Paper No. ___
`Filed: May 3, 2018
`
`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
`____________
`
`PETITIONER’S OPPOSITION TO PATENT OWNER’S
`CORRECTED CONTINGENT MOTION TO AMEND
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`INTRODUCTION ...........................................................................................1
`
`THE PROPOSED CLAIMS ARE INVALID FOR LACK OF
`WRITTEN DESCRIPTION ............................................................................2
`
`A.
`
`B.
`
`Proposed Claims 31-56 .........................................................................2
`
`Proposed Claims 36-38 and 48-50 ........................................................3
`
`PROPOSED CLAIMS 31-56 ARE INVALID FOR LACK OF
`ENABLEMENT ..............................................................................................5
`
`PROPOSED CLAIMS 31-56 ARE OBVIOUS BASED ON
`THE ART CITED IN THE PETITION...........................................................8
`
`PROPOSED CLAIMS 45, 52-53 ARE OBVIOUS OVER
`HANNA.........................................................................................................11
`
`A.
`
`B.
`
`Hanna Discloses Zoledronic Acid Dosage Forms Having
`Bioavailabilities Within the Claimed Ranges .....................................11
`
`Hanna Also Discloses Zoledronic Acid Dosage Forms
`Having Bioavailabilites within the Claimed Ranges in
`Fasted Dogs .........................................................................................13
`
`VI.
`
`PROPOSED CLAIMS 46-50, 51-52, AND 55-56 ARE
`OBVIOUS OVER HANNA ..........................................................................15
`
`A.
`
`B.
`
`C.
`
`Proposed Claims 46-50 .......................................................................15
`
`Proposed Claims 51, 55 and 56...........................................................16
`
`Proposed Claim 52 ..............................................................................17
`
`VII. PROPOSED CLAIMS 31-44 ARE OBVIOUS OVER FOX,
`LASLETT, HANNA, AND PAZIANAS......................................................17
`
`A.
`
`Proposed Claim 31 ..............................................................................17
`
`1.
`
`Hanna Discloses Oral Zoledronic Acid Dosage
`Forms According to Proposed Claim 31...................................17
`i
`
`

`

`2.
`
`3.
`
`4.
`
`Fox and Laslett Teach Administration of
`Zoledronic Acid for the Treatment of Knee Pain .....................17
`
`Pazianas Teaches the Fasting Limitations of Claim
`31...............................................................................................19
`
`A POSA Would Have Been Motivated to Combine
`the Teachings of Fox, Laslett, Hanna and Pazianas
`with a Reasonable Expectation of Success...............................20
`
`Proposed Claims 32-33 .......................................................................22
`
`Proposed Claims 34-38 .......................................................................23
`
`Proposed Claims 39-41 .......................................................................24
`
`Proposed Claims 42-43 .......................................................................25
`
`Proposed Claim 44 ..............................................................................25
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`VIII. CONCLUSION..............................................................................................25
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Cases
`Atlas Powder Co. v. IRECO Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) .......................................................................8
`
`Genentech, Inc. v. Novo Nordisk A/S,
`108 F.3d 1361 (Fed. Cir. 1997) .......................................................................7
`
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955).......................................................................16
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .....................................................................16
`
`In re Wertheim,
`541 F.2d 257 (C.C.P.A. 1976).......................................................................12
`
`Nat’l Recovery Techs., Inc. v. Magnetic Separation Sys., Inc.,
`166 F.3d 1190 (Fed. Cir. 1999) .......................................................................6
`
`Purdue Pharma L.P. v. Faulding Inc.,
`230 F.3d 1320 (Fed. Cir. 2000) ...................................................................4, 5
`
`See In re Woodruff,
`919 F.2d 1575 (Fed. Cir. 1990) .....................................................................12
`
`Statutes
`
`35 U.S.C. §103.....................................................................................................1, 25
`
`35 U.S.C. §112.....................................................................................................1, 25
`
`iii
`
`

