`Patent No. 8,729,094
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`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.
`
`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
`
`
`
`I, PATRICK P. DELUCA, hereby declare as follows:
`
`1.
`
`2.
`
`I am a U.S. citizen and a resident of the state of Kentucky.
`
`I am a Professor Emeritus in the Department of Pharmaceutical
`
`Sciences, College of Pharmacy, University of Kentucky. I received a B.S. and M.S.
`
`in Pharmacy from Temple University in 1957 and 1960, respectively. I received
`
`my Ph.D. in Pharmaceutical Sciences from Temple University in 1963.
`
`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. 1042.)
`
`4.
`
`I have received numerous awards and honors for my research and
`
`teaching achievements. I am a founding member and Fellow of the American
`
`Association of Pharmaceutical Scientists ("AAPS") and served as its President
`
`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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`Editor-in-Chief of the AAPS online journal PharmSciTech between 2000 and
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`Exh. 1040
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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
`
`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.)
`
`6.
`
`I was retained by Dr. Reddy's Laboratories, Ltd. and Dr. Reddy's
`
`Laboratories, Inc. to serve as an expert in the litigations between Helsinn
`
`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. I did
`
`not, however, give testimony in any of those litigations.
`
`7.
`
`I have separately been retained by Lerner, David, Littenberg,
`
`Krumholz & Mentlik, LLP ("counsel") to provide my opinions in the fields of
`
`pharmaceutical formulation and stability. I have read and understood U.S. Patent
`
`No. 8,729,094 ("the '094 Patent") (Exh. 1001) as well as all other references
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`discussed in this declaration. I am being compensated for my time in an amount
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`consistent with my customary consulting fee and my compensation IS not
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`contingent on my opinion or the outcome of this proceeding.
`
`I.
`
`A PERSON OF ORDINARY SKILL IN THE ART
`8.
`I understand from counsel that patents such as the '094 Patent are
`
`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
`
`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
`
`workers in the field.
`
`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
`
`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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`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
`
`of years' experience in developing IV formulations and bench experience. I also
`
`understand that Petitioner argued that formulation scientists would draw on the
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`pharmaceutical science literature, general
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`text books, research articles and
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`abstracts, and other sources of information, including from clinicians and
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`pharmacologists, and other scientists in the field.
`
`11.
`
`I would certainly agree that this definition is still broadly applicable
`
`here; and as regards the aspects of the claimed invention that relate to drug
`
`formulation, I consider myself to be a person of greater than ordinary skill.
`
`However, the claimed invention in the '094 Patent is, in my view, primarily
`
`directed to a method of medical treatment; and as such, I believe medical doctors
`
`and other medical professionals having experience specifically treating cancer and
`
`addressing the side effects of the use of highly emetogenic chemotherapies would
`
`be of at least equal import. Such doctors or clinicians would have a high level of
`
`formal education and several years of practical experience. In particular, they
`
`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
`
`implicated by the '094 Patent. I understand from counsel that a POSA may be a
`
`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
`
`the ' 094 Patent, in my opinion, a POSA would most appropriately be a composite
`
`of the types of individuals I have just noted.
`
`II.
`
`FORMULATION DEVELOPMENT
`12. By January 29, 2003, the general procedures for preparing parenteral
`
`formulations were well known, well understood, and well documented in general
`
`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. A representative text is entitled, "Pharmaceutical Preformulation and
`
`Formulation: A Practical Guide from Candidate Drug Selection to Commercial
`
`Dosage Form." (Exh. 1014, at 332 ("Gibson").) Gibson sets forth a number of
`
`"guiding principles," which, in my opinion, would be well known to every POSA
`
`in the formulations art. Many of these principles are so common that they would be
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`known to others outside the formulation world -
`
`including medical doctors,
`
`doctors of pharmacy and clinicians.
`
`14. One of the most important "guiding principles" to bear in mind when
`
`developing a formulation is the age-old adage "keep it simple." As Gibson states,
`
`"Wherever possible, formulations should be developed using excipients which
`
`have an established use in parenteral products administered by the same route as
`
`the product under development." (Exh. 1014, at 334.) "Both the excipient
`
`concentration, rate [sic] of administration and total daily dose should fall within the
`
`boundaries established by precedent in existing marketed products." (!d.
`
`at 334-35.)
`
`Formulation Work Based On Commercial Products
`A.
