`of years' experience in developing IV formulations and bench experience. I also
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`understand that Petitioner argued that formulation scientists would draw on the
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`pharmaceutical science literature, general textbooks, research articles and abstracts,
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`and other sources of information, including from clinicians and pharmacologists,
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`and other scientists in the field.
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`11.
`
`I would certainly agree that this definition is still broadly applicable
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`here; and as regards the aspects of the claimed invention that relate to drug
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`formulation, I consider myself to be a person of greater than ordinary skill.
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`However, the claimed invention in the '094 Patent is, in my view, primarily
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`directed to a method of medical treatment; and as such, I believe medical doctors
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`and other medical professionals having experience specifically treating cancer and
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`addressing the side effects of the use of highly emetogenic chemotherapies would
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`be of at least equal import. Such doctors or clinicians would have a high level of
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`formal education and several years of practical experience. In particular, they
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`should have experience in clinical study, and an interpretation of data from medical
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`studies as would be applied to treating patients. Whether these medical and
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`claimed professionals would consult with formulators or the reverse, is of lesser
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`importance to me, as all of their collectible knowledge and experience are
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`implicated by the '094 Patent. I understand from counsel that a POSA may be a
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`composite of different types of individuals, with each individual having a
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`somewhat different background from the others. When it comes to the claims of
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`the ' 094 Patent, in my opinion, a POSA would most appropriately be a composite
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`of the types of individuals I have just noted.
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`II. DRUG FORMULATION AND DEVELOPMENT
`12. By January 29, 2003, the general procedures for preparing parenteral
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`formulations were well known, well understood, and well documented in general
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`texts on the subject. Indeed, the formulations art had a good deal of experience in
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`formulating parenteral and injectable drugs, including the setrons.
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`13. Traditionally, optimization experimentation m pharmaceutical
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`development was conducted by a "one factor at a time" approach. Compared to
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`this traditional approach, modern experimental design (also referred to as "design
`
`of experiments" or "DOE") allows evaluation and optimization of multiple factors
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`with a minimum number of experiments. (See, e.g., Exh. 1014, at 309-13.)
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`14.
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`Since its initial application in the pharmaceutical field in the 1950s,
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`experimental design has become a routine and powerful tool at all stages of
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`pharmaceutical development, including preformulation and formulation screening
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`and optimization. (Exh. 1014, at 309-13.) Easy-to-use experimental design
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`computer software became commercially available m 1990s, enabling
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`pharmaceutical scientists with relatively little statistical training to readily conduct
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`design of experiments in pharmaceutical development. (!d.) In my opinion, this is
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`exactly what was done in accordance with the '094 Patent based on its own
`
`characterization of the work reflected in Examples 1-3. This process is now highly
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`standard and routine.
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`Preformulation Studies
`A.
`15. As every POSA knows, as part of the process of formulation
`
`development, a preformulation study is conducted to determine the basic
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`physiochemical properties of a drug substance prior to
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`the formulation
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`development of a particular dosage form. (See generally Exh. 1050, at 115-16.)
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`Knowledge of the properties of the active and/or general knowledge about
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`compounds in the same class, and specific knowledge about compounds of similar
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`structures (e.g., setrons, amines, etc.), is often valuable for solving formulation
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`and/or stability problems.
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`Attorney Docket No. REDDY 7.1R-012
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`16.
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`For a parenteral drug formulation, a preformulation study typically
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`includes the study of the chemical stability of the drug substance both in solution
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`and in the solid state. (See, e.g., id. at 115-16, 140-43.) "Taking into account early
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`pharmacological and biopharmaceutical data, preformulation studies yield key
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`information necessary to guide the formulator and analyst toward the development
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`of an elegant, stable dosage form with good bioavailability." (Exh. 1050, at 115.)
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`The preformulation study for a solution formulation often includes the study of the
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`effects of pH, light, temperature, oxygen, metal ions and chelating agents on
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`solution stability. (!d. at 115, 140-43.) The preformulation study also often includes
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`the identification of degradation products and potential degradation mechanism(s)
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`of the active pharmaceutical ingredient ("API"). (Jd. at 115.)
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`B.
`17.
