throbber
Post Grant Review No.
`Patent No. 9,173,942
`Petition for Post Grant Review
`Attorney Docket No. REDDY 7.2R-021
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________
`
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORIES, INC.
`Petitioners
`
`v.
`
`HELSINN HEALTHCARE S.A. and ROCHE PALO ALTO LLC
`Patent Owners
`
`U.S. Patent No. 9,173,942 to Giorgio Calderari et al.
`Issue Date: November 3, 2015
`Title: LIQUID PHARMACEUTICAL FORMULATIONS OF PALONOSETRON
`____________________________
`
`Post Grant Review No. xxxxx
`__________________________________________________________________
`
`EXHIBIT 1012
`DECLARATION OF DR. JOANNE BROADHEAD IN
`SUPPORT OF PETITION FOR POST GRANT REVIEW
`OF CLAIMS 1-6, 10, AND 11 OF U.S. PATENT NO. 9,173,942
`UNDER 35 U.S.C. §§ 321-329 AND 37 C.F.R. § 42.200 ET SEQ.
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`4389856_1.docx
`
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1012
`
`Exh. 1012
`
`

`
`
`
`I, DR. JOANNE BROADHEAD, declare and state as follows:
`
`1.
`
`I am a citizen of the United Kingdom and reside at 7 Willowcroft,
`
`Quorn, Leicestershire, LE12 8HQ, England.
`
`2.
`
`I have been retained by Dr. Reddy’s Laboratories, Ltd. and
`
`Dr. Reddy’s Laboratories, Inc. (collectively “DRL,” Petitioner,” or “Requestor”) to
`
`consider issues relating to the validity of claims 1-6, 10, and 11 of U.S. Patent
`
`No. 9,173,942 (“the ‘942 Patent”). I have also been retained by DRL to provide my
`
`expert opinions in connection with two of this patent’s predecessors, U.S. Patent
`
`Nos. 9,066,980 and 8,729,094, which are the subject of litigation in the U.S.
`
`District Court for the District of New Jersey (Civil Action No. 12-2867). I
`
`provided an expert report in connection with that matter. I understand that Helsinn
`
`Healthcare S.A. and Roche Palo Alto LLC (collectively “Helsinn”) are the Patent
`
`Owners.
`
`3.
`
`I am being compensated at the rate of $325.00/hr for time spent
`
`working on this matter, which includes my time for preparing this declaration. My
`
`compensation is not dependent on the outcome of this case.
`
`4.
`
`Since 2011, I have been a Pharmaceutical Consultant, specializing in
`
`all aspects of parenteral product development and manufacture. During this time I
`
`have worked with a diverse range of companies including both small SMEs and
`
`large multinationals. My projects have included advising on the formulation and
`
`4389856_1.docx
`
`Exh. 1012
`
`

`
`
`
`development of novel parenteral dosage forms, supporting clients with technology
`
`transfer and process validation, advising on the operation of aseptic facilities,
`
`assisting companies with selection of CROs, and providing training in parenteral
`
`product development and manufacturing, including formulation. Throughout this
`
`time, I have also worked with De Montfort University and have lectured on both
`
`undergraduate and Master’s Pharmaceutical Science courses. I am also part of the
`
`DMU Quality by Design team and work closely with industrial collaborators to
`
`help develop the University’s distance learning program in QbD. I am an active
`
`member of the Academy of Pharmaceutical Sciences, which is a professional
`
`organization for Pharmaceutical Scientists in the UK. For the last two years I have
`
`been co-chair of the APS Parenterals Focus group, which aims to support and
`
`disseminate scientific advances
`
`in parenteral product development. My
`
`employment history, education, professional activities, patents, and other
`
`miscellaneous publications are set forth in my curriculum vitae, attached as
`
`Exhibit 1013. Exhibit 1013 also includes a listing of publications including books
`
`and patents.
`
`5.
`
`I have a Bachelor of Pharmacy degree (University of Bath, UK) and
`
`have been a registered UK Pharmacist since 1989 (registered with the General
`
`Pharmaceutical Council, GPhC). I have a PhD in Pharmaceutical Sciences
`
`(University of Rhode Island, USA, 1993).
`
`4389856_1.docx
`
`2
`
`Exh. 1012
`
`