`15. One thing a POSA would always do when starting a formulation
`
`project would be to see what has worked in the past. Not surprisingly, the "guiding
`
`principles" include looking to formulation work already successfully done via
`
`commercial products. One "essential" source for such information suggested in
`
`Gibson is the Physicians' Desk Reference ("PDR"). (Exh. 1014, at 335.)
`
`16.
`
`I have reviewed the 2001 PDR, and it contains entries for three
`
`setrons. Ondansetron was a commercially available setron sold under the trade
`
`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
`
`hydrochloride dihydrate, 9.0mg sodium chloride (NaCl), 0.5mg citric acid
`
`monohydrate and 0.25mg sodium citrate dihydrate, buffered at pH 3.3 to 4.0. (!d.)
`
`Each 1ml solution in a 20ml multi-dose vial contained 2mg ondansetron as the
`
`hydrochloride dihydrate, 8.3mg sodium chloride, 0.5mg citric acid monohydrate
`
`and 0.25mg sodium citrate dihydrate, buffered at pH 3.3 to 4.0, and 1.2mg
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`methylparaben and 0.15mg propylparaben as preservatives. (/d.) Each 5ml
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`"premixed" solution contained 32mg ondansetron as the hydrochloride dihydrate,
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`2500mg dextrose, 26mg citric acid and 11.5mg of sodium citrate, buffered at
`
`pH 3.0 to 4.0. (!d.)
`
`17. 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 lmg/ml solution in
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`single-dose and multi-dose vials. (Exh. 1016, at 3104-05.) Each lml of the
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`single-dose solution contained 1.12mg granisetron hydrochloride and 9.0mg
`
`sodium chloride in an aqueous solution of pH 4.7 to7.3. (!d. at 3105.) Each 1ml of
`
`the multi-dose solution contained 1.12mg granisetron hydrochloride, 9mg sodium
`
`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
`
`via IV within 20 minutes before chemotherapy was initiated. (Exh. 1016, at 3106.)
`
`The dose was administered either undiluted over 30 seconds, or diluted and infused
`
`over five minutes. (!d.)
`
`18. 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 lml of the solution
`
`contained 20mg dolasetron mesylate and 38.2mg mannitol with an acetate buffer
`
`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.
`
`at 683.) For most patients, however, an alternative fixed dose of IOOmg could be
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`administered over 30 seconds. (!d.)
`
`19. Considering these known commercial formulations as a whole serves
`
`to underscore the "general principles" articulated by Gibson and discussed earlier.
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`Each formulation is relatively simple and of low volume, and most contain buffers
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`and tonicity agents, including those Gibson identified as the most common. They
`
`are all sterile, suitable for single unit doses, and the pH for all of them can be
`
`mildly acidic. Not surprisingly, all of this is true of the formulations used
`
`according to claims 22-30 of the '094 Patent as well.
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`20. Upon review of the '094 Patent, it is plain that the inventors followed
`
`these "guiding principles," and through routine experimentation
`
`the normal
`
`experimentation carried out by every
`
`formulation
`
`scientist on every
`
`product - developed a palonosetron formulation optimized for stability. The
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`methods and excipients used by Patent Owner suggest that it was not particularly
`
`difficult to extend the shelf-life of the formulation in Berger (Exh. 1010 Ex.13), an
`
`acknowledged prior art reference to the '094 Patent, from about a year to about24
`
`months. Indeed, a POSA would not have expected this to have even been a
`
`challenge; and as is clear from the '094 Patent, all that Patent Owner did to come
`
`up with its formulation was adjust a few common variables. And since dose would
`
`have been selected based primarily on efficacy considerations, and volume on
`
`known market conditions (i.e., 1, 2, 3, 4, or 5ml), there were only a few
`
`adjustments necessary.
`
`Sterility
`B.
`21. Among the "guiding principles" for simple parenteral solutions is
`
`sterility; and the requirement for sterility in parenteral products is "absolute."
`
`(Exh. 1014, at 336.) That the claims of the '094 Patent require a sterile product is
`
`thus of no significance, as sterility is required for all parenteral solutions.
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`Tonicity
`C.
`22. A POSA would certainly have used a tonicifying agent in an IV
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`solution of palonosetron to make it isotonic. As the "guiding principles" note,
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`"Wherever possible, parenteral products should be isotonic." (Exh. 1014, at 334.)
