Case IPR2015-
`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
`
`
`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.
`
`During my career of over 50 years, my research and teaching interests
`
`in pharmaceutical science and technology have been in various areas, including
`
`parenteral and intravenous pharmaceutical formulations and drug product stability.
`
`I have published over 225 research articles and authored or co-authored chapters in
`
`several textbooks in the field, including a textbook on formulating small volume
`
`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
`
`Pharmaceutical Development and Technology between 1995 and 1999, the first
`
`Editor-in-Chief of the AAPS online journal PharmSciTech between 2000 and
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`2007, and also served on the editorial boards of several other scientific journals in
`
`the broad field of pharmaceutical sciences with special focus on pharmaceutical
`
`technology and drug product development.
`
`5.
`
`In addition to my research and teaching, I have consulted over the
`
`years for both brand and generic pharmaceutical companies on matters related to
`
`pharmaceutical formulation and development. Additional details of my education,
`
`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.,
`
`Dr. Reddy's Laboratories, Inc., identified to the Patent Trial and Appeal Board in
`
`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
`
`discussed in this declaration. I am being compensated for my time in an amount
`
`2
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`consistent with my customary consulting fee and my compensation IS not
`
`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
`
`ordinary skill in the relevant art at the time invention was made, which I have been
`
`told by counsel to assume is January 29, 2003. I also understand from counsel that
`
`factors relevant to the level of skill in the art include, without limitation: the
`
`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
`
`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
`
`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
`
`methods of treating CINV per se. That must be contrasted with claims 22-30 of the
`
`'094 Patent, which appear on their face to relate to methods of treating CINV,
`
`albeit by administering the types of formulation that are the focus of the
`
`above-identified litigations.
`
`3
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`10. Because of my involvement in the aforementioned litigations, I know
`
`that Petitioner has taken the position that a person of ordinary skill in the art (a
`
`"POSA") as to the patents at issue in those cases, would be a formulation scientist,
`
`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
`
`pharmaceutical science literature, general
`
`text books, research articles and
`
`abstracts, and other sources of information, including from clinicians and
`
`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
`
`4
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`studies as would be applied to treating patients. Whether these medical and
`
`claimed professionals would consult with formulators or the reverse, is of lesser
`
`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
`
`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
`
`formulating parenteral and injectable drugs, including the setrons.
`
`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
`
`5
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`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
`
`6
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`a 2mg/ml solution, and a 32mg/50ml "premixed" solution. (Exh. 1015, at 1503.)
`
`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
`
`methylparaben and 0.15mg propylparaben as preservatives. (/d.) Each 5ml
`
`"premixed" solution contained 32mg ondansetron as the hydrochloride dihydrate,
`
`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
`
`2001 PDR, which was sold under the trade name KYTRIL ®_ Granisetron is an
`
`injectable aqueous solution of its hydrochloride salt in a lmg/ml solution in
`
`single-dose and multi-dose vials. (Exh. 1016, at 3104-05.) Each lml of the
`
`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
`
`7
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`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
`
`commercially available under the trade name ANZEMET® as an injectable
`
`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
`
`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
`
`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.
`
`Each formulation is relatively simple and of low volume, and most contain buffers
`
`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.
`
`8
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`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
`
`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.
`
`9
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`Tonicity
`C.
`22. A POSA would certainly have used a tonicifying agent in an IV
`
`solution of palonosetron to make it isotonic. As the "guiding principles" note,
`
`"Wherever possible, parenteral products should be isotonic." (Exh. 1014, at 334.)
`
`"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
`
`(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
`
`isotonic solution was found to be 4.15%." (!d. col.? 11.55-57.)
`
`10
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`24. Thus, in my opmwn, 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 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
`
`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
`
`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
`
`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
`
`11
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`one would make and sell a vial of 1.27ml or 3.62ml of a product unless there was
`
`some specific reason to do so. It would be sold 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.
`
`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,
`
`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 1ml, the resulting concentration will be 0.07mg/ml. Similarly, if 5mls of
`
`solution were used for the same dose, the resulting concentration will be
`
`0.014mg/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
`
`12
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`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
`
`0.21mg to 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). The claimed concentration is 0.05mg/ml.
