`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner
`_____________
`
`Case PGR2017-00022
`U.S. Patent No. 9,408,862
`_____________
`
`
`SUPPLEMENTAL
`DECLARATION OF DR. WILLIAM WARGIN
`
`
`
`
`
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`ANTECIP EXHIBIT 2024
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2017-00022
`
`
`
`I, William Wargin, Ph.D., do hereby declare and say:
`
`1.
`
`I am over the age of twenty-one (21) and competent to make this
`
`declaration. I can give testimony under oath. The facts and opinions listed below are
`
`within my personal knowledge.
`
`2.
`
`I am not an employee of the Patent Owner in this matter. Rather, I have
`
`been engaged by the Patent Owner in this matter to provide my independent analysis
`
`of certain issues I understand arise in connection with the above-mentioned Petition
`
`for Post Grant Review of U.S. Patent No. 9,408,862 (which I refer to as the ’862
`
`Patent) (Exhibit 1003). I have received no compensation for this declaration beyond
`
`my normal hourly rate of $375/hr. for time actually spent studying the matter, and I
`
`will not receive any added compensation based on the outcome of any proceeding
`
`related to the ’862 Patent.
`
`3.
`
`I have been asked by the Patent Owner to review certain documents,
`
`including the ’862 Patent (Ex. 1001), and to provide my opinions on how those of
`
`skill in the art (as defined herein) would understand those documents. For purposes
`
`of this declaration, the documents I was asked to review include the Petition in the
`
`aforementioned proceeding, including the documents discussed therein.
`
`4.
`
`I was asked to provide an opinion about how much experimentation
`
`would be required by a person skilled in the art, based on the ’862 Patent’s
`
`specification, to make dosage forms of [oral] zoledronic acid that practice the ’862
`
`1
`
`
`
`
`Patent’s claims, and in particular, that achieve a bioavailability in the range of about
`
`1.1% to about 4%.
`
`5.
`
`I am not offering any conclusions as to the ultimate determinations that
`
`I understand the Board will make in this proceeding. I am simply providing my
`
`opinion on the technical aspects of the documents (including, where asked, the
`
`application of what I understand the Patent Owner asserts is the appropriate
`
`construction of claim terms for this proceeding and the appropriate level of skill for
`
`one of skill in the art).
`
`BACKGROUND
`
`6.
`
`I am Executive Vice President, Pharmacokinetics, at Nuventra Pharma
`
`Sciences, Inc. Nuventra is a clinical pharmacology consulting firm specializing in
`
`pharmacokinetics (PK), pharmacodynamics (PD), and pharmacometrics (popPK). I
`
`was co-founder of Nuventra which now consists of 60+ employees and consultants.
`
`7.
`
`I received a Ph.D. in Pharmacokinetics from the University of
`
`Minnesota in 1978 and began my career as an Assistant Professor at the University
`
`of North Carolina School of Pharmacy as an Assistant Professor in pharmaceutics.
`
`8.
`
`I transitioned to industry in 1983 at Burroughs Wellcome (later Glaxo
`
`Wellcome) where I held senior leadership positions in pharmacokinetics and project
`
`management until 2001.
`
`2
`
`
`
`
`9.
`
`The positions I held at Burroughs Wellcome and and Glaxo Wellcome
`
`included International Director of Clinical Pharmacology for Oncology, Anti-emesis
`
`& Anesthesiology and US Site Director, R&D Worldwide Project Planning.
`
`10. Since 2001, I have maintained a successful consultancy in early phase
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`pharmaceutical research and development with an emphasis on pharmacokinetics.
`
`11.
`
`I have worked with over 70 clients in the pharmaceutical and biotech
`
`industry and was an expert reviewer for the Biopharmaceutics Branch of the FDA.
`
`12.
`
`I am an author or co-author of over 30 journal articles in
`
`pharmacokinetics/biopharmaceutics
`
`13. My educational background, professional achievements, and
`
`qualifications are detailed in my curriculum vitae, which is attached. (Ex. 2004).
