`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