Paper No. ___
`Filed: October 10, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`U.S. Patent No. 9,539,268
`____________
`
`DECLARATION OF CLIVE G. WILSON PH.D.
`
`ANTECIP EXHIBIT 2019
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2017-00022
`
`Page 1
`
`
`Filed: October 10, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`U.S. Patent No. 9,539,268
`____________
`
`DECLARATION OF CLIVE G. WILSON PH.D.
`
`ANTECIP EXHIBIT 2019
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2017-00022
`
`Page 1
`
`
`
`I, Clive G. Wilson, Ph.D., declare as follows:
`
`I.
`
`Qualifications
`
`1.
`
`I offer this declaration at the request of counsel for Grünenthal GmbH
`
`(“Petitioner”). I understand that Petitioner is seeking post-grant review (“PGR”) of
`
`claims 1-30 of U.S. Patent No. 9,539,268 (Exh. 1001, “the ’268 patent”).
`
`2.
`
`I am a Research Professor at the Strathclyde Institute of Pharmacy and
`
`Biomedical Sciences at the University of Strathclyde in Glasgow, Scotland. I was
`
`formerly the J.P. Todd Chair of Pharmaceutics at the same institution.
`
`3.
`
`I obtained my B.Sc. in Applied Biology in 1970 from Hatfield Polytechnic
`
`(CNAA) (currently known as the University of Hertfordshire) in Hatfield,
`
`Hertfordshire, United Kingdom. I then obtained my Ph.D. in Biochemistry (Drug
`
`Metabolism) in 1973 from the University of Surrey in Guildford, Surrey, United
`
`Kingdom.
`
`4.
`
`I was a fulltime Professor at the University of Strathclyde in Glasgow,
`
`Scotland from 1990 to 2016. Prior to that, I was a Reader in Applied
`
`Pharmacology at Nottingham University Medical School.
`
`5.
`
`I am also the Chairman of Biological Sciences Ltd., the former Chief
`
`Scientific Officer of Bioimages Research, Ltd., and a member of the Steering
`
`Committee of the European Federation of Pharmaceutical Sciences. From 2009 to
`
`1
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`Page 2
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`
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`2011, I served as the President of the European Federation of Pharmaceutical
`
`Sciences.
`
`6.
`
`I am a member of the British Society of Gastroenterology, the Controlled
`
`Release Society, the American Association of Pharmaceutical Sciences and the
`
`Academy of Pharmaceutical Sciences, among others. I was made a Fellow of the
`
`Controlled Release Society in 2010 and was made an Eminent Fellow of the
`
`Academy of Pharmaceutical Sciences in 2012.
`
`7.
`
`I have served on the Editorial Board of the European Journal of
`
`Pharmaceutics and Biopharmaceutics since 2000. I have also served on the
`
`Editorial Board of CRS Books since 2008. I was an Editor of the Taylor and
`
`Francis Series in Pharmaceutical Technology from 1992 to 1996.
`
`8.
`
`I have supervised the research and studies of 64 Ph.D. students and 1 M.D.
`
`student. I am currently supervising a research team of 3 Ph.D. students, 2
`
`postdoctoral fellows and 2 technicians.
`
`9.
`
`I have been a lecturer at numerous universities in the fields of Industrial
`
`Pharmacy, Physiology and Pharmacology, have served on expert panels and
`
`advisory panels, and have been retained as a consultant for pharmaceutical
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`companies including Allergan Pharmaceuticals USA, Ferring Pharmaceuticals, and
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`GSK Pharma Global, among others.
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`10. I have authored or co-authored over 250 peer-reviewed scientific articles
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`and book chapters.
`
`11. A copy of my curriculum vitae is attached as Exh. 1006, and it provides a
`
`comprehensive description of my academic and employment history. In the past
`
`four years, I have provided expert testimony in deposition or at trial in the
`
`following cases:
`
` Endo Pharmaceuticals v. Depomed Inc., Deposition, 2014; and
`
` Cosmos v. Actavis Fl Inc and Alvogen Pine Brook LLC, Deposition,
`
`2017.
`
`12. I am being compensated at my standard rate of $400.00 per hour. My
`
`compensation is not contingent on the nature of my findings or the outcome of any
`
`proceeding.