`

`I.
`
`INTRODUCTION
`
`In an attempt to avoid the prior art asserted in the Petition, Patent Owner
`
`contingently seeks to substitute original claims 2-30 with proposed claims 31-56,
`
`which, inter alia, narrow the claimed bioavailability ranges. But all the newly
`
`proposed claims are still unpatentable under 35 U.S.C. §112 and/or §103.
`
`The proposed claims’ narrower bioavailability ranges are nowhere disclosed
`
`in the ’241 application (Exh. 2027, the application leading to the ’862 patent).
`
`Therefore, these new claims, like the original claims, are invalid for lack of written
`
`description. Dependent claims 36-38 and 48-50 further lack adequate written
`
`description because their respective dosage amount limitations are also not
`
`described in the ’241 application.
`
`Also, like the original claims, the proposed claims are not enabled. The
`
`specification does not disclose a single example of a pharmaceutical formulation
`
`having the newly claimed bioavailability, and does not report any bioavailability
`
`data associated with any dosage form. Patent Owner’s expert, Dr. William
`
`Wargin, and Petitioner’s expert, Dr. Clive Wilson, agree that a POSA in May 2014
`
`would have been skeptical that different zoledronic acid salt forms would have
`
`bioavailabilities within the claimed ranges. They further agree that the ’862 patent
`
`provides no information that would cure that skepticism.
`
`1
`
`

`

`Because the ’862 patent specification contains no data or other disclosure
`
`that supports the new claimed ranges, Patent Owner may point to a dog study in a
`
`separate published patent application by the same inventor. But if that dog study
`
`data is sufficient to enable the claims, then they are obvious over Hanna (Exh.
`
`1079). Hanna discloses oral zoledronic acid dosage forms having bioavailabilities
`
`within the claimed ranges in dogs, and also discloses dosage forms that meet all of
`
`the elements of claims 45-56. It was also well-known that zoledronic acid could be
`
`used to treat knee pain and should be orally administered to fasting patients to
`
`improve absorption. Thus, it also would have been obvious to a POSA to use
`
`Hanna’s oral zoledronic acid formulations with improved bioavailability to treat
`
`knee pain under the fasting conditions described in claims 31-44.
`
`Moreover, Patent Owner’s amendments are insufficient to overcome the
`
`obviousness grounds asserted in the Petition against the original claims.
`
`II.
`
`THE PROPOSED CLAIMS ARE INVALID FOR LACK OF
`WRITTEN DESCRIPTION
`
`A.
`
`Proposed Claims 31-56
`
`Patent Owner’s proposed claims narrow the claimed bioavailability ranges to
`
`“1.1% to 2.3%” (claims 31-41, 44-53, and 55-56), “1.3% to 2.3%” (claims 42, 53),
`
`or “1.5% to 2.3%” (claims 43, 54). Yet the ’241 application does not disclose any
`
`of these ranges. Rather, these ranges are merely selected from the disclosed
`
`broader range of “about 0.01% to about 5%.” Exh. 2027 at [072].
`
`2
`
`

`

`Patent Owner argues extensively in its Patent Owner Response that a POSA
`
`would have recognized that the range of about 1.1% to about 4% as critical to the
`
`alleged invention. Patent Owner cannot now abandon that assertion and allege
`
`that, in fact, a POSA would have recognized the three amended narrower ranges as
`
`critical. Belying any notion of criticality, Dr. Wargin acknowledged that nothing
`
`in the ’241 application directs a POSA to the particular bioavailability ranges of
`
`proposed claims 31-56: “Q. But where -- within this Column 13, these ranges, and
`
`in ’862, are there any ranges in particular that a person of ordinary skill in the art
`
`would have targeted in terms of oral bioavailability? A. You know, I don't think
`
`there’s necessarily a particular range. . . .” Exh. 1083 61:22-62:2.
`
`B.
`
`Proposed Claims 36-38 and 48-50
`
`Proposed claims 36-38 further require the dosage form be administered in a
`
`monthly dose of “about 20 mg to about 500 mg” (claim 36), “about 50 mg to about
`
`300 mg” (claim 37), or “about 200 mg to about 300 mg” (claim 38). Proposed
`
`claims 48-50 require that the dosage form comprise zoledronic acid in an amount
`
`of “about 20 mg to about 50 mg” (claim 48), “about 50 mg to about 100 mg”
`
`(claim 49), or “about 100 mg to about 200 mg” (claim 50).
`
`The ’241 application (Exh. 2027) does not mention any of these claimed
`
`ranges, but instead list dozens of other ranges. For example, “[i]n some
`
`embodiments the weekly oral dose of zoledronic acid is about 1 mg to about 1000
`
`3
`
`

