Trials@uspto.gov
`Tel: 571-272-7822
`
`
`Paper 48
`Entered: April 29, 2019
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`GRÜNENTHAL GMBH,
`Petitioner,
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`Patent Owner.
`____________
`
`Case PGR2018-00001
`Patent 9,539,268 B2
`____________
`
`
`Before TONI S. SCHEINER, GRACE KARAFFA OBERMANN, and
`SHERIDAN K. SNEDDEN, Administrative Patent Judges.
`
`OBERMANN, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`Determining that Claims 3–30 are Unpatentable
`35 U.S.C. § 328(a)
`
`
`
`
`
`
`
`
`
`

`

`PGR2018-00001
`Patent 9,539,268 B2
`
`
`I. INTRODUCTION
`
`This is a post-grant review of claims 3–30 of U.S. Patent
`
`No. 9,539,268 B2 (Ex. 1001, “the ’268 patent”). Prior to institution of
`
`review, Patent Owner filed a statutory disclaimer of claims 1 and 2.
`
`Paper 13; Ex. 2008. We instituted review of claims 3–30 based on the
`
`grounds stated in the Petition (Paper 2, “Pet.”). See Paper 17 (“Dec.”), 2, 8–
`
`9, 38. Thereafter, in timely sequence, Patent Owner filed a Response
`
`(Paper 22, “Resp.”), Petitioner filed a Reply (Paper 36), and Patent Owner
`
`filed a Surreply (Paper 39). This decision resolves also Petitioner’s Motion
`
`to Exclude Evidence (Paper 40) and Patent Owner’s Motion to Exclude
`
`Evidence (Paper 42). We held a final oral hearing on February 7, 2019.
`
`Paper 47 (“Tr.”). The Board has jurisdiction under 35 U.S.C. § 6. We issue
`
`this Final Written Decision pursuant to 35 U.S.C. § 328(a).
`
`A.
`
`Related Proceedings
`
`The parties identify no related administrative or judicial proceedings.
`
`Pet. 4; Paper 3, 1. According to Petitioner, “[t]he ’268 patent is a
`
`continuation of the application that issued as Patent Owner’s U.S. Patent
`
`No. 9,408,862” (“the ’862 patent”), noting that the two patents “have nearly
`
`identical specifications.” Pet. 4. Petitioner states that it filed a post grant
`
`review of the ’862 patent on May 8, 2017, PGR2017-00022 (“PGR022”).
`
`Pet. 4. The Board entered a final written decision in PGR022 on
`
`November 14, 2018, and Patent Owner filed a notice of appeal of that
`
`decision. PGR022, Papers 50, 52. Petitioner states also that a patent in a
`
`different family involving similar technology is under challenge in
`
`PGR2017-00008 (“PGR008”), which involves the same parties as this
`
`
`
`2
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`

`

`PGR2018-00001
`Patent 9,539,268 B2
`
`proceeding. Pet. 4; see also Paper 3, 2. The Board entered a final written
`
`decision in PGR008 on June 22, 2018. PGR008, Paper 43.
`
`B. The ’268 Patent (Ex. 1001)
`
`The ’268 patent discloses that pharmaceutical compositions
`
`containing “zoledronic acid, Compound 1, and/or Compound 2 (subject
`
`compositions), may be used for a number of medical purposes, such as
`
`treatment of undesirable conditions or diseases, including disease or
`
`conditions related to bone, cancer, and/or pain.” Ex. 1001, 1:63–2:1.
`
`According to the ’268 patent:
`
`An oral dosage form comprising a subject composition
`may be used to treat, or provide relief of, any type of pain
`including, but not limited to, inflammatory pain, arthritis pain,
`complex regional pain syndrome, lumbosacral pain,
`musculoskeletal pain, neuropathic pain, chronic pain, cancer-
`related pain, acute pain, postoperative pain, etc. In some
`instances, pain relief may be palliative, or pain relief may be
`provided independent of improvement of the disease or
`condition or the underlying cause of the disease or condition.
`For example, although the underlying disease may not improve,
`or may continue to progress, an individual suffering from the
`disease may experience pain relief. In some embodiments,
`enhanced bioavailability of the zoledronic acid may be achieved
`in treating one of these conditions by administering a dosage
`form comprising a subject composition wherein zoledronic acid
`is in the form of a disodium salt. This may allow a reduced
`molar amount of the disodium salt to be used as compared to
`what would be used with the diacid form.
`
`Id. at 2:28‒46.
`
`The ’268 patent discloses that zoledronic acid “is also referred to as
`
`zoledronate” and has the structure shown in the following figure:
`
`
`
`3
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`