`
`II.
`
`Scope of Assignment and Summary of Opinion
`
`13. I have been asked by counsel for Petitioner to provide my opinion
`
`regarding whether certain limitations of claims 1-30 of the ’268 patent are taught
`
`or disclosed in the prior art.
`
`14. I have also been asked to provide my opinion as to the knowledge and
`
`qualifications of the person of ordinary skill in the art (“POSA”).
`
`15. I have also been asked to provide my opinion regarding how a POSA
`
`would have understood certain claim terms in the ’268 patent.
`
`3
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`Page 4
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`16. I have also been asked to provide my opinion as to whether the ’268 patent
`
`specification enables a POSA to make and use the claimed invention without
`
`undue experimentation.
`
`17. As discussed in detail below, it is my opinion that:
`
` The ’268 patent specification fails to enable a POSA to practice the full
`
`scope of the invention of claims 1-30 of the ’268 patent;
`
` Claims 1-2 of the ’268 patent are indefinite and could be interpreted in
`
`multiple ways by a POSA; and
`
` The pharmaceutical dosage forms recited in claims 3-30 of the ’268
`
`patent were disclosed in the prior art.
`
`III. Legal Standards
`
`a. Obviousness
`
`18. I have been informed by counsel and I understand that nonobviousness is a
`
`requirement for patentability. Specifically, I understand nonobviousness means
`
`that the subject matter of the claimed invention in a patent, taken as a whole and
`
`considered in light of the prior art references, would not have been obvious to a
`
`POSA at the time of the claimed invention.
`
`19. I have been informed by counsel and I understand that in an obviousness
`
`analysis, the patent challenger cannot rely on the hindsight of today’s knowledge,
`
`and that obviousness must be determined from the perspective of a POSA at the
`
`4
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`Page 5
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`
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`time of the claimed invention. For this reason, the party challenging the patent for
`
`obviousness may not use the patent as a blueprint or template to pick and choose
`
`references within the prior art, or portions thereof, to rely on in an obviousness
`
`analysis.
`
`20. I have been informed by counsel and I understand that a determination of
`
`obviousness requires analyzing the scope and content of the prior art, the level of
`
`ordinary skill in the relevant art, and the differences between the claims-at-issue
`
`and the prior art. I also have been informed by counsel and I understand that a
`
`claimed invention is not obvious unless it is shown that a POSA would have had a
`
`motivation to combine the teachings of the prior art references to obtain the
`
`claimed invention, and would have had a reasonable expectation of success in
`
`achieving the claimed result.
`
`21. I have been informed by counsel and I understand that demonstrating that
`
`each element of a challenged claim was independently known in the art is
`
`insufficient. Rather, the challenging party must show that a POSA had an apparent
`
`motivation to combine elements in the claimed manner, and that there was a
`
`reasonable expectation that the combination would be successful.
`
`b. Enablement
`
`22. I have been informed by counsel and I understand that a patent
`
`specification must teach a POSA how to make and use the claimed invention
`
`5
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`Page 6
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`
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`without undue experimentation. Whether undue experimentation would be
`
`required is evaluated by considering factors such as the quantity of
`
`experimentation necessary, the amount of direction or guidance present, the
`
`presence or absence of working examples, the nature of the invention, the state of
`
`the prior art, the relative skill of those in the art, the predictability or
`
`unpredictability of the art, and the breadth of the claims. I have been informed and
`
`I understand that the fact that experimentation may be complex does not
`
`necessarily make it undue, if the art typically engages in such experimentation.
`
`23. I have further been informed and I understand that the full scope of the
`
`claim must be enabled. Accordingly, when a range is claimed, there must be a
`
`reasonable enablement of the full scope of the range.
`
`c. Indefiniteness
`
`24. I have been informed by counsel and I understand that a patent
`
`specification must point out and distinctly claim the subject matter which the
`
`inventor(s) regards as the invention. I have been further informed and I understand
`
`that a POSA must be able to determine the scope of the invention with reasonable
`
`certainty based on the patent claims in light of the specification and prosecution
`
`history. Otherwise a claim is invalid as indefinite.