`
`
`
`6.
`
`I began my career at Creative BioMolecules, Hopkinton, MA, USA
`
`where I was responsible for the development of parenteral formulations of the
`
`company’s osteogenic protein. This included the development of both aqueous and
`
`semi-solid formulations. In 1996, I returned to the UK and worked for Astra
`
`Pharmaceuticals, later AstraZeneca. In this role I was a Senior Scientist in Product
`
`Development and my role included formulation and other aspects of parenteral
`
`product development. Subsequently I became a Team Manager responsible for a
`
`team of product development scientists, working mainly on parenteral but also
`
`some oral liquid and solid dosage forms. My roles in parenteral product
`
`development included both aqueous liquid and lyophilized dosage forms. I also led
`
`an initiative to expand the company’s research interests in the science of parenteral
`
`product formulation and following the merger with Zeneca, I was involved in
`
`cross-site initiatives to harmonize development processes for parenteral products.
`
`7.
`
`I later worked for a year at the company’s Macclesfield site, also
`
`managing a parenterals development team. From 2005 to 2006, I worked as a
`
`Senior Lecturer at De Montfort University, Leicester, UK, teaching aspects of
`
`pharmaceutical science
`
`to both Pharmacy and Pharmaceutical Science
`
`undergraduates. In 2006, I returned to AstraZeneca where I managed the pilot
`
`manufacturing facility for liquid (sterile and nonsterile) drug products. In this role,
`
`I was primarily responsible for the manufacture of clinical trials supplies but also
`
`4389856_1.docx
`
`3
`
`Exh. 1012
`
`

`
`
`
`worked very closely with the product development teams. In 2011, the
`
`Loughborough AZ site was closed.
`
`I.
`
`PERSON OF ORDINARY SKILL IN THE ART
`I understand that patents are read in light of the knowledge of a person
`8.
`
`of ordinary skill in the art (“POSA”) as of the earliest effective filing date of the
`
`patent. I have been told by counsel to assume that the earliest effective filing date
`
`is January 30, 2003, for purposes of this proceeding. All of the prior art relied on in
`
`my declaration was published more than a year before the earliest effective filing
`
`date.
`
`9.
`
`It has been explained to me that a POSA is a hypothetical person who
`
`is deemed to be aware of all of the relevant prior art. A POSA is also a person of
`
`ordinary creativity, not an automaton.
`
`10.
`
`I am further told by counsel that factors relevant to determining the
`
`level of skill in the art include: the educational level of the inventors, the types of
`
`problems encountered in the art, prior art solutions to those problems, the rapidity
`
`with which innovations are made, the sophistication of the technology, and the
`
`educational level of active workers in the field. I understand from counsel that a
`
`POSA may be a composite of different types of individuals.
`
`11.
`
`I understand from counsel that there was a dispute between the Patent
`
`Owner and Petitioner in connection with other of the ‘942 Patent’s family
`
`4389856_1.docx
`
`4
`
`Exh. 1012
`
`

`
`
`
`members in the U.S. District Court for the District of New Jersey. In that dispute,
`
`the Patent Owner took the position that a POSA was: “[s]omeone who is actively
`
`involved
`
`in the development of pharmaceutical products which
`
`involves
`
`collaborative teamwork among persons with relevant experience. This person
`
`would have a degree in chemistry, pharmaceutical chemistry, pharmacy, medicine,
`
`clinical pharmacology, or another pharmaceutical science-related field and
`
`experience in designing, developing, evaluating, and/or testing pharmaceutical
`
`formulations with a B.S. or masters degree in, and two to three years experience, or
`
`a Ph.D. or M.D. degree and one to two years of experience.” (Exh.1028,
`
`at 18:19-19:4.) I can accept this given the claims of the ‘942 Patent.
`
`II. THE ‘942 PATENT
`12. The ‘942 Patent states that it is directed to shelf-stable liquid
`
`formulations of palonosetron for reducing chemotherapy and radiotherapy induced
`
`nausea and vomiting that can be used in the preparation of intravenous and oral
`
`medicaments. (Exh. 1001 Abstract.) As the patent states in the “Background of the
`
`Invention,” palonosetron is a 5-HT3 receptor antagonist, a known class of drugs at
`
`the time of the alleged invention. They treat emesis by antagonizing cerebral
`
`functions associated with the 5-HT3 receptor. (Id. 1:28-33.) Drugs within this class
`
`include ondansetron, granisetron, alosetron, tropisetron, and dolasetron, which
`
`were all commercially available at the time of the alleged invention. (Id. 1:33-35,
`
`4389856_1.docx
`
`5
`
`Exh. 1012
`
`