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`Formulation Development Phase
`In the formulation development phase, formulations with varymg
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`compositions are prepared and evaluated for the selection of an optimal
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`composition. At this stage, each component of a typical intravenous solution, e.g.,
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`solvents, pH buffers, tonicifying agents and stabilizing agents, are optimized
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`through experiments. The information gained from the preformulation studies,
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`including the consideration of the literature, on the drug substance is used in this
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`process. (See, e.g., Exh. 1050, at 142.)
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`18.
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`For example, compositions with varying pHs surrounding the pH of
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`maximum stability (usually identified in the preformulation study) are screened for
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`the selection of the optimal pH, which may require consideration of other factors,
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`as well as to identify the appropriate pH buffer for the formulation, if any.
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`Moreover, when degradation and stability issues have been observed during
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`preformulation, formulations with and without various stabilizing agents are
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`compared in order to identify the effective stabilizing agent(s). Although different
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`tonicifying agents are generally not expected to cause significant differences in
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`stability, formulations with various tonicifying agents are often compared to see if
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`there is any advantage. The amount and concentration of each excipient is also
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`determined. All of these analyses are completely routine and have been employed
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`for decades. They are used in the development of virtually every drug product.
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`C.
`19.
`
`Formulation Work Based On The Relevant Prior Art
`In view of the formulation standard operating procedures just
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`outlined, when a formulator (typically working as a group) was instructed to make
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`a parenteral palonosetron product, it would have consulted whatever information
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`was available from pre-formulation and from the available literature. The
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`formulation group would have known that IV formulations were known from
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`sources like Berger, U.S. Patent No. 5,202,303, which specifically disclosed IV
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`formulations and provided concentration ranges, possible doses, and excipients.
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`(Exh. 1010 col.3 11.16-24, col.12 11.11-54, col.29 11.1-12.) They would also have
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`dosing information from the published Phase II studies and would know that a
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`successful IV formulation was indeed possible from the press releases of Patent
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`Owner, which noted that Phase III studies were soon to be completed on the IV
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`treatment of CINV, and that a new drug application would be filed imminently.
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`They would know of the normal components of IV formulations including
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`solvents, buffers, tonicity agents, stabilizers and the like. They would know that a
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`relatively narrow range of pHs, volumes, and concentrations was typical for
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`parenteral formulations. And they would have known of the existence of other
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`commercial setrons indicated for the same use, as well as their formulation.
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`Commercially Available Setrons
`1.
`20. As noted above, one thing a POSA would always do when starting a
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`formulation project would be to see what had worked in the past. Not surprisingly,
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`a POSA would therefore look to formulation work already successfully done via
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`commercial products. One essential source for such infonnation is the Physicians '
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`Desk Reference ("PDR").
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`21.
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`I have reviewed the 2001 PDR, and it contains entries for three
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`setrons. Ondansetron was a commercially available setron sold under the trade
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`name ZOF~ as an injectable aqueous solution of its hydrochloride salt in
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`a 2mg/ml solution and a 32mg/50ml "premixed" solution. (Exh. 1015, at 1503.)
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`Each 1 ml solution in a single-dose vial contained 2mg ondansetron as the
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`hydrochloride dihydrate, 9.0mg sodium chloride (NaCl), 0.5mg citric acid
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`monohydrate and 0.25mg sodium citrate dihydrate, buffered at pH 3.3 to 4.0.
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`(Exh. 101 5, at 1503.) Each lml solution in a 20-ml multi-dose vial contained 2mg
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`ondansetron as the hydrochloride dihydrate, 8.3mg sodium chloride, 0.5mg citric
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`acid monohydrate and 0.25mg sodium citrate dihydrate, buffered at pH 3.3 to 4.0,
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`and 1.2mg methylparaben and 0.15mg propylparaben as preservatives. (Jd.) Each
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`5ml "premixed" solution contained 32mg ondansetron as the hydrochloride
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`dihydrate, 2500mg dextrose, 26mg citric acid and 11 .5mg of sodium citrate,
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`buffered at pH 3.0-4.0. (!d.)