`
`6
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`Page 7
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`IV. The Person of Ordinary Skill in the Art
`
`25. I have been informed by counsel and I understand that the POSA is a
`
`hypothetical person who is presumed to be familiar with the relevant scientific
`
`field and its literature at the time of the invention. This hypothetical person is also
`
`a person of ordinary creativity capable of understanding the scientific principles
`
`applicable to the pertinent field.
`
`26. Claims 23-30 of the ’268 patent relate to pharmaceutical dosage forms
`
`comprising zoledronic acid in a salt form having a specified bioavailability. It is
`
`my opinion that a POSA for claims 23-30 would have a Ph.D. in biochemistry,
`
`medicinal chemistry, pharmacology, pharmaceutics, medicinal chemistry, or a
`
`related discipline, and at least 3-5 years of experience in formulating
`
`pharmaceutical dosage forms and studying their pharmacokinetics. In the
`
`alternative, a POSA could have less formal education but greater work experience.
`
`27. Claims 1-22 of the ’268 patent are directed to methods of treating arthritis
`
`by orally administering a dosage form containing zoledronic acid, wherein the
`
`zoledronic acid has a specified bioavailability. I understand that Petitioner’s expert
`
`Dr. Stephen Bruehl has opined claims 1-22 relate to the treatment of arthritis,
`
`which is in the field of pain management, and that a POSA for these claims would
`
`have an M.D. or a Ph.D. in a pain medicine relevant discipline, such as clinical
`
`health psychology or neuroscience, and at least 3 to 5 years of experience in the
`
`7
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`Page 8
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`
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`treatment of chronic pain or the study of chronic pain management. In my opinion,
`
`because claims 1-22 concern the administration of a pharmaceutical dosage form
`
`having a particular bioavailability, these claims also relate to the fields of
`
`pharmaceutical formulation and pharmacokinetics. Therefore, the hypothetical
`
`POSA would also have knowledge and experience in formulating pharmaceutical
`
`dosage forms and studying their pharmacokinetics, or access to a person with such
`
`knowledge and experience.
`
`28. With respect to claims 23-30 of the ’268 patent, based on my training and
`
`experience, I am (and was as of May 27, 2014) at least a POSA. With respect to
`
`the pharmacokinetic and pharmaceutical dosage form elements of claims 1-22 of
`
`the ’268 patent, based on my training and experience, I am (and was as of May 27,
`
`2014) at least a POSA.
`
`V.
`
`Claim Construction
`
`29. I have been informed and I understand that in proceedings before the
`
`Patent Trial and Appeal Board (PTAB), such as a PGR, a claim term should be
`
`given its broadest reasonable construction consistent with the specification, as
`
`understood by a POSA.
`
`8
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`Page 9
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`
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`a. “Zoledronic Acid”
`
`30. I have been asked to provide my opinion regarding how a POSA would
`
`have interpreted “zoledronic acid,” which appears in all of the ’268 patent claims
`
`either expressly or by dependency to another claim.
`
`31. The ’268 patent specification defines this term, stating:
`
`Zoledronic acid has the structure shown below and
`is also referred to as zoledronate.
`
`Zoledronic Acid
`Unless otherwise indicated, any reference to a compound
`herein, such as . . . zoledronic acid . . . by structure,
`name, or any other means, includes pharmaceutically
`acceptable salts, such as the disodium salt; alternate solid
`forms, such as polymorphs, solvates, hydrates, etc.;
`tautomers; or any other chemical species that may rapidly
`convert to a compound described herein under conditions
`in which the compounds are used as described herein.
`(Exh. 1001 col. 5, l. 66-col. 6, l. 20.)
`
`9
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`Page 10
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`32. Accordingly, a POSA would have understood the term “zoledronic acid” to
`
`include any form of zoledronic acid.
`
`33. A POSA would plainly understand “zoledronic acid” modified by the
`
`phrase “in a salt form,” as claimed in claims 23-30, to mean any salt form of
`
`zoledronic acid.
`
`34. A POSA would plainly understand “zoledronic acid” modified by the
`
`phrase “in a salt or an acid form” to refer to any salt form of zoledronic acid or any
`
`acid form of zoledronic acid, i.e., any form of zoledronic acid. A POSA would
`
`understand that “zoledronic acid in a salt or an acid form” is synonymous with
`
`“zoledronic acid.”