`
`
`
`2:12-43.) I understand from the ‘942 Patent that these drugs are often administered
`
`intravenously shortly before the initiation of chemotherapy or radiotherapy, and are
`
`effective in controlling acute emesis. (Id. 1:35-38, 47-53.)
`
`13. The specification of the ‘942 Patent acknowledges that the active
`
`compound palonosetron was already known, was disclosed in U.S. Patent
`
`No. 5,202,333 (“the ‘333 Patent” or “Berger”) (Exh. 1006.) as a 5-HT3 receptor
`
`antagonist, and is useful for the treatment of delayed emesis. (Exh. 1001,
`
`at 1:56-62.) However, according to the patent, formulating palonosetron in liquid
`
`formulations was not an easy task, typically due to shelf-stability issues. (Id.
`
`1:62-64.) The patent states that the intravenous palonosetron formulation in
`
`Example 13 of Berger had a “shelf stability of less than the 1-2 year time period
`
`required by health authorities in various countries.” (Id. 2:9-11.) It was an object of
`
`the invention to provide a palonosetron hydrochloride formulation with increased
`
`pharmaceutical stability. (Id. 2:44-60.)
`
`14. The ‘942 Patent then describes the alleged invention. The inventors
`
`stated that palonosetron could be formulated at concentrations of only about one
`
`tenth the amounts of other previously known compounds for treating emesis. (Id.
`
`3:4-10.) The specification discloses various concentration ranges of palonosetron
`
`4389856_1.docx
`
`6
`
`Exh. 1012
`
`

`
`
`
`in formulations. The broadest disclosed range is from about 0.01mg/mL1 to about
`
`5mg/mL palonosetron. (Id. 3:9-15.) Other disclosed palonosetron concentration
`
`ranges include from about 0.03mg/mL to about 0.2mg/mL, with 0.05mg/mL being
`
`identified as the optimal concentration. (Id. 5:3-6.)
`
`15. An advantage purportedly associated with
`
`lower dosages of
`
`intravenous palonosetron was the ability to administer the drug in a single
`
`intravenous bolus over a short, discrete time period. (Id. 5:7-12.) The patent also
`
`states that palonosetron concentration impacts stability, and the greatest stability
`
`was seen at the lowest palonosetron concentrations. (Id. 7:40-43.)
`
`16. By adjusting pH and/or excipient concentrations, the ‘942 Patent
`
`states that it is possible to increase the stability of palonosetron formulations. (Id.
`
`3:15-17.) The specification provides three instances in which this purportedly is
`
`the case.
`
`17. The specification discloses a pharmaceutically stable solution
`
`comprising palonosetron and a carrier, wherein the pH is “from about 4.0 to about
`
`6.0.” (Id. 3:19-23.) Other suitable ranges include “from about 4.5 to 5.5.”
`
`(Id. 5:28-29.) A solution pH value of 5.0 allegedly imparts the greatest stability.
`
`(Id. 5:30.)
`
`18. The specification further states that a solution of palonosetron
`
`1“mL” and “ml” are used interchangeably and both mean milliliter.
`
`4389856_1.docx
`
`7
`
`Exh. 1012
`
`