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`22. Granisetron was another commercially available setron found in the
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`2001 PDR, which was sold under the trade name KYTRIL ®_ Granisetron is an
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`injectable aqueous solution of its hydrochloride salt in a 1mg/ml solution in
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`single-dose and multi-dose vials. (Exh. 1016, at 3104-05.) Each 1ml of the
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`single-dose solution contained 1.12mg granisetron hydrochloride and 9 .Omg
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`sodium chloride in an aqueous solution of pH 4.7 to 7.3. (!d. at 3105.) Each 1ml of
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`the multi-dose solution contained 1.12mg granisetron hydrochloride, 9mg sodium
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`chloride, 2mg citric acid and 1 Omg benzyl alcohol as a preservative, in an aqueous
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`solution of pH 4.0 to 6.0. (!d.) The recommended dose was 1 OJ..Lg/kg, administered
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`via IV within 30 minutes before chemotherapy was initiated. (See id. at 3106.) The
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`dose was administered either undiluted over 30 seconds or diluted and infused over
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`five minutes. (See id. at 3106.)
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`23. Dolasetron is another setron found in the 2001 PDR and was
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`commercially available under the trade name ANZEMET® as an injectable
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`aqueous solution of its mesylate salt. (Exh. 1017, at 680.) Each 1ml of the solution
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`contained 20mg dolasetron mesylate and 38.2mg mannitol with an acetate buffer
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`for a resulting solution of pH 3.2 to 3.8. (!d.) The recommended IV dose was
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`1.8mg/kg as a single dose, approximately 30 minutes before chemotherapy. (!d.
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`at 683.) For most patients, however, an alternative fixed dose of lOOmg could be
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`administered over 30 seconds. (!d.)
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`24. Each IV formulation is relatively simple and of low volume, and most
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`contain buffers and tonicity agents that are considered among the most common.
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`They are all sterile, suitable for single unit doses, and the pH for all of them can be
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`mildly acidic. Not surprisingly, all of this is true of the formulations used
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`according to claims 22-30 of the '094 Patent as well.
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`Case IPR20 15-- - -
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`Attorney Docket No. REDDY 7.1R-012
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`Palonosetron Formulation Information
`2.
`25. The prior art also disclosed the use of IV solutions of palonosetron for
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`treatment of nausea and vomiting. For example, three press releases by Helsinn
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`disclosed the use of a single-dose intravenous formulation of palonosetron to treat
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`CINV in patients in clinical trials (Exhs. 1033-1035; Frame Decl. ~ 61.) Further, an
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`article published by Tang disclosed the use of an IV solution of palonosetron to
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`treat PONY in patients in a Phase 11 clinical study (Ex h. 10 19; Frame Decl.
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`~~ 48-55.) In particular, Tang disclosed that each dose of the medication used was
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`an isotonic sodium chloride solution of palonosetron administered intravenously.
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`(Exh. 1019, at 463.)
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`26. Berger disclosed a wide range of possible doses that could be used,
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`including a range of l.Ong/kg per day to l.Omg/kg per day based on body weight.
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`A preferred range specified is lOng/kg/day to 0.1/mg/kg/day. For a 70kg human,
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`the dose range would be between from 70ng/day to 70mg/day, preferably
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`700ng/day to 7.0mg/day. (See Exh. 1010 col. 12 11.11-18.) Converted to the units
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`claimed, this preferred range is 0.0007mg/day to 7.0mg/day. The patent notes,
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`however, that "[ o ]ne of ordinary skill in the art of treating such diseases will be
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`able, without undue experimentation and in reliance upon personal knowledge and
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`the disclosure of this application, to ascertain a therapeutically effective amount of
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`a compound of Formula I for a given disease." (!d. col.1211.19-24.) Pharmaceutical
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`compositions are also discussed, which can be given by, inter alia, oral and
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`parenteral routes. (See id. col.12 11.25-35.) These formulations could include
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`excipients, including sugars, water, and salt, to name but a few. (See Exh. 1010
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`col.12 11.42-54.)