`

`mg,” and “[i]n some embodiments, the monthly dose of zoledronic acid . . . is
`
`about 5000 mg or less.” Exh. 2027 at [069], [070].
`
`Although the myriad ranges listed in the specification are in many cases
`
`broader than the claimed range, this is not enough to satisfy the written description
`
`requirement. “[O]ne cannot disclose a forest in the original application, and then
`
`later pick a tree out of the forest and say ‘here is my invention.’ In order to satisfy
`
`the written description requirement, the blaze marks directing the skilled artisan to
`
`that tree must be in the originally filed disclosure.” Purdue Pharma L.P. v.
`
`Faulding Inc., 230 F.3d 1320, 1326-27 (Fed. Cir. 2000). Even if a claimed range
`
`is narrower than the ranges that can be gleaned from the specification, the written
`
`description requirement is not satisfied where, as here, the specification does not
`
`clearly disclose to a POSA that the inventors considered the claimed range to be
`
`part of their invention. See id. at 1328.
`
`Nothing in the ’241 application directs a POSA to the particular ranges of
`
`proposed claims 36-38 and 48-50. Dr. Wargin testified that “there’s no reason to
`
`believe . . . one or any of these [ranges in paragraph 66 the ’241 application] would
`
`be preferable to the others.” Exh. 1083 75:13-76:6. Indeed, even if these ranges
`
`were recited somewhere among the dozens of ranges in the ’241 application (they
`
`are not), nothing would suggest to a POSA that the specific ranges are an important
`
`or defining quality of the invention, which is required to satisfy written description
`
`4
`
`

`

`is such cases. Purdue Pharma L.P., 230 F.3d at 1326-27. Therefore, for these
`
`additional reasons, proposed claimed 36-38 and 48-50 fail to satisfy the written
`
`description requirement.
`
`III. PROPOSED CLAIMS 31-56 ARE INVALID FOR LACK OF
`ENABLEMENT
`
`Patent Owner succinctly concludes, without any explanation, that the
`
`narrowed bioavailability ranges in the proposed new claims are “fully enabled.”
`
`Paper 33 at 13. They are not. Dr. Wargin testified that a POSA would have been
`
`skeptical in May 2014 that different zoledronic acid salt forms could be used to
`
`achieve oral dosage forms of having bioavailabilities of between about 1.1% to
`
`about 4%—a range broader than those recited in the proposed amended claims 31-
`
`56—and that he could not think of anything in the ’862 patent that would have
`
`removed that skepticism. Exh. 1083 113:13-114:20. As such, the ’862 patent
`
`specification does not enable oral dosage forms having the zoledronic acid
`
`bioavailability required by each of proposed claims. Exh. 1076 ¶¶13-30.
`
`Dr. Wargin admitted that “there’s no bioavailability data in the [’862]
`
`patent.” Exh. 1083 20:20-21:1. He was also unable to point to any disclosure in
`
`the ’862 patent that would allow a POSA to determine that dosage forms having
`
`bioavailabilities within the claimed ranges are effective. Id. 45:17-25. Nor could
`
`he identify any information in the ’862 patent as to the efficacy of oral zoledronic
`
`acid forms that was not already known in the prior art. Id. 46:1-7.
`
`5
`
`

`

`Dr. Wargin testified that the information regarding “possible formulations”
`
`for zoledronic acid oral dosage forms in the ’862 specification at best “would give
`
`the POSA a starting point[ ] recognizing that it may be an iterative process, that the
`
`-- a bioavailability study, initial study on a particular formation may not provide a
`
`preselected range, but could provide one of the [bioavailability] ranges in Column
`
`13.” Id. 59:10-60:12. But it is not enough that the specification “provides a
`
`starting point from which one of skill in the art can perform further research in
`
`order to practice the claimed invention.” Nat’l Recovery Techs., Inc. v. Magnetic
`
`Separation Sys., Inc., 166 F.3d 1190, 1198 (Fed. Cir. 1999). Dr. Wargin, in fact,
`
`conceded that whether any of the excipients described in columns 14-15 would
`
`actually increase bioavailability of zoledronic acid by even a mere 20 percent (i.e.,
`
`to obtain a dosage form having a bioavailability of about 1.2%) “would be
`
`speculative” and “would have to be tested.” Exh. 1083 65:24-66:3.
`
`Patent Owner cannot cure this complete lack of disclosure by citing to the
`
`dog study described in Example 7 of the ’669 publication (Exh. 2005). Dr. Wargin
`
`conceded that a POSA could not look at Example 7 and determine whether the
`
`bioavailability of the disodium salt of zoledronic acid in humans falls within the
`
`cited ranges. Exh. 1083 107:1-5. And, as Dr. Wilson explains, Example 7 only
`
`concerns the degree of bioavailability improvement observed for the disodium salt
`
`form relative to the bioavailability of the free acid form. The prior art discloses
`
`6
`
`