`
`
`
`including a citrate buffer and EDTA can be stable. (Id. 3:24-29.) Such a
`
`formulation can include about 0.01 to about 5.0mg/ml palonosetron, about 10 to
`
`about 100 millimoles citrate buffer and about 0.005 to about 1.0mg/ml EDTA. (Id.)
`
`The patent concludes that an optimal formulation includes EDTA 0.05% and
`
`20mM citrate buffer, with a pH of 5. (Id. 7:37-40.)
`
`19. The specification further states that the addition of mannitol
`
`accompanied by a chelating agent, can increase the stability of palonosetron
`
`formulations. (Id. 3:31-33, 5:63-6:10.) The chelating agent is preferably EDTA.
`
`(Id. 6:10.) The suitable concentration range of EDTA is from about 0.005mg/mL to
`
`about 1.0mg/mL, with 0.5mg/mL disclosed as the optimal value. (Id. 6:11-14.)
`
`Likewise, the concentration of mannitol ranges from about 10.0mg/mL to about
`
`80.0mg/mL. (Id. 6:16-18.)
`
`20. The specification does not say which of the foregoing features, or
`
`combination of features, of a palonosetron formulation produces a particular level
`
`of stability (such as 24-month stability at room temperature). And the claims of the
`
`‘942 Patent are not limited to stable formulations. However, it discloses a
`
`representative formulation including palonosetron hydrochloride at a concentration
`
`of 0.05mg/ml, 41.5mg/ml of mannitol (a tonicifying agent), 0.5mg/ml of EDTA (a
`
`chelating agent), citrate buffer, a pH adjusting agent (i.e., NaOH/HCl) and water.
`
`4389856_1.docx
`
`8
`
`Exh. 1012
`
`

`
`
`
`This formulation is said to be useful for intravenous administration. (Id. 7:55-8:10,
`
`Example 4.)
`
`21. The specification does not disclose any tonicity agents other than
`
`sodium chloride and mannitol, does not mention a buffer other than citrate, and
`
`does not mention any chelating agents other than EDTA and citrate.
`
`III. CLAIM CONSTRUCTION
`I understand that the only claim terms to be construed for the purposes
`22.
`
`of
`
`this
`
`proceeding
`
`are
`
`the
`
`terms
`
`“formulation”
`
`and
`
`“pharmaceutical/pharmaceutically.” The
`
`term “formulation” as recited
`
`in
`
`claims 1-6, 10 and 11 is not defined in the specification. To a formulator, this term
`
`means,
`
`the composition or “recipe” of a product.
`
`(Exh. 1029, at 691
`
`(Formulate/formulation means “2. To prepare according to a specified formula.”
`
`Formula means “4a. A prescription of ingredients in fixed proportion; a recipe.”).)
`
`“Formulation,” per se, is not limited to “stable” formulations. “Formulation” is not
`
`limited to a single-use, unit dose, or indeed a dose at all. Nor does it imply sterility.
`
`“Formulation” is not limited to any intended use and certainly not reducing the
`
`likelihood of cancer chemotherapy-induced nausea and vomiting.
`
`23. The terms “pharmaceutical” and “pharmaceutically” are also not
`
`defined in the specification. However, the term “pharmaceutically acceptable” is
`
`defined as “that which is useful in preparing a pharmaceutical composition that is
`
`4389856_1.docx
`
`9
`
`Exh. 1012
`
`

`
`
`
`generally safe, non-toxic and neither biologically nor otherwise undesirable and
`
`includes that which is acceptable for veterinary use as well as human
`
`pharmaceutical use.” (Exh.1001, at 4:19-23.) From the specification and claims, it
`
`is clear that these pharmaceutical formulations are intended for injection or
`
`infusion. A dictionary definition of “pharmaceutical” is that it relates to a drug or
`
`medicine. (Exh.1030, at 1316 (The term pharmaceutical means “adj. Of or relating
`
`to pharmacy or pharmacists. n. A pharmaceutical product or preparation.” The
`
`term pharmacy means “The art of preparing and dispensing drugs.”).) The term
`
`pharmaceutics means “The science of preparing and dispensing drugs.” I think a
`
`POSA would
`
`therefore understand
`
`that
`
`the
`
`terms “pharmaceutical” and
`
`“pharmaceutically” mean that the claimed formulation is an injectable drug or
`
`medicine for humans or animals.
`
`24. But, that does not mean that the pharmaceutical formulation needs to
`
`be capable of providing any particular level of efficacy. These terms also do not
`
`mean that the formulation is administered as a single-use, unit dose, or that the
`
`pharmaceutical formulation constitutes a dose per se. These terms do not mean that
`
`the pharmaceutical formulation is limited to any intended use and certainly not to
`
`reducing the likelihood of cancer chemotherapy-induced nausea and vomiting.
`
`These terms also do not impart a requirement for any particular level or duration of
`
`storage or shelf stability. The ‘094 and ‘980 Patents, which I understand are related
`
`4389856_1.docx
`
`10
`
`Exh. 1012
`
`