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`27. Berger includes an example, Example 13, providing illustrative oral
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`and
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`intravenous formulations. The IV formulation
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`includes 10-100mg of
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`palonosetron, 1.05mg of citric acid monohydrate, 0.18mg sodium hydroxide,
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`dextrose monohydrate "q.s. to make isotonic" and water for injection to bring the
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`volume up to l.Oml. No dose is actually described; however, a concentration range
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`of 10-1 OOmg/ml is specified. Interestingly, while Example 13 describes the
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`compound as including citric acid and sodium hydroxide, and these form a buffer
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`system, Berger does not identify this use of citric acid as a buffer. The term
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`"buffer" is used in Berger, but never used in connection with citric acid or
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`Example 13. (See id. col.29 1.34 (Tris buffer), col.29 11.38-39 (homogenizing
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`buffer), col.29 1.41 (assay buffer), col.29 11.42-43 (Tris-Krebs assay buffer).)
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`Obviously, Berger knew of buffers and specified buffers when it intended to do so.
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`28. These known commercial formulations and the prior art as a whole
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`serve to assist a POSA in formulating a commercial product.
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`III. PATENT OWNER MERELY USED ROUTINE
`EXPERIMENTATION TO DEVELOP ITS FORMULATION
`29. Upon review of the '094 Patent, it is plain that the inventors followed
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`the traditional steps used by every POSA in the formulations field, and through
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`routine experimentation -
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`the normal experimentation carried out by every
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`formulation scientist on every product - developed a palonosetron formulation
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`optimized for stability. Indeed, the '094 Patent's unusually explicit description of
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`the routine nature of its own formulation work memorialized in Examples 1-3
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`proves that very point.
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`30. Moreover, the methods and excipients used by Patent Owner suggest
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`that it was not particularly difficult to extend the shelf life of formulations such as
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`those disclosed in Berger. (Exh. 1010.) This was exemplified in Example 2 of the
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`'094 Patent, which states
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`that
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`the
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`inventors performed "[a]
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`formulation
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`optimization study ... using [an] experimental design software." (Exh.1 001 col. 7
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`11.34-35.) Concentration ranges for palonosetron hydrochloride, citrate buffer, and
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`EDT A were tested. "The level of EDT A and citrate buffer were selected based on
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`the optimal formulation ... The results of this study indicated that palonosetron
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`concentration was also a critical factor in chemical stability . ... " (/d. col.7
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`11.39-46 (emphasis added).)
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`31. A POSA would not have expected this formulation and optimization
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`study to have been a challenge. Indeed, all that Patent Owner did to come up with
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`its formulation was adjust a few common variables. And since dose would have
`
`been selected based primarily on efficacy considerations, and volume on known
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`market conditions (i.e. , 1, 2, 3, 4, or 5ml), there were only a few adjustments
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`necessary.
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`32. Every intravenous solution drug product contains an appropriate unit
`
`amount of the active drug substance (also referred to as the "active pharmaceutical
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`ingredient" or "API''). In addition to the active drug substance, an intravenous
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`solution drug product contains a "carrier" or "vehicle," which typically is a sterile
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`aqueous carrier (i.e., sterile water as the solvent of the solution). (Exh. 1050,
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`at 174, 175, 190.) An intravenous drug product also often contains inactive
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`ingredients (excipients) for various purposes, e.g., to facilitate administration or to
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`maintain the quality of the drug product. (See, e.g., id. at 173-74.) Typical inactive
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`components
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`include: (1) pH buffers; (2) tonicifying agents; and (3) when
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`necessary, one or more stabilizing agents, such as antioxidants, chelating agents
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`and/or preservatives. The selection of the specific excipients and determining their
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`appropriate amounts is a primary task of formulation development.
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`A.
`33.
`
`Sterile Solution
`Sterility is manifest to IV solutions and is considered part of the
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`defmition of a parenteral: "A parenteral can be defmed as a sterile drug, solution,
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`or suspension that is packaged in a manner suitable for administration by
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`hypodermic injection, either in the form prepared or following the addition of a
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`suitable solvent or suspending agent." (Exh. 1050, at 173.) That the claims of the
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`'094 Patent require a sterile product is thus of no significance, as sterility is
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`required for all parenteral solutions.
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`Tonicifying Agent
`B.