`
`b. “Therapeutically Active Agent”
`
`35. I have also been asked to provide my opinion regarding how a POSA
`
`would have interpreted “therapeutically active agent,” which is a limitation of
`
`claims 3-30.
`
`36. The ’268 patent specification does not define “therapeutically active
`
`agent.” It does, however, use the terms “active ingredient,” “active agent,” “active
`
`compound,” and “therapeutically active ingredient” interchangeably. (See Exh.
`
`1001 col. 10, l. 60-col. 11, l. 7, col. 15, ll. 22-35.) These terms, along with the
`
`“therapeutically active agent,” are all synonyms for what a POSA would have
`
`10
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`Page 11
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`recognized as an “active pharmaceutical ingredient” of a pharmaceutical dosage
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`form.
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`37. The FDA defines an active ingredient as “a component of a drug product
`
`that is intended to furnish pharmacological activity or other direct effect in the
`
`diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the
`
`structure or any function of the body of man or other animals.” (21 C.F.R. §
`
`210.3(b)(7).)
`
`38. The World Health Organization uses a similar definition: “substances
`
`[that] are intended to furnish pharmacological activity or other direct effect in the
`
`diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the
`
`structure and function of the body.” (Exh. 1037 at 81.)
`
`39. A POSA would have understood that an active ingredient is a substance
`
`that is directly responsible for making the drug product effective for its indicated
`
`use. In a dosage form indicated for the treatment of arthritis, for example, the
`
`active ingredient(s) are those ingredient(s) that are directly effective at treating
`
`arthritis.
`
`40. A POSA would also have understood that a pharmaceutical dosage form
`
`may contain one or more active pharmaceutical ingredients and one or more
`
`excipients. An excipient is any ingredient other than an active pharmaceutical
`
`ingredient.
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`11
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`41. Therefore, a POSA would have understood the term “therapeutically active
`
`agent” to mean “an active pharmaceutical ingredient.”
`
`c. “(a) . . . or (b) one of the following: (1) . . . (2) . . . or (3) . . .”
`
`42. I have also been asked to provide my opinion regarding how a POSA
`
`would have interpreted “(a) zoledronic acid in a salt form [or an acid form in
`
`claims 3-22]; or (b) one of the following: 1) zoledronic acid [and Ion 1] . . . in an
`--
`amount that is less than 0.1% w/w and greater than 0% w/w; 2) zoledronic acid
`
`[and Ion 2] . . . in an amount that is less than 0.1% w/w and greater than 0% w/w;
`
`or 3) zoledronic acid . . . and a combination of [Ion 1] . . . in an amount that is less
`
`than 0.1% w/w and greater than 0% w/w, and [Ion 2] . . . in an amount that is less
`
`than 0.1% w/w and greater than 0 % w/w” (emphasis added) as recited in claim 2.
`
`43. Based on the use of the word “or” (rather than and, and/or, etc.), a POSA
`
`would have understood this element to be listing a series of alternatives requiring
`
`the claimed dosage form to meet either alternative (a) or alternative (b) but not
`
`both.
`
`44. Thus, a POSA would have understood that the claimed pharmaceutical
`
`compositions must comprise either the active ingredients specified in element (a),
`
`i.e., zoledronic acid in a salt form [or an acid form in claims 3-22] alone, or
`
`alternatively, the ingredients specified in element (b), i.e., zoledronic acid in a salt
`
`12
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`Page 13
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`
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`or an acid form in combination with Ion 1, in combination with Ion 2, or in
`
`combination with Ions 1 and 2.
`
`d. AUC Limitation of Claim 15
`
`45. I have been asked to provide my opinion regarding how a POSA would
`
`have interpreted “AUC of zoledronic acid of about 100 ng·h/mL to about 200
`
`ng·h/mL” as recited in claim 15.
`
`46. I note first that other than identifying it as the “area under the plasma
`
`concentration curve of zoledronic acid” (see, e.g., Exh. 1001 col. 8, ll. 56-61), the
`
`’268 patent does not expressly define AUC or provide any examples showing its
`
`measurement or calculation.
`
`47. I note further that based on the lack of information in the patent, it is my
`
`opinion that a POSA would not know what the term means (as I discuss in further
`
`detail below). My proposed construction is what I view to be the most reasonable
`
`construction under these circumstances.