`

`PGR2018-00001
`Patent 9,539,268 B2
`
`
`Id. at 5:66–6:10. The figure above shows the molecular structure of
`
`
`
`zoledronic acid. Id.
`
`The ’268 patent discloses:
`
`The oral bioavailability of zoledronic acid in a subject
`composition may be enhanced by orally administering the
`zoledronic acid in the disodium salt form. For example, the
`bioavailability of zoledronic acid may be improved by at least
`about 10%, at least about 20%, at least about 30%, at least
`about 50%, and/or up to about 100%, or up to about 200%, as
`compared to administration of zoledronic acid in the diacid
`form.
`
`Id. at 7:65–8:5.
`
`According to the ’268 patent:
`
`Because of the improved bioavailability of the disodium
`salt a dosage form may contain, or a mammal, such as a human
`being, may receive, on a molar basis, less of the disodium salt
`form of zoledronic acid than would otherwise be administered
`of the diacid form of zoledronic acid. For example, a dosage
`form may contain, or a mammal may receive, at least about
`10 mole % less, at least about 20 mole % less, at least about
`40 mole % less, at least about 50 mole % less, and/or up to
`about 90 mole % less or 95 mole % less, of the disodium salt
`form as compared to the amount of the diacid form of
`zoledronic acid that would otherwise be administered, such as a
`molar amount that would be administered of zoledronic acid in
`the diacid form in order to achieve the same plasma levels of
`zoledronic acid.
`
`Id. at 8:6‒19.
`
`
`
`4
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`

`

`PGR2018-00001
`Patent 9,539,268 B2
`
`
`
`The ’268 patent includes only one working example, which describes
`
`syntheses for compounds 1 and 2. Id. at 18:12‒19:18 (Example 1).
`
`The ’268 patent contemplates multiple embodiments. Id. at 19:19‒27:58.
`
`C.
`
`The Challenged Claims
`
`Claims 1 and 2 of the ’268 patent are disclaimed and no longer in
`
`dispute. Prelim. Resp. 3, Paper 13. Claims 3 and 23 are the remaining
`
`challenged independent claims of the ’268 patent and read as follows:
`
`3. A method of treating arthritis comprising orally
`administering a dosage form to a human being suffering from
`arthritis, wherein the dosage form comprises:
`a) zoledronic acid in a salt or an acid form; or
`b) one of the following:
`1) zoledronic acid in a salt or an acid form
`
`and
`
`
`
`
`(Ion 1) in a salt form, in an amount that is less than
`0.1% w/w and greater than 0% w/w; or
`2) zoledronic acid in a salt or acid form and
`
`
`(Ion 2) in a salt form, in an amount that is less than
`0.1% w/w and greater than 0% w/w;
`
`or
`
`3) zoledronic acid in a salt form or an acid
`form and a combination of Ion 1 in a salt form, in
`an amount that is less than 0.1 % w/w and greater
`
`
`
`5
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`