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`"Isotonic" means physiological, such as having the same osmotic pressure as
`
`blood. Some of the most common tonicity agents include mannitol and dextrose,
`
`along with sodium chloride. (Jd.) Gibson indicates, however, that mannitol or
`
`dextrose "may be preferable if the addition of sodium chloride is likely to have an
`
`adverse effect on the formulation." (!d.) This can occur when the drug is in the
`
`form of a hydrochloride salt due to a "common ion" effect. Palonosetron
`
`hydrochloride is used commercially. Moreover, the label for dolasetron specifically
`
`disclosed the use of mannitol as a tonicifying agent in its commercial IV solution.
`
`(Exh. 1017, at 680.)
`
`23.
`
`In Example 3 of the '094 Patent, tonicifying agents were tested
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`(Exh. 1001.) However, only two of the most well-known were considered: sodium
`
`chloride and mannitol. "The palonosetron hydrochloride formulation including
`
`mannitol showed superior stability. The optimum level of mannitol required for an
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`isotonic solution was found to be 4.15%." (!d. col.? 11.55-57.)
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`24. Thus, in my opmwn, the particular selection of mannitol as the
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`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 of some of 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 tonicifying
`
`agent in an amount to make an aqueous solution of palonosetron isotonic. The
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`appropriate amount would have been determined through nothing more than
`
`routine experimentation.
`
`D. Volume
`25. Another "guiding principle" is to select an administration volume and
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`concentration. (Exh. 1014, at 332.) For parenteral solutions, this often involves
`
`minimizing volume. (!d.) A POSA would seek to 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. (!d.) Gibson indicates that bolus
`
`injection, intramuscularly or via the subcutaneous route, is generally limited to
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`volumes up to about 4ml. (!d.) Consistent with this teaching, I am not surprised to
`
`hear that the Patent Owner's expert confmned at trial that up to a 5ml or so volume
`
`would be demanded by the market. (Exh. 1032, at 108:21-109:20). Moreover, no
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`one would make and sell a vial of 1.27ml or 3.62ml of a product unless there was
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`some specific reason to do so. It would be sold in whole integers of 1 to 5mls.
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`Thus, there were only a few actual choices for the volume to be utilized in the
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`formulation. Claim 22 recites a volume of 5ml.
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`Concentration
`E.
`26. The "guiding principles" indicated that the selection of an appropriate
`
`concentration for the active compound is another formulation step to be
`
`considered. In view of the volume selection discussed above (i.e., 1 to 5tnl), it
`
`follows that once the effective dose of the active ingredient (setron) is determined,
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`the resulting concentration of the setron is largely determined as a matter of course.
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`For example, if the effective dose is 0.07mg, and it is formulated in a total volume
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`of 1ml, the resulting concentration will be 0.07mg/ml. Similarly, if 5mls of
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`solution were used for the same dose, the resulting concentration will be
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`0.014mg/ml. And 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. ,
`
`1 ml, 2ml, 3ml, 4ml, or 5ml).
`
`27. To make a suitable and stable IV solution of palonosetron, a POSA
`
`would have preferred a low concentration of palonosetron based on clinical and
`
`formulation considerations suggested in the prior art. Specifically, from a clinical
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`perspective, as Dr. Frame discusses in his declaration, a POSA would have
`
`selected a dose of palonosetron between about 0.07mg to 0.7mg, and more likely
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`0.21mg to 0.7mg. (Exh. 1023 ~ 62.) Since the volume of each dose would be an
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`integer between 1 and 5ml, such would dictate the relatively small range of
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`possible concentrations of from between about 0.014mg/ml (0.7mg/5ml) to
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`0.7mg/ml (0.7mg/lml). The claimed concentration is 0.05mg/ml.
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`28.
`
`In fact, as Dr. Frame also discussed, the palonosetran dose would
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`likely range from 3J.Lg/kg [0.2lmg] to lOJ.Lg/kg [0.70mg]. (Exh. 1023 ~ 62.) This
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`dose range would result in a corresponding concentration range of from about
`
`0.04mg/ml to about 0.70mg/ml. (!d. ~ 36.)
`
`29.
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`Similar concentration ranges were suggested by the pnor art's
`
`formulations. Eglen taught the use of low concentration palonosetron IV solutions,
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`including solutions with concentrations close to the claimed 0.05mg/ml. As
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`discussed by Dr. Frame, Eglen taught concentration ranges from O.OOlmg/ml to
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`O.lOmg/ml. This range encompasses the claimed range. (Exh. 1023 ~ 34.)