`
`14. For these reasons and because of my technical experience and training
`
`as outlined in my curriculum vitae (Ex. 2004 ), I believe I am qualified to offer
`
`technical opinions regarding the ’862 Patent and the other documents I reviewed
`
`as part of my work in this matter. I believe that I am capable of providing opinions
`
`about the state of the art in these areas at various points in time relevant to the
`
`present proceedings (e.g. from the 1980s to the present), as I have been familiar
`
`with the scientific and clinical developments by academics and scientists working
`
`in the pharmaceutical industry, including commercial work being done by those in
`
`the industry during this time.
`
`3
`
`
`
`
`PERSON SKILLED IN THE ART (“POSA”)
`
`15. A person of ordinary skill in the art (“POSA”) as it pertains to claims
`
`17-30 of ’862 Patent at the relevant time (as early as May 27, 2014) would have a
`
`Ph.D. in pharmacokinetics, pharmacodynamics, pharmaceutics, pharmacology,
`
`biochemistry, chemistry, or a related discipline, or an M.D., and experience
`
`formulating pharmaceutical dosage forms and studying their pharmacokinetics.
`
`16. The ’862 Patent’s disclosure teaches two things that a POSA would not
`
`have known as of May 27, 2014, i.e., that an effective bioavailability range for oral
`
`zoledronic acid is about 1.1% to about 4%, and that this is achievable without the
`
`use of enhancers.
`
`17. A POSA does not have to engage in undue experimentation to
`
`determine which salt or other forms of zoledronic acid do and which do not do not
`
`fall within the recited range in the ’862 claims. She need only employ the simple
`
`assay of Leonard, once she makes the forms, to determine the bioavailability of each
`
`form. Performing these assays would not require a lot of time. Since bioavailability
`
`or bioequivalence trials are the most commonly conducted Phase 1 pharmacokinetic
`
`studies, and are considered routine for any person skilled in the art.
`
`18.
`
` The time it takes to conduct the clinical component of a comparative
`
`bioavailability is dependent on the number of formulations and the half-life of the
`
`drug. Most of this time is required to allow the drug to clear the subject’s system
`
`4
`
`
`
`
`which is approximately 5 half-lives of the drug. Due to its half-life oral zoledronic
`
`acid would take about 1 week for each dosing regimen tested. Most of this time is
`
`required to allow the drug to clear the subject’s system. There is nothing about
`
`zoledronic acid that would lead me to expect that a clinical trial to determine
`
`bioavailability would be anything but routine.
`
`19. The ’862 Patent’s specification also gives ample guidance to a person
`
`skilled in the art to create the oral dosage forms. It requires taking a suitable form
`
`of zoledronic acid, as discussed above, and mixing it with excipients. This is
`
`described, for example, at col. 14, line 25 through col. 15, line 23. The claims also
`
`give guidance. Specific doses of zoledronic acid, e.g., 50 mg to 100 mg, are called
`
`out in claim 22, for example, to identify the amount of zoledronic acid in the dosage
`
`form.
`
`20. The ‘862 Patent specification discloses numerous representative
`
`excipients, as well as ranges of amounts of those excipients, that a POSA can use to
`
`make a dosage form. See, e.g., at col. 14, lines 64 through col. 15-line 17. These
`
`paragraphs identify one example of inactive ingredients that make up an operative
`
`dosage form, i.e., microcrystalline cellulose, polyvinyl pyrrolidone, silica, and
`
`magnesium stearate. This disclosure, without more, suffices to allow a person
`
`skilled in the art to formulate and make the dosage forms in a tablet or other form.
`
`5
`
`
`
`
`21. A person skilled in the art, based on the information contained in the
`
`‘862 specification, would know more than simply which inactive ingredients could
`
`be used to make a suitable dosage form. A person skilled in the art would have
`
`known that the inventor of the ’862 Patent had already disclosed that he had made
`
`and tested a dosage form containing 50 mg of zoledronic acid, or 50 mg of the
`
`disodium salt form of zoledronic acid, in a 100 mg tablet, i.e., that the dosage form
`
`tested by the inventor contained 50% active ingredient. (See Ex. 2023, U.S. Patent
`
`No. 9,283,239 (’239 Patent), at col. 19-20, and particularly col. 19, line 28, col. 20
`
`lines 40-41, and col. 20, lines 50-52.)