`

`that the zoledronic acid has less than 1% bioavailability, and the ’862 patent
`
`discloses that the unenhanced bioavailability of zoledronic acid could be as low as
`
`0.01%. Exh. 1076 ¶29; Exh. 1001 at 13:11-14. Thus, even a dosage form with an
`
`84% improvement would not have a bioavailability within the claimed ranges.
`
`Exh. 1076 ¶29; Exh. 1083 80:21-81:20.
`
`Patent Owner also cannot rely on the prior art (e.g., Leonard or Fosamax) to
`
`supply the POSA with the knowledge necessary to make and use the alleged novel
`
`aspects of the proposed claims (i.e., enhanced bioavailability). “It is the
`
`specification, not the knowledge of one skilled in the art, that must supply the
`
`novel aspects of an invention in order to constitute adequate enablement.”
`
`Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366 (Fed. Cir. 1997). And
`
`if Patent Owner does rely on the prior art as teaching a POSA how to make and use
`
`oral zoledronic acid dosage forms having the claimed bioavailability, then it is
`
`clear that the ’862 patent adds nothing to what was already known to a POSA.
`
`Patent Owner admits that Aronhime (Exh. 1035) teaches a POSA how to make salt
`
`forms of zoledronic acid and that “[a] POSA need only make an oral dosage form
`
`containing that form of zoledronic acid, and perform a routine bioavailability test
`
`as in Leonard” to arrive at the original claims. Paper 27 (“POR”) at 13. If the
`
`same is true for the proposed claims, they are then plainly obvious based on
`
`Aronhime and Leonard. It is simply not inventive to discover an inherent property
`
`7
`
`

`

`of a known substance through routine testing. See Atlas Powder Co. v. IRECO
`
`Inc., 190 F.3d 1342, 1347-48 (Fed. Cir. 1999).
`
`IV. PROPOSED CLAIMS 31-56 ARE OBVIOUS BASED ON THE ART
`CITED IN THE PETITION
`
`Patent Owner’s principal argument to distinguish the proposed amended
`
`claims over the prior art cited in the Petition is that a POSA would not modify the
`
`dosage forms disclosed in Leonard (Exh. 1009) and the Merrion Poster (Exh. 1040,
`
`1081) to lower their bioavailability. In making this argument, Patent Owner
`
`primarily relies on the testimony of Petitioner’s expert, Dr. Stephen Bruehl. Paper
`
`33 at 11-12.
`
`Dr. Bruehl, however, is not an expert in bioavailability. Exh. 2026 9:17-
`
`10:11. On the other hand, testimony provided by both parties’ bioavailability
`
`experts clearly establishes that there is nothing inventive about lowering the
`
`bioavailability of Leonard and Merrion’s oral zoledronic acid dosage forms. Dr.
`
`Wargin - who has over 30 years’ experience in the field - testified that a POSA
`
`would have understood that because zoledronic acid accumulates in bone at a
`
`much higher concentration than in blood plasma, “having low bioavailability is not
`
`necessarily a disadvantage in this case.” Exh. 1083 23:2-17. Indeed, Dr. Wargin
`
`testified that “if a POSA had a belief that a bioavailability of 1.5 percent was
`
`sufficient to achieve therapeutic efficacy and they could do so in a dosage form
`
`8
`
`