`
`48. The claim indicates an AUC value, but does not specify any particular time
`
`period over which the AUC is to be measured. It also does not specify the dose of
`
`zoledronic acid administered or any other details as to how the AUC values should
`
`be measured. It is my opinion that, to the extent a POSA could understand claim 15
`
`at all, the POSA would have most reasonably understood the AUC values recited
`
`in the claim as covering any dosage form comprising any dose of zoledronic acid
`
`13
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`Page 14
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`that has an observed AUC of from about 100 ng·h/mL to about 200 ng·h/mL over
`
`any time period.
`
`VI. Background
`
`49. The ’268 patent is entitled “Therapeutic Compositions Comprising
`
`Imidazole and Imidazolium Compounds” and issued on January 10, 2017 from
`
`U.S. Patent Application No. 15/211,827. This application was filed on July 15,
`
`2016, but the ’268 patent claims priority to applications dating back to May 27,
`
`2014. I have used May 27, 2014 as the earliest possible priority date in my
`
`analysis but offer no opinion as to whether it is the actual priority date for the
`
`alleged invention of the ’268 patent.
`
`50. Broadly speaking, the ’268 patent claims pharmaceutical dosage forms
`
`comprising zoledronic acid having a specified bioavailability, and methods of
`
`treating arthritis by orally administering such dosage forms. Preliminarily, I note
`
`that the administration of a drug orally can be important for a variety reasons
`
`including, for instance, allowing for an improved administration profile (e.g., lower
`
`systemic dose given more frequently) which in turn can result in lower side-effects
`
`and easier dose titration. (See, e.g., Exh. 1040; Exh. 1009 col. 3, ll. 37-50.) Oral
`
`dosage forms also are generally easier to formulate and manufacture. (See, e.g.,
`
`Exh. 1040; Exh. 1009 col. 3, ll. 37-50.)
`
`14
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`Page 15
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`
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`51. More specifically, the dosage forms claimed or used in the methods
`
`claimed in the ’268 patent require that the bioavailability of zoledronic acid in the
`
`dosage form is within a particular range. The ranges required by each claim are
`
`shown in the following table:
`
`Claim(s)
`
`1-3, 5, 14-22
`4
`6
`7
`8
`9
`10
`11
`12
`13
`23-30
`
`Bioavailability of Zoledronic
`Acid or “Compound A”
`about 1.1% to about 4%
`1.3% to 3%
`1.3% to 4%
`1.4% to 3%
`1.4% to 4%
`1.5% to 3%
`1.6% to 3%
`1.6% to 4%
`1.8% to 3%
`1.8% to 4%
`about 1.2% to about 4%
`
`52. Bioavailability reflects “the amount of active drug delivered to the blood
`
`and the rate at which it is delivered.” (Exh. 1063 at 124.) When a drug is
`
`administered intravenously, the drug is placed directly in the blood; therefore, an
`
`IV injection has 100% bioavailability. (Id.) Drugs administered by an
`
`extravascular route (oral, buccal, rectal, topical, intramuscular, subcutaneous, etc.)
`
`must be transferred from the dosage form to the blood in order to bioavailable.
`
`(Id.)
`
`53. The absolute bioavailability of an extravascular dosage form, such as the
`
`oral dosage forms administered in the claimed methods, is defined relative to an IV
`15
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`Page 16
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`
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`injection. (Exh. 1063 at 124.) Bioavailability can be assessed by directly
`
`measuring its plasma concentration or by following its appearance in urine. (Id. at
`
`103.)
`
`54. Calculation of bioavailability of an extravascular dosage form based on
`
`plasma concentration can be understood mathematically based on the following
`
`formula:
`
`Bioavailability = ((AUCextravascular / AUCintravenous) (Dintravenous / Dextravascular)) 100
`
`where D = dosage.
`
`(Exh. 1063 at 125.)
`
`55. Calculation of bioavailability based on urinary excretion data can be
`
`understood mathematically based on the following formula:
`
`Bioavailability = ((Uextravascular/Uintravenous) (Dintravenous/Dextravascular)) 100
`
`where U = urinary excretion and D = dosage.
`
`(Exh. 1063 at 128.)