`34. A tonicity or tonicifying agent is used to make the solution "isotonic"
`
`so as to minimize pain upon injection (!d. at 207-08.) Therefore, a POSA would
`
`certainly have used a tonicifying agent to make the solution of palonosetron to
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`make it isotonic. "Isotonic" means physiological such as having the same osmotic
`
`pressure as blood. Some of the most common tonicity agents include: sodium
`
`chloride (NaCl, table salt), dextrose (sugar) and mannitol (sugar). When the active
`
`ingredient is a chloride salt, sodium chloride may be a less desirable tonicifying
`
`agent because of the potential adverse "common ion" effect caused by the chloride
`
`present in both the active ingredient and the sodium chloride. This generally
`
`leaves the sugars. The label for dolasetron specifically disclosed the use of
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`16
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`Exh. 1040
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`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
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`mannitol as a tonicifying agent in its commercial IV solution. (Exh. 1017, at 680.)
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`So there was precedent for this selection.
`
`35.
`
`In Example 3 of the '094 Patent, tonicifying agents were tested;
`
`however, only two of the most well-known were considered: sodium chloride and
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`mannitol. (Exh. 1001.) "The palonosetron hydrochloride formulation including
`
`mannitol showed superior stability. The optimum level of mannitol required for an
`
`isotonic solution was found to be 4.15%." (!d. col.711.55-57.)
`
`36. Thus, the particular selection of mannitol as the tonicifying agent in
`
`the '094 Patent would not have been inventive, since it would have been based on
`
`nothing more than a standard screening study involving only the most commonly
`
`used tonicifying agents. Moreover, the recited range of "about 1 O.Omg/ml to about
`
`80mg/ml" in claim 30 of the '094 Patent would have been obvious based on the
`
`prior art, because a POSA would have used a tonkifying agent in an amount to
`
`make an aqueous solution of palonosetron isotonic. The appropriate amount would
`
`have been determined through nothing more than routine experimentation.
`
`C. Volume
`37. The selection of an appropriate volume for delivery of the drug is
`
`another consideration for a POSA. (See, e.g., Exh. 1050, at 174.) For parenteral
`
`solutions, this often involves minimizing volume. A POSA would seek to
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`17
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`Exh. 1040
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`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
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`formulate using a relatively small volume, whether the drug is to be administered
`
`as a small volume or diluted prior to injection, such as being added to an IV bag.
`
`Consistent with this general understanding, I am not surprised to hear that the
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`Patent Owner's expert confirmed at trial that up to a 5ml or so volume would be
`
`demanded by the market. (Exh. 1032.) Moreover, no one would make or sell a vial
`
`of 1.27ml or 3 .62ml of a product unless there was some specific reason to do so. It
`
`would be formulated in whole integers of 1 to 5mls. Thus, there were only a few
`
`actual choices for the volume to be utilized in the formulation. Claim 22 recites a
`
`volume of 5ml.
`
`D. Concentration
`38. The selection of an appropriate concentration for the active compound
`
`IS another formulation step to be considered by the POSA. Concentration is
`
`nothing more than the amount of the drug dissolved in the selected volume. In
`
`view of the volume selection discussed above (i.e. , 1 to 5ml), it follows that once
`
`the effective dose of the active ingredient (setron) is determined, the resulting
`
`concentration of the setron is largely determined as a matter of course. For
`
`example, if the effective dose is 0.07mg, and it is formulated in a total volume of
`
`l ml, the resulting concentration will be 0.07mg/ml. Similarly, if 5mls of solution
`
`were used for the same dose, the resulting concentration will be 0.0 14mg/ml. And
`
`18
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`Exh. 1040
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`Case IPR20 15-- - -
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`Attorney Docket No. REDDY 7.1R-012
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`again, as a practical matter, unless there was an unusual need to do otherwise, there
`
`would be only five possible volume values to select from (i.e., lml, 2ml, 3ml, 4ml,
`
`or 5ml).
`
`39. And within this field of generally limited choices, a POSA would
`
`have preferred a low concentration of palonosetron based on clinical and
`
`formulation considerations suggested in the prior art. In general, a lower
`
`concentration would be expected to be more stable, though there are exceptions.