`
`22. The ’862 Patent’s specification provides specific guidance on what
`
`inactive ingredients to combine with the 50% active ingredient to make a dosage
`
`form. Specifically, the ’862 Patent’s disclosure states that a dosage form may
`
`comprise 20-75% microcrystalline cellulose, and it also calls out a narrow range of
`
`45-50% microcrystalline cellulose. It further identifies other excipients to be
`
`included, and specifically, crosslinked polyvinyl pyrrolidone, both in a broad range
`
`of 1-10% and a narrow range of 1-3%; fume silica, in broad range of 0.1 – 10% and
`
`a narrow range of 0.4-0.6%; and magnesium stearate, in a broad range of 0.1-10%
`
`and a narrow range of 0.4-0.6%. (Ex. 1001, ’862 Patent, at col. 14, lines 64 through
`
`col. 15-line 17.)
`
`
`6
`
`
`
`
`Excipient
`
`Narrow
`Range (%)
`
`Midpoint
`
`microcrystalline cellulose
`
`45-50
`
`crosslinked
`polyvinylpyrrolidone
`
`fumed silica
`
`magnesium stearate
`
`Total
`
`
`
`1-3
`
`0.4-0.6
`
`0.4-0.6
`
`
`
`47.5
`
`2
`
`0.5
`
`0.5
`
`50.5
`
`23. Simply choosing the midpoint of the narrow ranges would result in a
`
`dosage form that was 50% inactive ingredients. A POSA would know that this was
`
`likely to be or could be in a tablet form. The identity and percentages of excipients
`
`are included in the specifications of both the ’862 and ’239 patents, so a POSA would
`
`understand that the dosage form in the ’239 Patent could be used for the dosage form
`
`claimed in the ’862 patent, or at a minimum, that it would be a good starting point
`
`in selecting the non-active ingredients, including amounts.
`
`24.
`
`If a POSA knows, based on the ’239 Patent disclosure that one is using
`
`a dosage form that is 50% active ingredient, then making the dosage form in the ’862
`
`Patent is trivial based on the inventor’s disclosure of the ranges of non-active
`
`ingredients: 45-50% microcrystalline cellulose, 1-3% polyvinyl pyrrolidone, 0.4-
`
`0.6% fume silica, and 0.4-0.6% magnesium stearate. A POSA would recognize the
`
`narrow ranges of these excipients disclosed in the ‘862 disclosure together add up to
`
`7
`
`
`
`
`the 50% inactive ingredients to be combined with the 50% active ingredient,
`
`zoledronic acid, in the dosage form. A POSA would recognize that this formula is
`
`likely to be the dosage form in the ’862 Patent and could make the dosage form
`
`without undue experimentation. [Col. 14-line 64- col. 15 line 23]. A POSA would
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`have recognized this formula as being for an immediate release formulation, which
`
`can be prepared as a solid dosage form (e.g. a tablet) using well established steps of
`
`mixing, granulating, compressing, etc., and routine testing such as dissolution and
`
`stability testing. The ’862 disclosure, in other words, is more than sufficient to enable
`
`a POSA to make and use the dosage form.
`
`25.
`
`I understand that as to claims 3 and 4, Petitioner contends that the ’862
`
`Patent does not provide any data showing how the recited AUC range can be
`
`achieved. A person skilled in the art would immediately recognize how an AUC
`
`within the recited ranges can be achieved. It is known in the art that the AUC for
`
`oral zoledronic acid is dose proportional. (Ex. 2023 (’239 Patent), col. 20, ll. 28-
`
`29.) Thus, she would know, because it is a matter of definition, that there is a
`
`predictable relationship between dosage amount, bioavailability, and AUC. If one
`
`knows the bioavailability and the dose, one can calculate the AUC. Any two of these
`
`measurements will give you the third.
`
`26. The claims of the ’862 Patent give a person skilled in the art direction
`
`on how to achieve the AUC ranges in claims 3 and 4. For example, claim 9
`
`8
`
`
`
`
`designates a monthly dose of 200-300 mg. If administering 1 mg of intravenous
`
`zoledronic acid results in an AUC of 140 ng·hr/mL, and dosage form has a
`
`bioavailability of 2%, as specified, for example, at col. 13, lines 28-29 (about 1.8%
`
`to about 2%), then the AUC over one month (e.g. over a period defined by 4 weekly
`
`doses) would be about 560 ng·hr/mL for a monthly dose of 200 mg and about 840
`
`ng·hr/mL for 300 mg. The entire monthly dosage range of claim 9 is within the AUC
`
`range of claim 3.