`

`without the need of adding an enhancer, that might be preferable [sic] to a dosage
`
`form having a bioavailability of 3 percent including an enhancer.” Id. 69:17-23.
`
`Dr. Wargin’s testimony is consistent with that of Petitioner’s expert Dr.
`
`David Brayden, who explains that given a choice, a POSA would avoid the
`
`incorporation of sodium caprate in the formulations of Leonard to increase
`
`bioavailability. Sodium caprate (an enhancer) needs to be present in tablets at
`
`concentrations that would have led to concerns over its perceived long term safety
`
`in patients requiring repeat administration. Exh. 1084 ¶¶19-25. To ameliorate
`
`such potential safety concerns while still sufficiently enhancing bioavailability, a
`
`POSA would have been motivated to reduce the amount of sodium caprate in the
`
`Leonard and Merrion Poster formulations, resulting in a bioavailability of from
`
`1.1% to 2.3%, as required by proposed claims 45-56. Id.
`
`A POSA also would have been motivated to combine the disclosures of Fox,
`
`Laslett, Leonard, and the Merrion Poster to arrive at the methods of treating knee
`
`pain of proposed claims 31-44. Exh. 1003 ¶86. As discussed above, oral
`
`zoledronic acid formulations having 1.1% to 2.3% bioavailability would have been
`
`obvious based on Leonard and the Merrion Poster. Patent Owner does not dispute
`
`that a POSA would have expected dosage forms having bioavailability of 1.1% or
`
`higher to be therapeutically effective. See POR at 32-34. And, as discussed in the
`
`Petition, based on Fox and Laslett, a POSA would have known that zoledronic acid
`
`9
`
`

`

`was effective to treat knee pain. Paper 2 (“Pet.”) at 59-62. Thus, a POSA would
`
`have been motivated to administer zoledronic acid dosage forms having a
`
`bioavailability of from 1.1% to 2.3% for treatment of knee pain and would have
`
`had a reasonable expectation of success that such dosage forms would be effective.
`
`Exh. 1076 ¶66; Exh. 1098 ¶¶15-17.
`
`Patent Owner argues that “none of the[ ] fasting protocols in [the Merrion
`
`Poster] matches the method of substitute claims 31-44, or the testing parameters of
`
`substitute claims 45-56.” Paper 33 at 8-11. However, these fasting limitations do
`
`nothing to confer patentability of the proposed amended claims. Even though the
`
`Merrion Poster’s 90% confidence interval might vary under different fasting
`
`conditions, it remains obvious for a POSA to take the Merrion Poster’s oral
`
`zoledronic acid formulations with improved bioavailability and administer them to
`
`treat knee pain with a reasonable expectation of achieving a bioavailability within
`
`the claimed ranges of the proposed amended claims under the standard fasting
`
`conditions of those claims. Exh. 1076 ¶¶31-32. Furthermore, Leonard Example
`
`17 expressly teaches that a bioavailability of 2.5% can be achieved on an
`
`overnight fast and, as discussed above, a POSA would be motivated to reduce this
`
`bioavailability by reducing the amount of sodium caprate in the dosage form.
`
`10
`
`

`

`V.
`
`PROPOSED CLAIMS 45, 52-53 ARE OBVIOUS OVER HANNA
`
`Claim 45 covers oral zoledronic acid dosage forms having from 1.1% to
`
`2.3% bioavailability when the subject is fasted for 10 hours before and 4 hours
`
`after administration. Claims 53-54 change the low end of the range to 1.3% and
`
`1.5% respectively. Such dosage forms are obvious over Int’l Patent Publication
`
`No. WO 2011/097269 (“Hanna,” Exh. 1079), which was published August 11,
`
`2011 and is therefore prior art to the proposed amended claims. Exh. 1098 ¶¶12-
`
`13. Hanna concerns “new forms of . . . zoledronic acid, with improved
`
`physicochemical properties, such as improved aqueous solubility, rate of
`
`dissolution, and, particularly, improved permeability resulting in enhanced
`
`bioavailability.” Exh. 1079 at 4-5.
`
`A.
`
`Hanna Discloses Zoledronic Acid Dosage Forms Having
`Bioavailabilities Within the Claimed Ranges
`
`Hanna discloses that the “compositions of the present invention comprising
`
`an amino acid have increased permeability of the API (compared to the
`
`corresponding composition with the amino acid). . . . The increase in permeability
`
`results in an increase in bioavailability of the API.” Id. at 19. Hanna further
`
`discloses embodiments wherein “the increase in oral bioavailability” ranges from
`
`“at least 10%” to “at least five fold.” Id. at 9-10, 19-20. Hanna elsewhere notes
`
`that the oral bioavailability of unenhanced zoledronic acid is “approximately 1%.”
`
`Id. at 3. Because this information was obtained from the US Food and Drug
`
`11
`
`