`
`56. In addition to requiring bioavailability of zoledronic acid between “about
`
`1.1% to about 4%,” claim 15 also requires administration that results in a specific
`
`AUC value over a particular time interval (i.e., AUC/time). Specifically, claim 15
`
`requires administration in an amount that results in an “AUC of zoledronic acid of
`
`about 100 ng·h/mL to about 200 ng·h/mL.”
`
`16
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`Page 17
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`57. The AUC reflects the actual exposure to a drug after administration of a
`
`dose of the drug. An example plasma concentration versus time curve is illustrated
`
`below.
`
`0
`0
`
`0 -
`
`c,.
`
`c,,.
`
`::;o
`::c~
`'"'
`=t -
`<.!>
`
`zo
`0~
`-co
`,-
`cc
`a: ,-
`zo
`wo
`u·
`II
`z"
`I
`0
`II
`u
`111
`CCo
`111
`::co
`en •
`II
`a:"' 111
`...J
`11 1
`0..
`111 1
`1111
`
`0
`0
`
`s.oo
`
`6.00
`
`9.00
`TIME
`
`21. 00
`
`2 .oo
`
`58. “The AUC for a plasma concentration versus time curve can be determined
`
`using the trapezoidal rule. For this calculation [as illustrated above], the curve is
`
`divided into vertical segments . . . . The top line of each segment is assumed to be
`
`straight rather than slightly curved, and the area of the segment is calculated as
`
`though it were a trapezoid . . . . The total AUC is then obtained by summing the
`
`areas of the individual segments.” (Exh. 1063 at 125.)
`
`17
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`Page 18
`
`
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`59. Mathematically, the trapezoidal rule can be understood according to the
`
`following formula:
`
`AUC = (½ (C1 + C2)) (t2 – t1) + (½ (C2 + C3)) (t3 – t2) . . .
`+ (½ (Cn-1 + Cn)) (tn – tn-1)
`
`where C = drug concentration and t = time.
`
`(Exh. 1063 at 125.)
`
`60. Pharmaceutical formulation and pharmacokinetics are unpredictable fields.
`
`Without data or other guidance, the bioavailability and AUC of a particular dosage
`
`form of a particular drug cannot be predicted. A POSA would have known, for
`
`example, that different dosage forms of the same drug may have different
`
`bioavailabilities. Often, for example, a compressed tablet or capsule will have a
`
`lower bioavailability than a suspension or aqueous solution of the same active
`
`ingredient. Exh. 1086 at 1146. There are also various variable characteristics of
`
`the active ingredient and pharmaceutical composition that can alter bioavailability,
`
`often in unpredictable ways, including the crystal form, salt form, wettability,
`
`solubility, and particle size of the active ingredient, as well as the particular
`
`excipients included in the formulation and the manufacturing process used to make
`
`it (for example, different types of granulation techniques). Exh. 1085 at 997.
`
`Thus, without specific guidance from the specification or the published literature, a
`
`POSA would not have known how to prepare a pharmaceutical composition
`
`comprising zoledronic acid having a particular bioavailability.
`
`18
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`VII. A POSA Would Not Have Known How to Make and Use Dosage Forms
`Satisfying the Bioavailability Limitations of the ’268 Patent.
`
`61. As noted above, all of the claims of the ’268 patent have limitations
`
`specifying that the bioavailability of zoledronic acid in the dosage forms claimed
`
`or used in the methods of treatment claimed is about 1.1% to about 4%, or a
`
`narrower range of bioavailability included within that range (such as 1.2% to 4% in
`
`claims 23-30). In my opinion, the claims are overly broad and not enabled in this
`
`respect.
`
`62. The specification of the ’268 patent indicates that “any reference to a
`
`compound herein, such as . . . zoledronic acid . . . by structure, name, or any other
`
`means, includes pharmaceutically acceptable salts, such as the disodium salt;
`
`alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or
`
`any other chemical species that may rapidly convert to a compound described
`
`herein under conditions in which the compounds are used as described herein.”
`
`(Exh. 1001 col. 6, ll. 12-20.)