`

`PGR2018-00001
`Patent 9,539,268 B2
`
`
`than 0% w/w, and Ion 2 in a salt form, in an
`amount that is less than 0.1 % w/w and greater
`than 0% w/w;
`wherein the dosage form is free of
`therapeutically active agents that are not
`zoledronic acid in a salt or acid form, Ion 1 in a
`salt form, or Ion 2 in a salt form;
`wherein any amount in % w/w is based upon
`the total weight of zoledronic acid in a salt or an
`acid form, Ion 1, Ion 2, and any corresponding
`counter ions; and
`wherein the bioavailability of zoledronic
`acid in the dosage form is from about 1.1% to
`about 4%.
`
`23. A pharmaceutical dosage form for oral
`administration comprising:
`a) zoledronic acid in a salt form; or
`b) one of the following:
`1) zoledronic acid in a salt or an acid form
`
`and
`
`
`(Ion 1) in a salt form, in an amount that is less than
`0.1% w/w and greater than 0% w/w;
`2) zoledronic acid in a salt or an acid form
`
`
`
`and
`
`
`(Ion 2) in a salt form, in an amount that is less than
`0.1% w/w and greater than 0% w/w; or
`
`
`
`6
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`PGR2018-00001
`Patent 9,539,268 B2
`
`
`3) zoledronic acid in a salt or an acid form
`and a combination of Ion 1 in a salt form, in an
`amount that is less than 0.1 % w/w and greater
`than 0% w/w, and Ion 2 in a salt form, in an
`amount that is less than 0.1 % w/w and greater
`than 0% w/w;
`wherein the dosage form is free of
`therapeutically active agents that are not
`zoledronic acid in a salt or acid form, Ion 1 in a
`salt form, or Ion 2 in a salt form;
`wherein any amount in % w/w is based upon
`the total weight of zoledronic acid in a salt or an
`acid form, Ion 1, Ion 2, and any corresponding
`counter ions; and
`wherein the bioavailability of zoledronic
`acid in the dosage form is from about 1.2% to
`about 4% in a human being.
`
`Ex. 1001, 29:20–61, 30:56–32:3.
`
`D.
`
`The Asserted Grounds of Unpatentability
`
`As discussed above, Patent Owner filed a disclaimer of claims 1 and 2
`
`of the ’268 patent; accordingly, we do not discuss claims 1 and 2, or the two
`
`grounds in the Petition directed solely to claims 1 and 2, in this decision.
`
`See 37 C.F.R. § 42.207(e) (“No post-grant review will be instituted based on
`
`disclaimed claims.”). The following chart identifies the challenges
`
`remaining in dispute following disclaimer of claims 1 and 2.
`
`Claims
`
`Statutory Basis
`
`References
`
`3–30
`
`15
`
`35 U.S.C. § 112(a)
`(lack of enablement)
`
`35 U.S.C. § 112(b)
`(indefiniteness)
`
`
`
`
`
`
`
`7
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`