`
`Here, as Dr. Frame discusses in his declaration, a POSA would have selected a
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`dose of palonosetron between about 0.07-0.7mg. (Exh. 1023 ~ 62.) Since the
`
`volume of each dose would be an integer between 1 and 5ml, such would dictate
`
`the relatively small range of possible concentrations of from between about
`
`0.014mg/ml (0.7mg/5ml) to 0.7mg/ml (0.7mg/lml). (Jd. ~ 36.) The claimed
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`concentration is 0.05mg/ml. In fact, the palonosetron dose would likely range from
`
`3f.Lg/kg [0.2lmg] to lOf.Lg/kg [0.70mg]. This dose range would result in a
`
`corresponding concentration range of from about 0.04mg/ml to about 0.70mg/ml.
`
`(!d. ~~ 62, 36.)
`
`40.
`
`Similar concentration ranges were suggested by the pnor art's
`
`formulations. Tang taught the use of low concentration palonosetron IV solutions,
`
`including solutions with concentrations close to the claimed 0.05mg/ml. As
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`19
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`Exh. 1040
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`Case IPR20 15-- - -
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`Attorney Docket No. REDDY 7.1R-012
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`discussed
`
`by Dr. Frame, Tang
`
`taught
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`concentration
`
`ranges
`
`from
`
`0.0005-0.14mg/ml. (Exh. 1023 ~55.) This range encompasses the claimed range.
`
`Plainly, the 0.05mg/ml range claimed in the '094 Patent is included within this
`
`range. Moreover, both of these ranges overlap with the range dictated by
`
`formulating with the successful dose in the demanded commercial volumes.
`
`E.
`pH Buffer
`41. A pH buffer will often be included to control and maintain an
`
`appropriate solution pH. (Exh. 1050, at 193-95.) The pH buffer is an important
`
`component of an intravenous solution drug product because solution pH plays a
`
`key role in the physiological acceptability, solubility and stability of a drug
`
`substance in solution. (See, e.g. , id. at 193-95.)
`
`42. One of the initial experiments that is carried out as part of the
`
`preformulation study is the generation of a pH-stability profile over a wide range
`
`of pH values (e.g. , between pH 2 to 12). (Exh. 1050, at 142.) Aqueous buffers are
`
`used to produce solutions at various pH values, and the solution stability is
`
`measured at different pHs, temperatures and other conditions. (!d. at 142-43.)
`
`Usually the pH range that yields maximum stability can readily be identified based
`
`on the results of these studies and the identified pH range would be recommended
`
`for formulation development. (!d. at 142.)
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`20
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`Exh. 1040
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`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-012
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`43. The generally acceptable pH range for a small volume intravenous
`
`solution is 3.0 to 10.5, while parenterals administered by other routes are generally
`
`adjusted to a pH between 4 and 9. (Exh. 1050, at 195.) Nonetheless, the pH of
`
`optimal stability is determined experimentally for each drug product. This is a step
`
`done in designing every parenteral formulation.
`
`44.
`
`pH buffers have corresponding pH ranges, and for a particular drug
`
`product, the pH buffer is chosen according to the target pH. (See, e.g., Exh. 1050,
`
`at 193-95.) For example, citrate buffer, which is among the most commonly used
`
`pH buffers, is typically used at concentrations of 1-5% to maintain the pH of a
`
`solution between 2.5 and 6. (!d. at 194.)
`
`45. Consistent with these general principles, the '094 Patent states in its
`
`background that the prior art IV formulations disclosed in Berger (Exh. 1 010
`
`Ex.13) had a pH of 3.7 and used a citrate buffer. That, of course, could have been
`
`determined by merely making and testing that formulation. It was therefore already
`
`known to formulate palonosetron in acidic conditions using a citrate buffer,
`
`suggesting to a POSA a pH range of between about 3.7 and 7.4. This would also
`
`suggest to a POSA the possibility of stability issues for palonosetron formulations.
`
`46. Moreover, the fact that the prior art commercial setrons were known
`
`to be formulated in mildly acidic conditions using these "most commonly
`
`21
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`Exh. 1040
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`Case IPR20 15-- - -
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`Attorney Docket No. REDDY 7.1R-012
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`encountered" buffers, namely, citrate
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