`
`63. Furthermore, the ’268 patent specification explicitly states: “bioavailability
`
`enhancement is not necessary for an oral dosage form to be effective. In some
`
`embodiments, the dosage form is substantially free of bioavailability-enhancing
`
`agents.” (Id. col. 13, ll. 50-53.)
`
`64. These disclosures suggest that the ’268 patent should teach a POSA how to
`
`make and use zoledronic acid dosage forms with bioavailabilities within the
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`19
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`Page 20
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`
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`claimed ranges, wherein zoledronic acid is in any pharmaceutically acceptable
`
`form (claims 1-22) or any pharmaceutically acceptable salt form (claims 23, 30).
`
`Since the claims do not require bioavailability enhancement, the patent should
`
`teach a POSA how to make such a dosage form wherein the zoledronic acid’s
`
`bioavailability is unenhanced. However, as discussed below, it is my opinion that
`
`the ’268 patent fails to enable a POSA to practice the full scope of the claimed
`
`invention.
`
`65. For starters, the ’268 patent lacks any pharmacokinetic data whatsoever
`
`demonstrating that any zoledronic acid dosage form has an oral bioavailability of
`
`from about 1.1% to about 4%, or within any of the other claimed bioavailability
`
`ranges.
`
`66. Furthermore, a POSA would have known that bisphosphonates like
`
`zoledronic acid have poor oral bioavailability. In fact, zoledronic acid has an oral
`
`bioavailability in humans of 1% or lower unless some type of enhancer is used.
`
`(Exh.1027 ¶[006]; Exh.1028 at 184; Exh. 1029 at 124; Exh. 1030 at 395.) The
`
`state of the prior art would have suggested to a POSA that, without bioavailability
`
`enhancement, zoledronic acid had a bioavailability in humans of 1% or less.
`
`67. This is confirmed by the ’268 patent itself, which states that “[w]ithout
`
`ingredients or other methods to enhance bioavailability, zoledronic acid typically
`
`has a low bioavailability in an oral dosage form.” (Exh. 1001 col. 13, ll. 57-59.)
`
`20
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`Page 21
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`
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`In embodiments where bioavailability is “unenhanced or substantially
`
`unenhanced,” the oral bioavailability of zoledronic acid may be as low as 0.01%.
`
`(Id. col. 13, ll. 59-62.)
`
`68. The ’268 patent suggests only one method of achieving the improvement
`
`in zoledronic acid’s bioavailability as claimed in claims 24-29 – by orally
`
`administering a dosage form wherein zoledronic acid is in the form of a disodium
`
`salt. (See, e.g., Exh. 1001 col. 2, ll. 39-46, 60-67.) Though again, there is no
`
`actual data showing such a bioavailability was actually observed.
`
`69. The ’268 patent likewise fails to suggest any other way by which
`
`bioavailability could be improved. The patent specification contains no examples
`
`of any zoledronic acid dosage forms and does not list any bioavailability-
`
`enhancing ingredients that might be added to improve zoledronic acid’s
`
`bioavailability to at least about 1.1%.
`
`70. Furthermore, as of May 27, 2014, there were at least eleven different
`
`disodium salt forms of zoledronic acid known in the prior art. (Exh. 1035 3:30-
`
`4:7, 8:22-11:2.) The prior art also taught different methods for preparing these
`
`various disodium salt forms. (Id.) A POSA would have expected that different
`
`disodium salt forms could have different properties, including different solubilities
`
`and different bioavailabilities. The ’268 patent does not identify any particular
`
`disodium salt form having the recited bioavailability or provide any information as
`
`21
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`Page 22
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`
`
`to how to prepare particular disodium salt forms having the recited bioavailability.
`
`A POSA would not have known which, if any, of the disodium salt forms disclosed
`
`in the prior art, to select for inclusion in the claimed dosage forms. It is also
`
`theoretically possible that the inventor of the ’268 patent could have produced a
`
`new disodium salt form, but the ’268 patent specification does not characterize it
`
`or describe how it could be made.
`
`71. The ’268 patent specification also does not state a specific bioavailability
`
`percentage that can be achieved using a disodium salt form of zoledronic acid.