`

`PGR2018-00001
`Patent 9,539,268 B2
`
`
`Claims
`
`Statutory Basis
`
`References
`
`15–22
`
`35 U.S.C. § 112(a)
`(lack of enablement)
`
`23
`
`23
`
`23–30
`
`3–15
`
`
`
`35 U.S.C. § 102
`(anticipation)
`
`35 U.S.C. § 103
`(obviousness)
`
`35 U.S.C. § 103
`(obviousness)
`
`35 U.S.C. § 103
`(obviousness)
`
`
`
`Leonard
`
`Leonard
`
`Leonard, Aronhime, Merrion Poster
`
`Fox, Laslett, Leonard, Merrion
`Poster
`
`The Petition is supported by a declaration of Stephen Bruehl, Ph.D.
`
`(Ex. 1003) and a declaration of Clive G. Wilson, Ph.D. (Ex. 1005). The
`
`Response is supported by a declaration of Dr. William Wargin (Ex. 2017).
`
`II. ANALYSIS
`
`As an initial matter, the parties agree that the ’268 patent is eligible
`
`for post-grant review. Pet. 5–6; Tr. 40:1–6. We organize our analysis into
`
`three parts. First, we resolve the ordinary skill level in the art. Second, we
`
`address claim construction. Third, we consider whether claims 3–30 are
`
`unpatentable for lack of enablement under 35 U.S.C. § 112(a).
`
`A. A Person of Ordinary Skill in the Art
`
`Petitioner offers two different definitions pertaining to the person of
`
`ordinary skill in the art at the time of the invention: one for claims 3‒22 and
`
`one for claims 23‒30. Pet. 9‒10. As to claims 3‒22, Petitioner contends an
`
`ordinarily skilled artisan would have had “an M.D. or a Ph.D. in a pain-
`
`medicine-relevant discipline, such as clinical health psychology or
`
`
`
`8
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`PGR2018-00001
`Patent 9,539,268 B2
`
`neuroscience, and at least 3-5 years of experience in the treatment of arthritis
`
`or related chronic pain conditions, or in the study of arthritis or related types
`
`of chronic pain.” Id. at 9 (citing Ex. 1003 ¶¶ 27‒31). Petitioner asserts an
`
`ordinarily skilled artisan would also have had “knowledge and experience in
`
`formulating pharmaceutical dosage forms and studying their
`
`pharmacokinetics, or have access to a person with such knowledge and
`
`experience.” Id. at 9‒10. As to claims 23‒30, Petitioner contends that an
`
`ordinarily skilled artisan generally would have had “a Ph.D. in biochemistry,
`
`medicinal chemistry, pharmacology, pharmaceutics, or a related discipline,
`
`and at least 3‒5 years of experience in formulating pharmaceutical dosage
`
`forms and studying their pharmacokinetics,” but may have had less formal
`
`education and more work experience. Id. at 10.
`
`
`
`Patent Owner counters that, as to claims 3–22, one of ordinary skill
`
`would have had “a degree related to drug development in the pain area, such
`
`as an M.D., a Pharm.D., or a Ph.D. in a drug development-related field, such
`
`as formulation or medicinal chemistry, biology, pharmacology, or
`
`pharmacokinetics, and experience in supervising, carrying out, or
`
`collaborating in animal or human testing, including off-label treatment of
`
`patients, related to drug development in the pain area.” Resp. 10. As to
`
`claims 23‒30, we understand Patent Owner to argue1 that one would have
`
`had “a Ph.D. in pharmacokinetics, pharmacodynamics, pharmaceutics,
`
`pharmacology, biochemistry, chemistry, or a related discipline, or an M.D.,
`
`
`1 We determine that Patent Owner intends to mirror Petitioner’s claim
`groupings, even though Heading II.B of Patent Owner’s Response refers to
`“[c]laims 22–30” and the accompanying argument refers to “claims 17–30.”
`Resp. 10. In any event, no combination of claim groupings would alter our
`ultimate decision that the specification does not enable claims 3–30.
`
`
`
`9
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`PGR2018-00001
`Patent 9,539,268 B2
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`and experience formulating pharmaceutical dosage forms and studying their
`
`pharmacokinetics.” Id. at 10–11.
`
`For purposes of this decision, we adopt Patent Owner’s definitions;
`
`however, we would reach the same conclusion on enablement even under
`
`Petitioner’s proposed levels of ordinary skill. In our view, moreover, the
`
`prior art itself demonstrates the level of skill in the art at the time of the
`
`invention. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001)
`
`(explaining that specific findings regarding the ordinary skill level are not
`
`required “where the prior art itself reflects an appropriate level and a need
`
`for testimony is not shown”) (quoting Litton Indus. Prods., Inc. v. Solid
`
`State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985)).
`
`B. Claim Construction
`
`The Board interprets claims in an unexpired patent using the broadest
`
`reasonable construction in light of the specification of the patent in which
`
`they appear. 37 C.F.R. § 42.200(b) (2018).2 Under that standard, we assign
`
`claim terms their ordinary and customary meaning as understood by one of
`
`ordinary skill in the art at the time of the invention, within the context of the
`
`entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed.
`
`Cir. 2007). Only claim terms in controversy need be construed, and then
`
`only to the extent necessary to resolve the dispute. Vivid Techs., Inc. v. Am.
`
`Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999). We determine that
`
`no claim term requires express construction for purposes of this decision.
`
`
`2 A recent amendment to this rule does not apply here, because the Petition
`was filed before November 13, 2018. See “Changes to the Claim
`Construction Standard for Interpreting Claims in Trial Proceedings Before
`the Patent Trial and Appeal Board,” 83 Fed. Reg. 51,340 (Oct. 11, 2018)
`(amending 37 C.F.R. § 42.200(b) effective November 13, 2018).
`
`
`
`10
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`