`
`
`
`to the ‘942 Patent, both expressly recite 18- or 24-month storage stability. No such
`
`term appears in the claims of the ‘942 Patent. I must conclude from this that the
`
`claims of the ‘942 Patent were not intended to be limited to any particular level or
`
`duration of storage stability.
`
`25. From the context of the claims and in particular claim 1, the claimed
`
`“pharmaceutical” “formulation” is simply an aqueous solution including a
`
`palonosetron salt, and a defined amount of mannitol in an appropriate container
`
`(needed to maintain sterility). The formulation has a recited pH and concentration
`
`and is safe to administer to a human or animal intravenously.
`
`IV. GENERAL PRINCIPLES OF FORMULATION DEVELOPMENT
`26. By January 29, 2003, the general principles for developing parenteral
`
`formulations were well known and well understood. Such formulation procedures
`
`were documented in general texts on the subject including a book chapter I
`
`authored, Parenteral Dosage Forms, in: Pharmaceutical Preformulation and
`
`Formulation: A Practical Guide from Candidate Drug Selection to Commercial
`
`Dosage Form (“Gibson” (Exh.1007)). Other well-known general texts discussing
`
`these steps include: Kenneth E. Avis et al., Pharmaceutical Dosage Forms:
`
`Parenteral Medications, Vol. 1, Chapters 2, 4 & 5 (Marcel Dekker Inc. 2nd ed.
`
`1992) (“Avis” (Exh. 1023)) ; L. Lachman et al., The Theory and Practice of
`
`Industrial Pharmacy, 642-644 and 783-784 (Lea & Febiger 3rd ed. 1986)
`
`4389856_1.docx
`
`11
`
`Exh. 1012
`
`

`
`
`
`(“Lachman” (Exh.1032)); and James Swarbrick et al., 19 (Suppl.2) Encyclopedia
`
`of Pharmaceutical Technology 137-72, Vol. 19, Supp. 2 (1988) (“Swarbrick”
`
`(Exh.1033)). My review of the ‘942 Patent indicates that the Patent Owner simply
`
`followed these well-known steps and developed the formulation in a way that was
`
`routine in the art.
`
`1. Preformulation Studies
`27. Prior to the development of prototype formulations, it is essential that
`
`preformulation studies are conducted to determine the basic physiochemical
`
`properties of a drug substance which underpin formulation development. (See
`
`generally Gibson Ch. 6 (Exh.1007).) Knowledge of the properties of the active,
`
`such as degradation mechanisms, solubility, stability, etc. is often invaluable in
`
`solving formulation and stability problems. Knowledge relating to compounds with
`
`similar structures (e.g., setrons, amines, etc.) can also be useful in this respect.
`
`28. For a parenteral drug formulation, fundamental elements of a
`
`preformulation study would include an evaluation of both solubility and stability
`
`since these parameters are critical to the development of a viable formulation. (See,
`
`e.g., Exhs.1023 at 140-43; 1007, at 196-210.) These investigations would typically
`
`include an evaluation of the pH/solubility and pH/stability relationships so that the
`
`optimum pH range for formulation development can be established. Where
`
`solubility is not limiting, the pH range will be selected to maximize stability whilst
`
`4389856_1.docx
`
`12
`
`Exh. 1012
`
`