`

`Administration (FDA) Summary Basis of Approval, a POSA would have
`
`understood that bioavailability was experimentally determined under the FDA-
`
`recommended fasting regimen, which corresponds to the conditions in proposed
`
`amended claims 45-56. Id.; Exh. 1076¶52; see also POR at 50. Thus, Hanna
`
`discloses dosage forms having a bioavailability from at least 1.1% (i.e., an increase
`
`of “at least 10%”), which completely overlaps the claimed ranges, up to at least
`
`5.0% (i.e., an increase of “at least five fold”).
`
`Where, as here, the claimed ranges lie inside prior art ranges, a prima facie
`
`case of obviousness exists. In re Wertheim, 541 F.2d 257, 267 (C.C.P.A. 1976).
`
`And the ’862 patent specification is devoid of any suggestion that administration of
`
`a zoledronic acid dosage form having a bioavailability of from about 1.1% (or
`
`from about 1.3% or 1.5%) to about 2.3% is critical or has any unexpected results
`
`over the broader range described in Hanna that could rebut the prima facie case.
`
`See In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990).
`
`Claim 45 further requires that the “dosage form is free of therapeutically
`
`active agents that are not zoledronic acid, Compound 1, or Compound 2.” Hanna
`
`discloses several such compositions—for example the dog studies used capsules
`
`wherein the zoledronic acid complex of the invention was the only API. Exh. 1079
`
`at 68-69; Exh. 1076 ¶53. Hanna also refers to embodiments where zoledronic acid
`
`12
`
`

`

`is “the API,” which the inventors define as “the substance in a pharmaceutical drug
`
`that is biologically active.” Exh. 1079 at 15, 19, 64-67, 162-166 (emphasis added).
`
`Claim 45 also requires that the “dosage form is suitable for oral
`
`administration to a human being.” Hanna discloses this limitation. Exh. 1076 ¶74.
`
`Hanna teaches that “[i]n one aspect the pharmaceutical composition is an oral
`
`dosage form. In one embodiment the oral dosage form is a solid oral dosage
`
`form.” Exh. 1079 at 20. Hanna gives ample guidance as to how to prepare such
`
`dosage forms. Id. at 53-67.
`
`B.
`
`Hanna Also Discloses Zoledronic Acid Dosage Forms Having
`Bioavailabilites within the Claimed Ranges in Fasted Dogs
`
`As Patent Owner’s expert Dr. Wargin testified, “there’s no bioavailability
`
`data in the [’862] patent.” Exh. 1083 20:20-21:1. As such, Patent Owner is forced
`
`to look to the ’669 publication’s Example 7 for bioavailability data to support the
`
`original claims, and is expected to do so again to support the amended claims. But
`
`its own expert Dr. Wargin conceded that “a [POSA] cannot look at Example 7 and
`
`say the absolute bioavailability of the disodium salt of zoledronic acid is between
`
`1.1 and 4 percent in humans.” Id. 107:1-5. It therefore remains Petitioner’s
`
`position, consistent with the testimony of Drs. Wilson and Wargin, that all of the
`
`original and proposed amended claims are not enabled and reference to the dog
`
`study in the ’669 publication does not save them. Pet. at 19-25, 28-31.
`
`13
`
`