`PGR2018-00001
`Patent 9,539,268 B2
`
`
`C. Enablement—Claims 3–30
`
`In this section, we assess whether the disclosure of the ’268 patent
`
`specification is sufficient to permit the ordinarily skilled artisan to select,
`
`make, and use pharmaceutical dosage forms that enable the full scope of
`
`bioavailability ranges set forth in claims 3–30.3 Pet. 16‒27; Resp. 11–42;
`
`Reply 22–24; Surreply 15–20.
`
`i. Analysis
`
`In Petitioner’s view, the ’268 patent “specification does not teach” an
`
`ordinarily skilled artisan “how to make and use any dosage form having a
`
`zoledronic acid bioavailability within the claimed ranges.” Pet. 16. In that
`
`regard, we find that claims 3–30 broadly embrace zoledronic acid in a salt or
`
`acid form, with or without the addition of one or more bioavailability-
`
`enhancing ingredients. Ex. 1001, claims 3 and 23 (the independent claims).
`
`The touchstone of enablement is whether undue experimentation
`
`would have been required to practice the claimed invention. In re Wands,
`
`858 F.2d 731, 737 (Fed. Cir. 1988) (listing non-exclusive factors to assist in
`
`making this determination). Petitioner addresses the Wands factors in its
`
`challenge to the claims. Pet. 17–27. We consider those factors below.
`
`a. The Nature of the Invention, Level of Skill in the Art,
`and Unpredictability of the Art
`
`Claims 3–30 are drawn to pharmaceutical dosage forms, or methods
`
`of administering those forms, comprising zoledronic acid of a specified
`
`bioavailability. Ex. 1001, 29:20–32:34 (claims 3–30); Pet. 18. Claim 3
`
`
`3 We decline to address a second enablement ground, based on area-under-
`the-curve limitations of claims 15–22, which stands or falls with our
`resolution of the instant enablement ground. Dec. 26–29.
`
`
`
`11
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`

`PGR2018-00001
`Patent 9,539,268 B2
`
`“covers dosage forms wherein the zoledronic acid bioavailability is from
`
`about 1.1% to about 4%,” and the remaining claims have that limitation, or
`
`more narrowly define a high endpoint of 3% bioavailability. Id.
`
`
`
`The claimed invention, according to Dr. Wilson, Petitioner’s witness,
`
`is within the unpredictable field of pharmaceutical formulations. Pet. 18
`
`(citing Ex. 1005 ¶ 60). An ordinarily skilled artisan would have expected
`
`that “different dosage forms of the same drug may have different
`
`bioavailabilities” and, further, that “[v]arious properties of the active
`
`ingredient, including the crystal form, salt form, wettability, solubility, and
`
`particle size of the active ingredient, and the particular excipients and
`
`manufacturing process used to make the dosage form, can also have
`
`unpredictable effects on bioavailability.” Id. at 18‒19 (citing Ex. 1005
`
`¶ 60). Patent Owner does not dispute those factual contentions, and offers
`
`no reasons why Petitioner’s witness, Dr. Wilson, is wrong in describing the
`
`relevant field as unpredictable. See generally Resp.; Surreply.
`
`b. The State of the Prior Art
`
`“Zoledronic acid and zoledronic acid salts were known in the art at
`
`least as early as 2000,” and one asserted prior art reference, Aronhime,
`
`“disclosed eleven different disodium salt forms.” Pet. 19 (citing Ex. 1034;
`
`Ex. 1035, 3:30‒4:7, 8:22‒11:1; Ex. 1005 ¶¶ 140‒142). An ordinarily skilled
`
`artisan would have understood and expected that bisphosphonates, such as
`
`zoledronic acid, have poor bioavailability, and that, in the absence of
`
`enhancement, the bioavailability in a human would be 1% or lower. Id.
`
`at 19‒20 (citing Ex. 1005 ¶¶ 66‒67; Ex. 1027 ¶ 6; Ex. 1028, 184; Ex. 1029,
`
`122, 124; Ex. 1030, 395‒397).
`
`
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`12
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`Patent 9,539,268 B2
`
`
`Patent Owner confirms that an ordinarily skilled artisan would have
`