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`Moreover, the range tested for dogs was broader and would result in a
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`concentration range of0.003mg/ml to 3.0mg/ml. (Jd.) Plainly, the 0.05mg/ml range
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`claimed in the ' 094 Patent is included within both of these ranges. Moreover, both
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`of these ranges overlap with the range dictated by formulating with the successful
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`dose in the demanded commercial volumes.
`!!!!
`F.
`30. Another "guiding principle" consideration by formulators is that
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`parenteral solutions should be formulated with a pH close to physiological, "unless
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`stability or solubility considerations preclude this." (Exh. 1014, at 333.) "Often, the
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`pH selected for the product is a compromise between the pH of maximum stability,
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`solubility and physiological acceptability . . . Many products are fonnulated at a
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`slightly acidic pH because of solubility or stability considerations, and the vast
`
`majority of licensed products have a pH between 3 and 9." (!d.) Moreover, Gibson
`
`notes that "a reasonably wide pH range can be tolerated, particularly when dosing
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`is via the IV route, and dilution with blood is rapid." (Id.) Because pH is an issue
`
`in every formulation, it would have been investigated by a POSA.
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`31. To maintain the desired pH of the formulation, a buffer is typically
`
`used. A pH buffer is an important component of an IV solution, which is included
`
`to control and maintain an appropriate solution pH. Gibson indicates that "the most
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`commonly encountered" buffers in parenteral products are phosphate, citrate or
`
`acetate.
`
`(Exh. 1014, at 333.) "Phosphate
`
`is useful
`
`for buffering around
`
`physiological pH [about pH 7] whereas acetate and citrate are used when the
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`required pH is lower." (!d.) For example, citrate buffers are utilized when one
`
`wishes to maintain a pH between 2.1 to 6.2 (!d. at 334.)
`
`32. Consistent with these general principles, the '094 Patent states in its
`
`background that the prior art IV formulations disclosed in Berger (Exh. 1010
`
`Ex.l3) 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.
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`33. Moreover, the fact that the prior art commercial setrons were known
`
`to be formulated in mildly acidic conditions using these "most commonly
`
`encountered" buffers, namely, citrates and acetates, further amplified
`
`the
`
`suggestion of stability issues. (See Exh. 1015, at 1503; Exh. 1016, at 3105;
`
`Exh. 1017, at 680.) Notably, the use of these buffers in the prior commercial
`
`setrons would further suggest stability was a wider issue among this class of
`
`compounds. This would plainly provide a reason to formulate palonosetron at a pH
`
`that was above pH 3.7 and below physiological pH (7.4). It would also motivate a
`
`POSA to look for possible stability issues and/or to employ other stability
`
`promoting measures prophylactically. One of these measures would involve the
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`use of chelating agents. Citric acid, while known as a buffer, is also a well-known
`
`chelating agent. (Exh. 1036, at 140; Exh. 1046, at 106:2-107:18.)
`
`34. Consistent with the "guiding principles," the '094 Patent specification
`
`indicates in Example I that a study was conducted to determine the effect of pH on
`
`formulations containing palonosetron hydrochloride. The stability of palonosetron
`
`hydrochloride was measured at 80°C, utilizing only four different pH values,
`
`namely, pH 2.0, 5.0, 7.4, and 10.0. (Exh. 1001 col.? 11.18-27.) According to the
`
`patent, palonosetron hydrochloride was "most stable at pH 5.0." (!d.) An
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`exhaustive study was apparently not necessary. Thus, it appears that the selected
`
`pH of 5.0±0.5 was merely the best of the four pHs tested at 80°C. There was
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`nothing new or nonobvious about this choice. Plainly, the "guiding principles"
`
`(i.e., standard practices) were merely followed to conduct a pH screening study on
`
`palonosetron as part of a routine preformulation study. From such a study, the
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`POSA would have readily discovered that such a slightly acidic pH would be the
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`"optimal" pH for the formulation.
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`35. Claim 26 of the '094 Patent recites that the formulation of claim 22
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`must include a buffer, and that the buffer is a citrate buffer. As discussed above,
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`Gibson indicated that citrate buffers are among the "most commonly encountered"
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`in parenteral products. (Exh. 1014, at 333.) Moreover, citrate buffers had already
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`been utilized in connection with other setrons, including ondansetron. (Exh. 1015,
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`at 1503). Indeed, the use of citrate buffers in palonosetron formulations were
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`admittedly known. (Exh. 1001 col.1 1.64 to col.2 1.8.) The recited pH and buffer
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`certainly do not reflect anything inventive about the claimed formulations.
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`36.