`
`
`
`bearing in mind physiological constraints. The vast majority of licensed products
`
`therefore have a pH in the range of 3-9 to avoid injection site reactions and tissue
`
`damage linked to extremes of pH. (Exh.1007, at 333-34.) The preformulation study
`
`for a solution formulation may also include the study of the effects of light,
`
`temperature, oxygen, and metal ions on solution stability. (Exhs.1007, at 314;
`
`1034, at 152, 190.)
`
`29. The preformulation study would usually include a preliminary
`
`assessment of potential degradation mechanism(s) (e.g., oxidation or hydrolysis)
`
`and the identification of degradation products of the active pharmaceutical
`
`ingredient (“API”). (Exhs.1007, at 34; 1034, at 152-53.). This facilitates the
`
`development of a stability-indicating assay for the API and is useful for the
`
`formulator in selecting the most appropriate components for the formulation.
`
`2. Formulation Development Phase
`In the formulation development phase, formulations with varying
`
`30.
`
`compositions are prepared and evaluated to enable the selection of an optimal
`
`composition. At this stage, the qualitative and quantitative composition is
`
`optimized through experimentation. This would include identifying appropriate
`
`buffers, tonicifying agents, stabilizers, etc., and their respective concentrations.
`
`The
`
`information gained from
`
`the preformulation studies,
`
`including prior
`
`4389856_1.docx
`
`13
`
`Exh. 1012
`
`

`
`
`
`knowledge of the drug substance stability, is used in this process. (See, e.g.,
`
`Exhs.1007, at 175, 196, 333; 1023, at 115-16.)
`
`31. A routine aspect of initial formulation development would be the
`
`selection of a buffer system, if required, to achieve the desired pH range. As
`
`described earlier, a pH range of 3-9 is preferred to minimize adverse physiological
`
`effects. An appropriate buffer needs
`
`to be chosen from
`
`the range of
`
`pharmaceutically acceptable buffers. For low pH, citrate and acetate are most
`
`commonly used buffers (typically 10-100mM). Phosphate is most common at
`
`physiological pH (pH 7.4). (Exhs.1033, at 146-48; 1007, at 333-34.)
`
`32.
`
`Injectable formulations should preferably be isotonic, or nearly so,
`
`particularly if administered by the intravenous route, to ensure physiological
`
`tolerability. Hypertonic formulations can be tolerated where the volume is small
`
`and are sometimes necessary because of the dose requirements or the need to add
`
`stabilizing excipients. Hypotonic formulations should be avoided because of the
`
`risk of hemolysis. Sodium chloride (NaCl), dextrose, and mannitol are among the
`
`most commonly used tonicity adjustment excipients. (Exh.1007, at 334.) All of
`
`these excipients are present in numerous marketed formulations. (See generally
`
`Exh.1035.) Determining how much of a particular tonicity agent to include to
`
`produce an isotonic solution is a simple computation based on the measured
`
`osmolarity of the other formulation components. For mannitol, an isotonic solution
`
`4389856_1.docx
`
`14
`
`Exh. 1012
`
`

`
`
`
`requires approximately 5% of mannitol (50mg/ml). The amount of mannitol that
`
`would be required to make a formulation isotonic would vary, however, depending
`
`upon the relative amounts and osmolality of the other components in the
`
`formulation.
`
`33. Formulation studies might include the investigation of parameters
`
`such as drug concentration, buffer type and concentration, pH, excipient type and
`
`concentration, presence/absence of oxygen (e.g., nitrogen headspace), addition of
`
`an antioxidant, chelating agent etc. However the exact design of the study would
`
`depend on the prior knowledge of the API properties, including the data from
`
`preformulation studies. For an API which is sensitive to oxidation, strategies such
`
`as the elimination of oxygen, (e.g., by purging with nitrogen) and/or the use of
`
`antioxidants or metal chelators, e.g., EDTA, would be explored. (Exh.1007,
`
`at 341-42; Exh.1034 at 170-72.) The range of excipients acceptable for parenteral
`
`use is relatively narrow and normal practice is to include excipients with a prior
`
`history of use in parenteral products. This information was available via the FDA
`
`Inactive Ingredient Guide in 2003, as well as the series of publications by
`
`Strickley, the PDR, and other prior art I discuss in this report and in my chapter of
`
`Gibson. (See Exh.1007, at 335.) As stated in my chapter: “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
`
`4389856_1.docx
`
`15
`
`Exh. 1012
`
`