`
`28.
`
`In fact, as Dr. Frame also discussed, the palonosetran dose would
`
`likely range from 3J.Lg/kg [0.2lmg] to lOJ.Lg/kg [0.70mg]. (Exh. 1023 ~ 62.) This
`
`dose range would result in a corresponding concentration range of from about
`
`0.04mg/ml to about 0.70mg/ml. (!d. ~ 36.)
`
`29.
`
`Similar concentration ranges were suggested by the pnor art's
`
`formulations. Eglen taught the use of low concentration palonosetron IV solutions,
`
`including solutions with concentrations close to the claimed 0.05mg/ml. As
`
`discussed by Dr. Frame, Eglen taught concentration ranges from O.OOlmg/ml to
`
`O.lOmg/ml. This range encompasses the claimed range. (Exh. 1023 ~ 34.)
`
`Moreover, the range tested for dogs was broader and would result in a
`
`concentration range of0.003mg/ml to 3.0mg/ml. (Jd.) Plainly, the 0.05mg/ml range
`
`claimed in the ' 094 Patent is included within both of these ranges. Moreover, both
`
`13
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`of these ranges overlap with the range dictated by formulating with the successful
`
`dose in the demanded commercial volumes.
`!!!!
`F.
`30. Another "guiding principle" consideration by formulators is that
`
`parenteral solutions should be formulated with a pH close to physiological, "unless
`
`stability or solubility considerations preclude this." (Exh. 1014, at 333.) "Often, the
`
`pH selected for the product is a compromise between the pH of maximum stability,
`
`solubility and physiological acceptability . . . Many products are fonnulated at a
`
`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
`
`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.
`
`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
`
`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
`
`14
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`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.
`
`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
`
`15
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`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
`
`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
`
`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
`
`POSA would have readily discovered that such a slightly acidic pH would be the
`
`"optimal" pH for the formulation.
`
`35. Claim 26 of the '094 Patent recites that the formulation of claim 22
`
`must include a buffer, and that the buffer is a citrate buffer. As discussed above,
`
`Gibson indicated that citrate buffers are among the "most commonly encountered"
`
`in parenteral products. (Exh. 1014, at 333.) Moreover, citrate buffers had already
`
`16
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`been utilized in connection with other setrons, including ondansetron. (Exh. 1015,
`
`at 1503). Indeed, the use of citrate buffers in palonosetron formulations were
`
`admittedly known. (Exh. 1001 col.1 1.64 to col.2 1.8.) The recited pH and buffer
`
`certainly do not reflect anything inventive about the claimed formulations.
`
`36.
`
`I should also note that citric acid/citrate is a well-known chelating
`
`agent. Kibbe, The Handbook of Pharmaceutical Excipients, identifies citric acid as
`
`a chelating agent. (Exh. 1036, at 140.) I understand during the trial involving
`
`patents related to the '094 Patent, one of Patent Owner's experts discussed a book
`
`which he authored. He confirmed in testimony that citric acid and EDT A, as
`
`explained in his book, are the most useful chelating agents. (Exh. 1046,
`
`at I 06:2-107: 18.)
`
`37.
`
`I also understand that in one of the litigations between the parties
`
`involving one of the '094 Patent's direct ancestors, U.S. Patent No. 7,947,724 ("the
`
`'724 Patent") (Exh. I 002), a Markman hearing was held and The Honorable Judge
`
`Cooper, U.S.D.J., issued an order on February 19, 2015, construing the term
`
`"chelating agent" to mean "a multidentate ligand that can form a ring structure by
`
`reacting with a metal ion." (Exh. 1045.) Citric acid undeniably is "a multidentate
`
`ligand that can form a ring structure by reacting with a metal ion."
`
`17
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`38. Thus, whether or not, for example, the citric acid disclosed in Berger
`
`and in the 2001 PDR for ondansetron being a buffer, it was known to be, among
`
`other things, a chelating agent, too. Had there been any metals present in the
`
`solutions, some of the citric acid in solution would have chelated that metal.