`
`27. Claim 4, to give an example, can be achieved by giving the dosage form
`
`of claim 21 once. If administering 1 mg of intravenous zoledronic acid results in an
`
`AUC of 140 ng·hr/mL, administering 50 mg with a bioavailability of 2% would
`
`result in an AUC of about 140 ng·hr/mL. Administering 100 mg with a
`
`bioavailability of 2% would result in an AUC of 380 ng·hr/mL. Thus, the entire
`
`dosage range of claim 21 would fall within the AUC range of claim 4.
`
`28. Claims 18, 19, 20, and 21 all encompass 50 mg of zoledronic acid. So,
`
`if administering 1 mg of intravenous zoledronic acid results in an AUC of 140
`
`ng·hr/mL, and the dosage form has a bioavailability of 2%, following the dosage
`
`form of any of these claims will result in a commensurate AUC, about 140 ng·hr/mL,
`
`that falls within the range of Claim 4.
`
`29.
`
`If the 50 mg dosage forms of claims 18, 19, 20, and 21 referred to in ¶
`
`27 are given once a week, over a four-week period, as in Claim 12, administering
`
`9
`
`
`
`
`the 50 mg will result in an AUC of 560 ng·hr/mL, which falls within the AUC range
`
`of claim 3.
`
`30. Thus, the bioavailability and doses of the claims lead a person skilled
`
`in the art right to the AUC ranges recited in claims 3 and 4. All she has to do is try
`
`the doses in some of the claims, and he or she will achieve an AUC in the recited
`
`range. That is all that enablement would require. Again, there are three related
`
`variables—dosage amount, bioavailability, and AUC—and three types of claims that
`
`cover that relationship.
`
`31. The short answer is, a POSA can readily follow the claims of the ‘862
`
`patent, calculating the AUC based on the dose and bioavailability prescribed by
`
`those claims, to obtain the recited range of AUC in claims 3 and 4.
`
`32. The bioavailability ranges that Dr. Wilson derived from Leonard-
`
`2.54% to 5.77% and 6.53% to 12.99% (Ex. 1005 (Wilson Decl.), ¶¶ 100-101), are
`
`simply point estimates that are typically calculated as the ratio of the geometric least
`
`squares means (GLSMs) of a test and reference formulation. These ranges are
`
`derived from a statistical range that identifies, to 90% confidence, where the actual
`
`bioavailability of the dosage form will lie, but does not necessarily include that 90%
`
`confidence interval as these need to be derived from a study relative bioavailability
`
`study. The 90% confidence intervals are therefore dependent on the study design
`
`including the number of subjects in the study.
`
`10
`
`
`
`
`33. Thus, to the extent that the experiment that gave rise to the 90%
`
`confidence interval can be reproduced, the entire 90% confidence interval, not just
`
`part of it, is more or less a property of the dosage form itself as it is compared to the
`
`reference formulation. A POSA could not simply choose a new 90% confidence
`
`interval for bioavailability that overlaps or lies within Leonard’s 90% confidence
`
`interval, do the same experiment, and expect the dosage form to have a substantially
`
`different 90% confidence interval.
`
`34. A POSA cannot simply carve up a 90% confidence interval to suit her
`
`purposes. In order to have a substantially different 90% confidence interval for
`
`bioavailability in a reproducible experiment, you would need to have a substantially
`
`different dosage form. Thus, for example, a dosage form that had a 90% confidence
`
`interval for bioavailability that is 1.1% to 4% would never be the same thing as a
`
`dosage form that had a 90% confidence interval for bioavailability that was 2.54%
`
`to 5.77%. Thus, the 90% confidence intervals in Leonard do not describe a dosage
`
`form of the claims.
`
`35. Normally, when a POSA refers to bioavailability, it is assumed that the
`
`value is that achieved by fasting the subject sufficiently long that the bioavailability
`
`is not reduced.
`
`36. For example, Leonard states that “[t]he oral bioavailability of
`
`alendronate is very low and independent of the dose (5-80 mg), averaging 0.76% in
`
`11
`
`
`
`
`women and 0.59% in men. (Ex. 1009 (Leonard), col. 2, ll. 35-37.) Leonard then
`
`explains that food and medication can reduce bioavailability. (Ex. 1009 (Leonard),
`
`col. 2, lines 42-47.)