`

`However, to the extent that the data in the ’669 publication enables the
`
`proposed claims, those claims are obvious over the dog study disclosed in Hanna.
`
`Hanna discloses the results of a dog study comparing intravenous administration of
`
`zoledronic acid to various oral formulations containing zoledronic acid complexes.
`
`Exh. 1079 at 84-92. Hanna teaches that oral administration of capsules containing
`
`specific dosages of zoledronic acid/lysine complexes achieve absolute
`
`bioavailabilities in fasted dogs of between 1.43% and 2.04%. Exh. 1076 ¶¶57-58,
`
`Appendix A. These values, if appropriate to extrapolate to humans as Patent
`
`Owner argues in reference to the ’669 publication, would fall squarely within the
`
`ranges recited in the proposed claims 45 and 53-54. Id.
`
`*
`
`*
`
`*
`
`Consequently, it would have been obvious to a POSA that oral dosage forms
`
`containing zoledronic acid complexes, as described in Hanna, could be orally
`
`administered to human beings fasted according to the schedule recited in the
`
`claims to achieve bioavailabilities within the claimed ranges. Based on the
`
`disclosures and/or animal data in Hanna, a POSA would have had a reasonable
`
`expectation of success that such dosage forms could be formulated and
`
`administered to achieve the claimed bioavailabilities.
`
`14
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`VI. PROPOSED CLAIMS 46-50, 51-52, AND 55-56 ARE OBVIOUS OVER
`HANNA
`
`All of the other elements of the newly proposed claims depending from
`
`claim 45 are expressly disclosed in—and therefore obvious over—Hanna.
`
`A.
`
`Proposed Claims 46-50
`
`Proposed claims 46-50 require a particular amount of zoledronic acid be
`
`present in the claimed compositions. Hanna discloses and tests oral compositions
`
`having bioavailabilities within the claimed ranges wherein the dosage form
`
`contains between 50.0 and 54.7 mg. Exh. 1079 at 85-97; Exh. 1076 ¶64. These
`
`values fall within the dosage ranges of claims 46-49. Hanna also discloses ranges
`
`that completely overlap with the ranges of claims 47-50. Exh. 1079 at 54.
`
`Hanna’s range of “about 1 mg to about 500 mg” (Id.) is broader than and
`
`encompasses the ranges recited in proposed claims 46-50. The ’862 patent
`
`specification does not suggest that the dosing ranges recited in claims 47-50 are
`
`critical to the claimed invention, or associated with any advantageous or
`
`unexpected results. Exh. 1076 ¶65. To the contrary, the specification discloses
`
`dozens of ranges and states that “[a]ny suitable amount of zoledronic acid may be
`
`used.” Id.; Exh. 1001 at 11:10-33.
`
`In addition, it would have been obvious for a POSA to determine the amount
`
`of zoledronic acid to use. Exh. 1076 ¶66. A POSA would have understood that
`
`the amount of zoledronic acid in a pharmaceutical composition may vary
`
`15
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`

`

`depending upon the type of dosage form to be used and the particular disease or
`
`condition to be treated. Id. A POSA would have been motivated to use routine
`
`experimentation to determine the amount of zoledronic acid to use in particular
`
`dosage forms for particular therapeutic applications. Id. Indeed, “[w]here the
`
`general conditions of a claim are disclosed in the prior art, it is not inventive to
`
`discover the optimum or workable ranges by routine experimentation.” In re Aller,
`
`220 F.2d 454, 456 (C.C.P.A. 1955). “The normal desire of scientists or artisans to
`
`improve upon what is already generally known provides the motivation to
`
`determine where in a disclosed set of percentage ranges is the optimum
`
`combination of percentages.” In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir.
`
`2003).
`
`B.
`
`Proposed Claims 51, 55 and 56
`
`Proposed claim 51 requires that the “dosage form is solid.” Hanna discloses
`
`this limitation. Exh. 1076 ¶¶71-72. Hanna teaches that “[i]n one aspect the
`
`pharmaceutical composition is an oral dosage form. In one embodiment the oral
`
`dosage form is a solid oral dosage form.” Exh. 1079 at 20. Proposed claims 55
`
`and 56 additionally require that the dosage form is a tablet or a capsule. Hanna
`
`also discloses these limitations. Exh. 1076 ¶¶72-73; Exh. 1079 at 39; see also id.
`
`at 55.
`
`16
`
`