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`I should also note that citric acid/citrate is a well-known chelating
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`agent. Kibbe, The Handbook of Pharmaceutical Excipients, identifies citric acid as
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`a chelating agent. (Exh. 1036, at 140.) I understand during the trial involving
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`patents related to the '094 Patent, one of Patent Owner's experts discussed a book
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`which he authored. He confirmed in testimony that citric acid and EDT A, as
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`explained in his book, are the most useful chelating agents. (Exh. 1046,
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`at I 06:2-107: 18.)
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`37.
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`I also understand that in one of the litigations between the parties
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`involving one of the '094 Patent's direct ancestors, U.S. Patent No. 7,947,724 ("the
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`'724 Patent") (Exh. I 002), a Markman hearing was held and The Honorable Judge
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`Cooper, U.S.D.J., issued an order on February 19, 2015, construing the term
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`"chelating agent" to mean "a multidentate ligand that can form a ring structure by
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`reacting with a metal ion." (Exh. 1045.) Citric acid undeniably is "a multidentate
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`ligand that can form a ring structure by reacting with a metal ion."
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`38. Thus, whether or not, for example, the citric acid disclosed in Berger
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`and in the 2001 PDR for ondansetron being a buffer, it was known to be, among
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`other things, a chelating agent, too. Had there been any metals present in the
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`solutions, some of the citric acid in solution would have chelated that metal.
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`Ill. MERE OPTIMIZATION OF THE FORMULATION
`39. The ' 094 Patent admits that its selection of concentration, pH,
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`tonicity, and the like, and the excipients used to achieve those characteristics, are
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`mere optimizations. But they were not optimized to improve the claimed method of
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`treatment (e.g., for efficacy or bioavailability); rather, the formulations were
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`optimized merely to increase the shelf-life of the palonosetron IV solutions. And
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`the single unit dose, low volume and sterility recitations were not even
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`optimizations or improvements over the known commercial setrons -
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`they were
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`merely obvious characteristics shared by all of the commercial setrons.
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`40. Moreover, it is plain that the inventors merely followed the "guiding
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`principles" understood by every POSA in the formulations field, and through
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`routine experimentation, developed a palonosetron formulation optimized for
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`stability. Indeed, the ' 094 Patent's unusually explicit description of the routine
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`nature of its own formulation work, memorialized in Examples 1-3, proves that
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`point.
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`41 . Further, the methods and excipients used by the inventors suggest that
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`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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`EDTA were tested. "The level of EDTA 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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`11.3 9-46 (emphasis added).)
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`42. Clearly and by admission, the ' 094 Patent selected concentration, pH
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`and tonicity, as well as the agents used to accomplish them, based only upon a
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`desire to optimize the stability of the formulation. Optimization of the method of
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`treatment was neither considered nor disclosed.
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`43. The Patent Owner also chose its excipients from the most widely
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`known buffers and tonicity agents (Exh. 1014, at 333-34), buffers and tonicity
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`agents that are among the very limited palate of agents used in the FDA-approved,
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`commercial setron products that were known in the prior art (Exhs. 1015, at 1503;
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`1016, at3105; 1017, at680.) The recitations of single-use unit dose, low volume,
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`and sterility are just as obvious from the same sources. (/d.) Thus, it appears that
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`the Patent Owner considered only the bare minimum number of formulation issues
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`common to every parenteral product, utilizing the most common methods and
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`excipients known for exactly that purpose.
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`44.
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`Significantly, the Patent Owner did none of its optimizations to
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`improve the efficacy or reduce side effects of its palonosetron formulation.
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`Instead, it merely adjusted the formulations to increase the shelf life of the product
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`by a year or so. Increasing the shelf life of the product up to another year required
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`the Patent Owner to simply follow the guiding principles of Gibson, and through
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`routine experimentation, determine the appropriate modifications that would
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`improve the stability of its formulations. Such modifications included lowering the
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`concentration of the palonosetron, optimizing the pH, and/or including other
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`excipients, such as EDT A. Such efforts were plainly not inventive but would have
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`been obvious to a POSA.
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`I hereby declare under penalty of perjury under the laws ofthe United States
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`of America that the foregoing is true and correct, and that all statements made of
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`my own knowledge are true and that all statements made on information and belief
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`are believed to be true. I understand that willful false statements and the like are
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`punishable by fme or imprisonment, or both (18 U.S.C. § 1001).
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`Executed on:
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`July 1, 2015
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`41 14206 _ l.docx
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`Patrick P. DeLuca
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`21
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`Exh. 1040