`
`
`
`development.” (Id. at 334.) The use of excipients with a prior history of use in
`
`parenteral formulations usually avoids the need for further toxicology evaluations
`
`on the excipient.
`
`34. Since the therapeutic dose of active drug usually has not been
`
`finalized at the time of formulation development, it is normal practice for
`
`formulators of parenteral drugs to consider and test a range of concentrations.
`
`Typically, that would include testing formulations at the lowest and highest
`
`anticipated concentrations; this would include stability testing.
`
`35. One way of evaluating a number of prototype formulations is to
`
`utilize statistical design of experiment (DoE) techniques. This approach maximizes
`
`the information which can be obtained from a set of experiments by enabling
`
`interaction effects between variables to be identified as well as the effect of
`
`individual variables. These ways of working were already known in 2003 and the
`
`use of such a DoE technique to evaluate the impact of a range of parameters would
`
`have been considered good practice then as it is today. (Exh.1007, at 309-11.)
`
`36.
`
`Indeed, in my opinion, Examples 1-3 of the ‘942 Patent exemplifies
`
`the standard practice of formulators in optimizing the composition of a parental
`
`pharmaceutical formulation. The patent owner conducted a routine pH/stability
`
`study to determine the pH of maximum stability followed by an optimization study
`
`to evaluate the optimum concentrations of palonosetron, buffer and EDTA for
`
`4389856_1.docx
`
`16
`
`Exh. 1012
`
`

`
`
`
`product stability. Finally the patent owner compared two of the three most
`
`commonly used tonicity adjusting agents to determine whether the choice of
`
`tonicity agent impacted stability. These are all routine steps in formulation
`
`development as described in the preceding paragraphs. The examples even
`
`acknowledge that they are optimization studies. Furthermore the Patent Owner
`
`neither provides an indication of the impact of these adjustments on product
`
`stability nor provides any data to support their claims for improved stability
`
`37. A POSA would know that it is a regulatory requirement that
`
`parenteral products are sterile. (Exhs.1033, at 137; 1007, at 202, 336.) The
`
`majority are presented as single use formulations which avoids the need for
`
`preservation. The majority of products for IV administration are aqueous
`
`solutions, but in some cases may be solid (usually lyophilized) formulations for
`
`reconstitution prior to administration as an aqueous solution. A small number of
`
`emulsion products are marketed for IV administration; these are complex
`
`products and usually developed to overcome solubility issues.
`
`38. All of the principles, studies, and strategies described above reflect the
`
`core role of a formulator working on the development of a parenteral product. I
`
`would have expected a POSA working in the field of parenterals development in
`
`2003 to have considered all of the aspects described.
`
`4389856_1.docx
`
`17
`
`Exh. 1012
`
`

`
`
`
`B. The Formulation Features Of Claims 1-6, 10, And 11 Of The
`‘942 Patent Would Have Been Readily Apparent To A POSA
`39. Producing an aqueous sterile solution at a concentration and pH that
`
`were known from the prior art (or similar to those known), and adjusting its
`
`tonicity with a commonly used tonicifying agent, were routine steps for a
`
`formulator making this type of product before January of 2003. The development
`
`of the claimed palonosetron formulation represents nothing more than the
`
`straightforward development of an IV formulation using standard strategies and
`
`excipients. The specific formulation elements of the asserted claims, including a
`
`specific concentration of active drug, a slightly acidic pH, an amount of 0.25mg,
`
`the use of mannitol as a tonicifying agent, the use of a chelating agent and the use
`
`of a citrate buffer, would have been readily apparent choices based both on the
`
`prior art and from conducting routine preformulation and formulation studies. The
`
`claims do not use any unconventional or unknown components, and do not apply
`
`any unconventional or unknown formulation techniques in creating a formulation.
`
`40.
`
`In terms of describing a pharmaceutical formulation to a POSA,
`
`claim 1 of the ‘942 Patent is incomplete in that it specifies a concentration of the
`
`active ingredient (palonosetron) but no volume or total amount. Without including
`
`this additional information, concentration alone is not particularly meaningful in
`
`describing a formulation. Generally speaking, concentration is a result, or a
`
`consequence, of trying to formulate a particular dose or range in one or more
`
`4389856_1.docx
`
`18
`
`Exh. 1012
`
`