`“believed that the oral bioavailability in humans of all forms for zoledronic
`
`acid could not be above 1% without an enhancer.” Resp. 1 (emphasis in
`
`original). “Without ingredients or other methods to enhance
`
`bioavailability,” the ordinarily skilled artisan would have expected all
`
`dosage forms of zoledronic acid to have relatively low bioavailabilities that
`
`fall outside the ranges specified in the challenged claims. Pet. 20 (citing
`
`Ex. 1001, 13:57‒59). The critical inquiry is whether the specification
`
`contains disclosure that, in the face of that expectation, would have guided
`
`the artisan to a selection of zolendronic acid dosage forms, with or without
`
`enhancers, sufficient to attain the full range of claimed bioavailabilities of at
`
`least 1.1% and up to 3% or 4%. Aronhime discloses at least 22 dosage
`
`forms of zoledronic acid, including eleven disodium salt forms. Pet. 23;
`
`Resp. 20. An ordinarily skilled artisan would have expected that those
`
`eleven disodium salt forms could have different properties, including
`
`different solubilities and bioavailabilities. Pet. 23 (citing Ex. 1034;
`
`Ex. 1035, 3:30‒4:7; 8:22‒11:1; Ex. 1005 ¶ 70).
`
`c. The Breadth of the Claims, Lack of Guidance, and
`Absence of Working Examples
`
`Claims 3–30 are “broad, covering any oral zoledronic acid dosage
`
`form having the claimed bioavailabilities.” Pet. 20. The claims employ the
`
`transitional phrase “comprising” and, thus, are open to the inclusion of
`
`bioavailability-enhancing ingredients. Id.
`
`The specification does not disclose any examples of zoledronic acid
`
`dosage forms and identifies no bioavailability-enhancing ingredients that
`
`may be added to improve zoledronic acid’s bioavailability to at least 1.1%.
`
`Ex. 1005 ¶ 69; Pet. 21–22. Nor does the specification contain
`
`
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`13
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`Patent 9,539,268 B2
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`pharmacokinetic data identifying any zoledronic acid dosage forms that will
`
`achieve a bioavailability in humans that falls within the scope of the claims.
`
`Ex. 1005 ¶¶ 64‒65, 69; Pet. 21–22. On that point, even Dr. Wargin, Patent
`
`Owner’s witness, agrees that the specification is silent:
`
`Q. There is no actual data on any particular dosage form of
`
`zoledronic acid regarding bioavailability?
`
`A. There is no actual data, that’s true.
`
`Ex. 1093, 89:17–22 (deposition transcript); Reply 18.
`
`
`
`The ’268 patent informs that “[t]he oral bioavailability of zoledronic
`
`acid may be enhanced by orally administering the zoledronic acid in the
`
`disodium salt form.” Ex. 1001, 7:65–67. The ’268 patent also informs that
`
`the disodium salt form of zoledronic acid “is much more soluble in water
`
`than the diacid form” and, therefore, “may be more bioavailable” or “more
`
`rapidly absorbed when taken orally as compared to the diacid form.”
`
`Ex. 1001, 6:31‒36. The claims, however, are not limited to the disodium
`
`salt form. Ex. 1001, 2:39‒65, 3:9‒13; Pet. 22; Ex. 1005 ¶ 68.
`
`The specification acknowledges that the bioavailability of zoledronic
`
`acid may be as low as 0.01%. Ex. 1001, 14:8–11. Without providing any
`
`data or guidance for identifying workable dosage forms, the specification
`
`states that the bioavailability of zoledronic acid may be enhanced by as
`
`much as 200% by administering the diacid form. Id. at 7:67–8:5. However,
`
`Dr. Wargin, Patent Owner’s witness, likened the belief “that some salt forms
`
`of oral zolendronic acid” could “provide oral bioavailability, without
`
`enhancers, to within the range of 1.1%” (the lowest bioavailability embraced
`
`by the claims) to a “belie[f] in ‘fairies.’” Resp. 1 (quoting Ex. 2014,
`
`137:21–138:8). The specification includes “hypothetical values” pertaining
`
`
`
`14
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`