`
`37.
`
`In Merrion Poster, the fasting parameters were adjusted to determine
`
`how long a subject should be fasted to achieve the bioavailability that a POSA
`
`normally refers to as the bioavailability of the drug. (Ex. 1040 (Merrion Poster),
`
`middle column, “MER-102-02 Study.”) Because the Merrion poster experiments
`
`with fasting parameters, many of the 90% confidence intervals in Merrion Poster do
`
`not actually reflect what a POSA would consider to be the bioavailability of the
`
`Leonard/Merrion dosage forms. Thus, many of Merrion Poster’s ranges describe
`
`something different than the bioavailability range of the claims.
`
`38. For example, Dr. Wilson’s declaration identifies a bioavailability 90%
`
`confidence interval of 1.7-6.4% for the “15 mg Tablet Fasted,” 1.88-5.4% for the
`
`“20 mg Tablet Fasted,” and 0-2.35% for the “20 mg Tablet Fed.” (Ex. 1005 (Wilson
`
`Decl.), ¶¶ 109.) However, according to Merrion Poster, the two “Fasted” groups
`
`were fasted for 30 minutes or less. (Ex. 1040 (Merrion Poster), middle column,
`
`“MER-101-02 Study” and right column, “Tables.”) Merrion Poster states “Post-
`
`dose fasting time impacts bioavailability. A half-hour fast is not sufficient in all
`
`patients.” (Ex. 1040 (Merrion Poster), middle column, “Results.”) Similarly, with
`
`respect to the “Fed” group, Merrion Poster states “Administration of the 20mg tablet
`
`12
`
`
`
`
`with food results in a large reduction in bioavailability.” (Ex. 1040 (Merrion Poster),
`
`middle column, “Overall Conclusions.”)
`
`39. Furthermore, a POSA would recognize that the 90% confidence
`
`intervals for these three groups do not actually represent the 90% confidence
`
`intervals for any group because many of the patients were excluded because of poor
`
`results. For the 28 subjects in the “15 mg Fasted” group, 7 subjects had “no
`
`absorption” and 11 subjects had “poor absorption.” (Ex. 1040 (Merrion Poster),
`
`right column, third table.) According to Merrion Poster, the 90% confidence
`
`intervals reported for AUC “excludes all subjects with substantial food
`
`effects.” (Ex. 1040 (Merrion Poster), right column, first and second tables). Thus,
`
`the 90% confidence interval in Wilson’s declaration for this group only reflects the
`
`bioavailabilities of 10 of the 28 subjects in the group. Similarly, for the 27 subjects
`
`in the “20 mg Fasted” group, 3 subjects had “no absorption” and 7 subjects had “poor
`
`absorption.” (Ex. 1040 (Merrion Poster), right column, third table.) Thus, the 90%
`
`confidence interval in Wilson’s declaration for this group only reflects the
`
`bioavailabilities of 17 of the 28 subjects in the group. Finally, for the 26 subjects
`
`in the “20 mg Fed” group, 7 subjects had “no absorption” and 21 subjects had “poor
`
`absorption.” (Ex. 1040 (Merrion Poster) right column, third table.) Thus, the 90%
`
`confidence intervals for bioavailability for these groups do not actually reflect what
`
`a person of ordinary skill in the art would view as the bioavailability of Merrion’s
`
`13
`
`
`
`
`
`
`-:-—:‘:sage forms. As a result. they do not describe the same type of range as the ‘862
`
`claims. The remaining 90% confidence interval from Merrion POSter that
`
`IS
`
`calculated in Dr. Wilson’s declaration "LS-11.5% does not overlap with the
`
`claims. Thus, Merrion Poster describes a dosage iorm that is materially curterem
`
`lIOIIl are Claims, and Leonard and lvierrion do not describe the dosage form claimed
`
`in the 'GOA patent.
`
`I declare that all statements made of my own knowledge are true and that all
`
`statements made on information and belief are believed to be true. and that these
`
`statements were made with the knowledge that willful false statements and the like
`
`are punishable bv fine or imorisonment. or beth. under secrion l001 chi-flc \? vi
`
`the United States Coil—
`
`date: February 8, 2018
`
`m
`
`www
`William Wargin
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`1/3
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`
`
`
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