`
`Ill. MERE OPTIMIZATION OF THE FORMULATION
`39. The ' 094 Patent admits that its selection of concentration, pH,
`
`tonicity, and the like, and the excipients used to achieve those characteristics, are
`
`mere optimizations. But they were not optimized to improve the claimed method of
`
`treatment (e.g., for efficacy or bioavailability); rather, the formulations were
`
`optimized merely to increase the shelf-life of the palonosetron IV solutions. And
`
`the single unit dose, low volume and sterility recitations were not even
`
`optimizations or improvements over the known commercial setrons -
`
`they were
`
`merely obvious characteristics shared by all of the commercial setrons.
`
`40. Moreover, it is plain that the inventors merely followed the "guiding
`
`principles" understood by every POSA in the formulations field, and through
`
`routine experimentation, developed a palonosetron formulation optimized for
`
`stability. Indeed, the ' 094 Patent's unusually explicit description of the routine
`
`nature of its own formulation work, memorialized in Examples 1-3, proves that
`
`point.
`
`18
`
`Exh. 1040
`
`
`
`Case TPR2015-__ _
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`41 . Further, the methods and excipients used by the inventors suggest that
`
`it was not particularly difficult to extend the shelf-life of formulations such as
`
`those disclosed in Berger (Exh. 1010.) This was exemplified in Example 2 of the
`
`'094 Patent, which states
`
`that
`
`the
`
`inventors performed "[a]
`
`formulation
`
`optimization study ... using an experimental design software." (Exh.1 001 col. 7
`
`11.34-35.) Concentration ranges for palonosetron hydrochloride, citrate buffer, and
`
`EDTA were tested. "The level of EDTA and citrate buffer were selected based on
`
`the optimal formulation . .. The results of this study indicated that palonosetron
`
`concentration was also a critical factor in chemical stability ... . " (!d. col.7
`
`11.3 9-46 (emphasis added).)
`
`42. Clearly and by admission, the ' 094 Patent selected concentration, pH
`
`and tonicity, as well as the agents used to accomplish them, based only upon a
`
`desire to optimize the stability of the formulation. Optimization of the method of
`
`treatment was neither considered nor disclosed.
`
`43. The Patent Owner also chose its excipients from the most widely
`
`known buffers and tonicity agents (Exh. 1014, at 333-34), buffers and tonicity
`
`agents that are among the very limited palate of agents used in the FDA-approved,
`
`commercial setron products that were known in the prior art (Exhs. 1015, at 1503;
`
`1016, at3105; 1017, at680.) The recitations of single-use unit dose, low volume,
`
`19
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`and sterility are just as obvious from the same sources. (/d.) Thus, it appears that
`
`the Patent Owner considered only the bare minimum number of formulation issues
`
`common to every parenteral product, utilizing the most common methods and
`
`excipients known for exactly that purpose.
`
`44.
`
`Significantly, the Patent Owner did none of its optimizations to
`
`improve the efficacy or reduce side effects of its palonosetron formulation.
`
`Instead, it merely adjusted the formulations to increase the shelf life of the product
`
`by a year or so. Increasing the shelf life of the product up to another year required
`
`the Patent Owner to simply follow the guiding principles of Gibson, and through
`
`routine experimentation, determine the appropriate modifications that would
`
`improve the stability of its formulations. Such modifications included lowering the
`
`concentration of the palonosetron, optimizing the pH, and/or including other
`
`excipients, such as EDT A. Such efforts were plainly not inventive but would have
`
`been obvious to a POSA.
`
`20
`
`Exh. 1040
`
`
`
`Case IPR20 15-- - -
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-010
`
`I hereby declare under penalty of perjury under the laws ofthe 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 fme or imprisonment, or both (18 U.S.C. § 1001).
`
`Executed on:
`
`July 1, 2015
`
`41 14206 _ l.docx
`
`Patrick P. DeLuca
`
`21
`
`Exh. 1040
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