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`Patent 9,539,268 B2
`
`to the bioavailability ranges that may be desired, but no actual data obtained
`
`from any dosage form, or any other information explaining how to make a
`
`dosage form having a bioavailability that falls within the claimed ranges.
`
`Ex. 1093, 129:7–130:10; see Reply 18–19; Ex. 1001, 8:20–35.
`
`d. The Quantity of Experimentation Required
`
`Petitioner contends that “the complete lack of guidance and
`
`information in the specification” results in a situation where the ordinarily
`
`skilled artisan “would not have known where to begin in trying to formulate
`
`a dosage form having the claimed bioavailabilities.” Pet. 24‒25 (citing
`
`Ex. 1005 ¶ 74). Patent Owner counters that the inventors disclosed a
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`“disodium zoledronate tetrahydrate form”—not in the disclosure of the
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`specification, but rather, in a “public reference that predates the” patent “and
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`is presumed to be part of the [ordinarily skilled artisan’s] knowledge.”
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`Resp. 31 (citing Ex. 1074).
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`Setting aside for a moment whether that extrinsic evidence can
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`substitute for disclosure in the specification to provide enabling support for
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`the inventive aspects of the claimed invention, we observe that the public
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`reference advanced by Patent Owner describes the bioavailability of
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`zoledronic acid in beagle dogs. Pet. 25; Ex. 1074, Fig. 8, ¶¶ 142–146 (U.S.
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`Patent Publication No. 2014/0051669, reporting the results of a dog study).
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`An ordinarily skilled artisan would have recognized that bioavailability in
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`humans differs from bioavailability in beagle dogs due, for example, to
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`differences in gastric pH and emptying rate. Pet. 25 (citing Ex. 1005 ¶ 105,
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`Ex. 1087; Ex. 1088). Beagles have a more basic gut pH than humans, which
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`may make acidic drugs like zoledronic acid more soluble and more
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`bioavailable in beagles as compared to humans. Id. The beagle dog study,
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`therefore, would not have provided sufficient guidance to an ordinarily
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`skilled artisan seeking to practice the full scope of the challenged claims,
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`including the limitations that require dosage forms having a bioavailability
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`of up to 3% or 4% in a human being. Resp. 31; Reply 20–21. Patent
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`Owner’s witness agrees that an ordinarily skilled artisan would not have
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`understood bioavailability data obtained from dogs to correlate well to
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`humans. Reply 21 (citing Ex. 1011, 34:4–19, 35:1–10).
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`Patent Owner further argues that the “specification tells an” ordinarily
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`skilled artisan “that the recited range of about 1.1% to about 4% is
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`achievable without using enhancers.” Resp. 24 (citing Ex. 1001, 7:65–8:6,
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`13:62). That observation is not persuasive to show that the specification
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`tells an ordinary artisan how to achieve the recited range. Even Dr. Wargin
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`admits, “we don’t know today whether any of the salt forms in Aronhime
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`[aside from Form VII], if tested, would have a bioavailability within the
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`ranges claimed in the ’268 patent.” Ex. 1093, 37:1–7 (emphasis added).
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`Dr. Wargin explains that ascertaining the bioavailability of a dosage
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`form would have required a year’s worth of effort and cost about one million
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`dollars. Ex. 1093, 79:24–80:20. Patent Owner contends that such an
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`endeavor would have been “routine,” dismissing any difficulty involved in
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`ascertaining which forms of zoledronic acid, and which bioavailability-
`
`enhancing ingredient (if any), would have been logical starting points for so
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`expensive and time-consuming an exercise. See Surreply 19–20. Patent
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`Owner argues that the testimony of its own witness should be discounted
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`because it relates to a phase one study (id.), but a fair reading of the
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`testimony reveals that the million-dollar figure and one-year time frame
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`identified by Dr. Wargin would have applied to an ordinarily skilled
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`artisan’s efforts to ascertain whether any given dosage form would exhibit “a
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`bioavailability within the claimed range.” Ex. 1093, 79:25–80:20; see
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`Pet. 24–27 (and evidence cited therein); Reply 21 (and evidence cited
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`therein).
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`Perhaps because the guidance provided within the four corners of the
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`specification is so scant, Patent Owner looks outside the disclosure of the
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`patent for information that may have guided an ordinarily skilled artisan’s
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`selection of dosage forms. Resp. 13–20, 31. “It is the specification,”
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`however, “not the knowledge of one skilled in the art, that must supply the
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`novel aspects of an invention in order to constitute adequate enablement.”
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`Genentech Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1366 (Fed. Cir. 1997).
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`On that point, we find it significant that Patent Owner’s witness, Dr. Wargin,
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`was unable to identify disclosure “in the ’268 patent that says that the
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`bioavailability of the disodium salt” form of “zoledronic acid actually falls
`
`within any of the claimed ranges.” Ex. 1093, 89:24–90:3.