`
`Instead, it merely states that the disodium salt form can improve the bioavailability
`
`of zoledronic acid by as much as about 200% percent compared to administration
`
`of the diacid form. (Exh. 1001 col. 7, l. 65-col. 8, l. 5.) The ’268 patent
`
`specification states that the bioavailability of “zoledronic acid” in the dosage forms
`
`can range from about 0.01% to 10%. (Id. col. 14, ll. 8-11.) Assuming this range
`
`applies to the diacid form, the maximum improvement in bioavailability of the low
`
`end of the range (i.e., 0.01%) would be only 0.03% bioavailability (i.e., 200%
`
`improvement on 0.01%). The ’268 patent provides no information from which a
`
`POSA would know how to formulate a disodium salt of zoledronic acid to achieve
`
`the claimed bioavailability.
`
`72. Nevertheless, even assuming that a dosage form of zoledronic acid
`
`comprising the form of a disodium salt achieves the claimed bioavailability,
`
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`
`
`because the patent contains no pharmacokinetic data or exemplary formulations of
`
`any dosage forms, there is no indication that any other form of zoledronic acid
`
`(e.g., the diacid form or any other salt form) could achieve the claimed
`
`bioavailability.
`
`73. The ’268 patent also does not disclose any examples of excipients to use in
`
`the claimed compositions, nor does it disclose any examples of particular methods
`
`of manufacture, such as wet or dry granulation or direct tablet compression, to use
`
`in making compositions having the claimed bioavailability. Hence, the POSA also
`
`would not have known which excipients and methods of manufacture to use to
`
`obtain the claimed bioavailability.
`
`74. A POSA would have had to perform a large amount of trial and error
`
`experimentation to (potentially) arrive at the claimed invention, far beyond the
`
`type of experimentation that would be considered “routine.” A POSA would have
`
`needed to experiment with different quantities of ingredients in the formulations,
`
`different forms of the active ingredient, and different methods of manufacture.
`
`Given the complete lack of guidance and information in the specification, the
`
`POSA would not have even known where to begin in trying to create a zoledronic
`
`acid composition having the claimed bioavailability.
`
`23
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`Page 24
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`
`
`VIII. The ’268 Patent Does Not Describe and a POSA Would Not Have
`Known How to Make and Use Dosage Forms Covered by Claim 1
`Containing Any “Compound A” other than Zoledronic Acid.
`
`75. Challenged claims 1-2 cover the oral administration of dosage forms
`
`comprising “Compound A” wherein the bioavailability of Compound A is from
`
`about 1.1% to about 4%. Compound A is defined by the following chemical
`
`formula:
`
`OH
`
`“wherein each A is independently an acidic functional group.” (Exh. 1001 claim 1;
`
`col. 1, ll. 30-50.)
`
`76.
`
`A POSA would plainly recognize that if A is a phosphonate (PO3H2)
`
`group, Compound A is zoledronic acid. However, because A can be any acidic
`
`functional group, Compound A includes at least dozens, if not hundreds, of
`
`compounds other than zoledronic acid.
`
`77.
`
`The ’268 patent specification does not identify any compound
`
`meeting the definition of Compound A other than zoledronic acid. The
`
`specification also does not indicate that any other compound meeting the definition
`
`of Compound A has a bioavailability of from about 1.1% to about 4% as claimed.
`
`24
`
`Page 25
`
`
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`Not only does the specification lack supporting data, it does not even state that any
`
`compound other than zoledronic acid meeting the definition of Compound A has
`
`the claimed bioavailability. Only the purported bioavailability of zoledronic acid
`
`is discussed. (See, e.g., Exh. 1001 col. 14, ll. 8-29.)
`
`78.
`
`A POSA would reasonably expect that different compounds with
`
`different functional groups at the A position could have different properties,
`
`including different bioavailabilities. The ’268 patent simply does not teach a
`
`POSA which acidic groups can be used to make a formulation having the claimed
`
`bioavailability.
`
`79.
`
`Consequently, it is my opinion that the specification of the ’268 patent
`
`does not indicate that the inventor was in possession of and actually invented the
`
`entirety of the invention of claims 1-2, and a POSA would not have been able to
`
`make and use compositions satisfying claims 1-2 with any “Compound A” other
`
`than zoledronic acid without undue experimentation.
`
`IX. A POSA Could Have Interpreted Claims 1-2 in Multiple Ways.
`
`80. Claim 1 recites:
`
`A method
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