`

`C.
`
`Proposed Claim 52
`
`Proposed claim 52 requires that “at least 10% of the weight of the dosage
`
`form is zoledronic acid.” Hanna discloses numerous examples that meet this
`
`limitation. See Section V.B. above; Exh. 1076 ¶75.
`
`VII. PROPOSED CLAIMS 31-44 ARE OBVIOUS OVER FOX, LASLETT,
`HANNA, AND PAZIANAS
`
`A.
`
`Proposed Claim 31
`
`1.
`
`Hanna Discloses Oral Zoledronic Acid Dosage Forms
`According to Proposed Claim 31
`
`Claim 31, like Claim 45, requires an orally administered dosage form
`
`comprising zoledronic acid wherein the dosage form is free of therapeutically
`
`active agents that are not zoledronic acid, Compound 1, or Compound 2, and
`
`wherein the bioavailability of zoledronic acid in the dosage form is from 1.1% to
`
`2.3% in human beings. As discussed in detail above, Hanna expressly discloses
`
`such pharmaceutical compositions.
`
`2.
`
`Fox and Laslett Teach Administration of Zoledronic Acid
`for the Treatment of Knee Pain
`
`Proposed claim 31 requires that the claimed dosage forms be administered to
`
`a human being suffering from knee pain for the purpose of diagnosing, curing,
`
`mitigating, or preventing knee pain. Fox and Laslett teach treatment of pain, in
`
`particular knee pain, using zoledronic acid. Exh. 1098 ¶¶18-44.
`
`17
`
`

`

`Fox describes “[a] method for the treatment of pain, in particular
`
`antinociceptive or anti-allodynic treatment of pain, in a patient in need of such
`
`treatment . . . which comprises administering an effective amount of a
`
`bisphosphonate, e.g. zoledronic acid or salts or hydrates thereof, to the patient.”
`
`Exh. 1007, abstract; Exh. 1098 ¶¶26-27. Fox further teaches that “zoledronic acid
`
`and similar bisphosphonates may have direct, fast acting, anti-nociceptive and anti-
`
`allodynic activity on pain.” Id. ¶¶[0005], [0012]; Exh. 1098 ¶36. Antinociceptive
`
`treatment of pain works by blocking the detection of noxious stimuli by
`
`nociceptors, i.e., sensory neurons. Exh. 1098 ¶¶37-38. A POSA would expect that
`
`this antinociceptive action would not be limited to any particular body part, and
`
`would be effective in treating pain in any part of the body, including the knee. Id.
`
`¶38. Fox also discloses treatment of osteoarthritis pain, a common type of knee
`
`pain. Id. ¶¶25, 33-34; Exh. 1007 ¶[0011].
`
`In addition, Fox describes animal studies demonstrating that zoledronic acid
`
`effectively treats pain. Exh. 1007 ¶¶[0102], [0104], [0106]; Exh. 1098 ¶31. Fox
`
`states that “[t]hese data show that Zoledronate reverses mechanical hyperalgesia in
`
`models of chronic inflammatory and neuropathic pain in the rat.” Id. ¶[0106];
`
`Exh. 1098 ¶31. A POSA would have understood that hyperalgesia is an increased
`
`sensitivity to pain. Exh. 1098 ¶32. Consequently, a POSA would have understood
`
`Fox’s disclosure of reversal of hyperalgesia as confirming that zoledronic acid can
`
`18
`
`

`

`be administered to treat pain. Id ¶35; Exh. 1007 ¶[0009]. In other words, Fox
`
`teaches a POSA that zoledronic acid can be used for direct treatment of pain and
`
`has pain relieving properties. Exh.1098 ¶¶28-30.
`
`Fox further teaches that “[p]referably, the pharmaceutical compositions are
`
`adapted to oral . . . administration.” Exh. 1007 ¶[0072]. In sum, Fox teaches oral
`
`formulations containing zoledronic acid as the only active ingredient that can be
`
`used for the treatment of pain, which a POSA would have understood includes
`
`knee pain. Exh. 1098 ¶39.
`
`Zoledronic acid’s efficacy in treating knee pain, specifically, is confirmed by
`
`Laslett. Exh. 1008; Exh. 1098 ¶¶40-44. Laslett describes a double blind, placebo
`
`controlled, randomized clinical trial that demonstrated that a single infusion of
`
`intravenous zoledronic acid was effective in reducing knee pain. Exh. 1008 at
`
`1322-23, 1326-27. Thus, even if Fox did not teach that zoledronic acid is effective
`
`for treating knee pain specifically, Laslett clearly does. Exh. 1098 ¶¶40-44.
`
`3.
`
`Pazianas Teaches the Fasting Limitations of Claim 31
`
`Proposed claim 31contains the further limitation that the dosage form is
`
`orally administered to the human being after at least one hour of fasting and that
`
`the human being fast for at least one hour aft