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`e. Weighing the Wands Factors
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`The specification provides no guideposts that would have illuminated
`
`a path toward even one dosage form that has a bioavailability that falls
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`within the scope of any claim. See, e.g., Ex. 1001, 29:20–61, 30:56–32:3.
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`Unmodified zoledronic acid would have been understood to have an oral
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`bioavailability of less than 1%. See, e.g., Ex 10274 ¶ 6. The ’268 patent
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`specification discloses no working examples for any zoledronic acid dosage
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`forms. Nor does the specification identify, with any particularity, a
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`bioavailability-enhancing ingredient that would increase the oral
`
`
`4 Hanna et al., WO 2011/014781 A1, published February 3, 2011.
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`bioavailability of zoledronic acid from the art-recognized level of less
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`than 1% to levels within the claimed ranges.
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`Patent Owner submits that an ordinarily skilled artisan could have
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`taken “the salt and other forms of zoledronic acid identified in Aronhime”
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`and “screened” each one “for solubility and dissolution rates using routine
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`tests to eliminate the forms that have properties that are dissimilar to” a form
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`used in the beagle studies reported in an extrinsic reference (namely, a
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`“disodium zoledronate tetrahydrate form”). Resp. 20; Ex. 1074. Further,
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`according to Patent Owner, that artisan could have performed
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`“[b]ioavailability studies on a few remaining forms, far less than the 22
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`forms described in Aronhime, selected for their solubility and dissolution
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`properties, again routine in nature,” in order to “determine which forms fall
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`within the range of the claims.” Id.
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`In Patent Owner’s view, the screening required “can be performed
`
`using a routine dog study or, alternatively, human clinical studies.” Id.
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`Where an ordinarily skilled artisan “could have identified and made all
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`known forms of zoledronic acid as set forth in Aronhime, made oral dosage
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`forms of those screened for higher solubility, and tested them to determine
`
`their bioavailability,” Patent Owner contends that “practic[ing] the full scope
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`of the claimed dosage forms” would have fallen within the ambit of “routine,
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`not undue, experimentation.” Resp. 23 (footnote omitted).
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`We disagree. Performing those steps to determine whether even one
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`dosage form falls within the scope of the claimed bioavailability ranges
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`would have required, according to Patent Owner’s witness, about one
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`million dollars and a year’s worth of effort. Ex. 1093, 79:25–80:20
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`(testimony of Dr. Wargin); Pet. 24–27 (and evidence cited therein); Reply 21
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`(and evidence cited therein). Taking those steps with respect to “all known
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`forms of zoledronic acid” (Resp. 23) to enable the practice of the full scope
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`of the claims represents the epitome of undue experimentation.
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`On this record, we do not agree that an ordinarily skilled artisan
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`“would understand that the ’268 patent specification further identifies that
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`with certain forms of zoledronic acid, one does not need to use an enhancer
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`to achieve the bioavailabilities” required by the claims, including
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`bioavailabilities as high as 3 or 4%. Resp. 27. Even if “the specification
`
`expressly tells [the ordinarily skilled artisan] that a disodium form of
`
`zoledronic acid can have an oral bioavailability in humans from about 1.1 to
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`about 4%,” that does not end the inquiry. Id. (citing Ex. 2017 ¶ 24). The
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`central problem with Patent Owner’s position, in that regard, is that the
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`claims broadly include all forms of zoledronic acid, with or without an
`
`enhancer, and whether or not employed in the form of a disodium salt, as
`
`long as they meet the claimed bioavailability limitation. Not even Patent
`
`Owner argues, however, that all of those dosage forms, or even all known
`
`disodium salt forms, have a bioavailability above 1%. Resp. 20 (“It is
`
`believed that a significant number of the disodium salts, but not all, will
`
`have solubility and dissolution properties that are similar to disodium
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`zoledronate tetrahydrate”—a form identified in an extrinsic reference—“and
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`thus are likely to have bioavailabilities within the range of the claims.”)
`
`(emphasis added).
`
`The specification includes no disclosure that explains how one may
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`reliably distinguish dosage forms that fall within the scope of the claims
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`from those that do not––short of preparing the forms and testing their
`
`bioavailability. The only example provided in the specification of the
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`’268 patent demonstrates the synthesis of compounds 1 and 2; it contains no
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`guidance for selecting forms of zoledronic acid having the requisite
`
`bioavailability. Ex. 1001, 18:12 (Example 1). As to excipients, the
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`specification teaches only that they may be determined by using standard
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`pharmaceutical practice. Id. at 10:54‒63.
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`As explained above, the art of pharmaceutical dosage formulation is
`
`unpredictable. See supra 11–12. Where an ordinarily skilled artisan would
`
`have understood that unmodified zoledronic acid has an oral bioavailability
`
`of less than 1%, that artisan could not have been expected to resolv