`
`
`
`possible volumes. Dose or dose range are targets set by toxicologists or clinicians
`
`depending on the stage of drug development. Knowing the dose or range, and the
`
`mode of administration (in this case bolus injection, which necessarily means a
`
`relatively small volume) a formulator will attempt to provide a formulation that is
`
`capable of delivering that dose or range in a suitable volume. This results in a
`
`solution of a particular concentration. While concentration can be important in
`
`fully describing a formulation, it is not generally a goal per se, of the formulation
`
`process.
`
`V. THE PRIOR ART
`A. Berger
`41. As the ‘942 Patent acknowledges, the prior art Berger patent, U.S.
`
`Patent No. 5,202,333 (“Berger”) (Exh.1006) taught palonosetron HC1 (see
`
`Exh.1001, at 1:56-2:11).
`
`42. As Berger explained, palonosetron could be employed as a
`
`pharmaceutically acceptable salt, including as the hydrochloride salt. (Exh. 1006,
`
`3:13-15, 4:66-5:2.) Berger specifically disclosed the hydrochloride salt among a
`
`list of “pharmaceutically acceptable salts,” and taught that the compounds of
`
`Formula I, which include palonosetron, may “be converted to the corresponding
`
`acid addition salt with a pharmaceutically acceptable inorganic or organic acid.”
`
`(Id. 4:66-5:20, 19:30-33.)
`
`4389856_1.docx
`
`19
`
`Exh. 1012
`
`

`
`
`
`43. Specifically, Berger noted that the compounds disclosed and claimed
`
`are 5-HT3 receptor antagonists, and they can be used to produce pharmaceutical
`
`compositions and in methods of treating diseases involving, inter alia, emesis. (See
`
`id. 1:9-16, 3:16-24, 10:6-9.) Berger taught that palonosetron could be administered
`
`to humans (id. 9:50-55) as a pharmaceutical composition by the intravenous route,
`
`preferably “in a single unit dosage form” (id. 12:25-29, 13:1-5), and that the drug
`
`could be administered to treat CINV (id. 10:6-9 (“Compounds of Formula I are of
`
`particular value
`
`in
`
`treating
`
`(especially preventing)
`
`the emesis
`
`induced
`
`by . . . treatment for cancer with . . . chemotherapy. . . .”).
`
`44. Berger discusses a range of possible doses of compounds, including
`
`palonosetron, that could be used in a therapeutically effective amount, including a
`
`range of 1.0ng/kg per day to 1.0mg/kg per day based on body weight, and a
`
`preferred range of 10ng/kg to 0.1mg/kg. (Id. 12:11-16.) As Berger explains, for a
`
`standard 70kg human, the preferred dose range is from 700ng/day to 7.0mg/day
`
`(Id., 12:11-18.) Converted to milligrams, the unit of measurement utilized in
`
`claim 2 of the ‘942 Patent, this preferred range is 0.0007mg to 7.0mg. (Exh.1026
`
`¶ 34.) The amount of palonosetron claimed in claim 2 falls within this range.
`
`45. Berger also notes that: “One of ordinary skill in the art of treating
`
`such diseases will be able, without undue experimentation and in reliance upon
`
`personal knowledge and the disclosure of this application, to ascertain a
`
`4389856_1.docx
`
`20
`
`Exh. 1012
`
`

`
`
`
`therapeutically effective amount of a compound of Formula I for a given disease.”
`
`(Exh.1006, at 12:19-24.) Berger taught single unit doses. (Id. 13:2.)
`
`46. Berger also notes the amount of palonosetron in final dosage forms
`
`preferably ranges from 0.00001% w to 1.0%w. (Id. 12:66-67.) This range equates
`
`to 0.0001mg/ml to 10mg/ml. The concentration claimed in claim 1 of 0.05mg/ml,
`
`when converted to % w/v, would be 0.005% w. (Exh.1026 ¶ 35.) Thus the
`
`concentration claimed in claim 1 of the ‘942 Patent also falls within the
`
`concentration range described in Berger.
`
`47. Example 13 of Berger discloses a range of amounts of palonosetron
`
`per 1ml from 10-100mg. This is clearly a reference to a concentration, as the
`
`example does not specify how much of this exemplified f

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

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.

throbber

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.

Become a Member

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

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket