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 REPLY
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`CLAIMS 2-30 ARE NOT ENABLED............................................................1
`
`A.
`
`B.
`
`C.
`
`D.
`
`Patent Owner’s Expert Conceded that the ’862 Patent
`Adds Nothing to the Prior Art...............................................................1
`
`The Specification Does Not Enable Oral Dosage Forms
`Satisfying the Bioavailability Limitations of Claims 2-30
`Without the Use of Enhancers...............................................................2
`
`Dr. Wargin Admitted That the ‘669 Publication Does Not
`Demonstrate That the Bioavailability of the Disodium
`Salt Is Within the Claimed Range.........................................................5
`
`Patent Owner Cannot Rely on the Prior Art for
`Enablement............................................................................................7
`
`II.
`
`CLAIMS 17-30 ARE ANTICIPATED BY OR OBVIOUS
`OVER LEONARD ..........................................................................................8
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Patent Owner—Not Petitioner—Has the Burden to Prove
`Leonard Is Not Enabling .......................................................................8
`
`Leonard Expressly Discloses Bioavailability Overlapping
`the Claimed Ranges.............................................................................11
`
`Leonard’s Bioavailability Range Does Not Operate
`Differently than the Claimed Ranges..................................................12
`
`Leonard Discloses Dosage Forms Where Zoledronic
`Acid Is the Sole Active Ingredient......................................................14
`
`Leonard Anticipates or Renders Obvious Claims 21-22,
`25 .........................................................................................................15
`
`III. CLAIMS 17-30 ARE OBVIOUS BASED ON LEONARD
`AND THE MERRION POSTER ..................................................................16
`
`A.
`
`B.
`
`The Merrion Poster Is Prior Art ..........................................................16
`
`Claims 17-30 Do Not Exclude Dosage Formulations That
`Include an Enhancer............................................................................17
`
`i
`
`

`

`C.
`
`A POSA in May 2014 Would Have Been Motivated to
`Formulate Zoledronic Acid in an Oral Dosage Form
`Having a Bioavailability Below 2.5% Based on Leonard
`and the Merrion Poster ........................................................................18
`
`IV. CLAIMS 2-15 ARE OBVIOUS OVER LEONARD, THE
`MERRION POSTER, FOX, AND LASLETT..............................................20
`
`A.
`
`B.
`
`It Would Have Been Obvious to a POSA to Treat Knee
`Pain with an Oral Zoledronic Acid Dosage Form Having
`the Bioavailabilities of Claims 2-15....................................................20
`
`Fox Describes Dosage Ranges That Encompass those
`Recited in Claims 8 and 9 ...................................................................21
`
`V.
`
`NO SECONDARY CONSIDERATIONS OF
`NONOBVIOUSNESS SUPPORT PATENTABILITY................................23
`
`VI. CONCLUSION..............................................................................................23
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Cases
`AK Steel Corp. v. Sollac,
`344 F.3d 1234 (Fed. Cir. 2003) .......................................................................7
`
`Amgen Inc. v. Hoechst Marion Roussel, Inc.,
`314 F.3d 1313 (Fed. Cir. 2003) .....................................................................10
`
`Atlas Powder Co. v. IRECO Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) .......................................................................8
`
`Creston Elecs., Inc. v. Intuitive Building Controls, Inc.,
`IPR2015-01460, Paper 14 (P.T.A.B. January 14, 2016)...............................17
`
`Elec. Arts Inc. v. White Knuckle IP, LLC,
`IPR2015-01595, Paper 38 (P.T.A.B. Jan. 12, 2017) .....................................17
`
`Genentech, Inc. v. Novo Nordisk A/S,
`108 F.3d 1361 (Fed. Cir. 1997) .......................................................................7
`
`Hoffman-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .............................................................. 10, 23
`
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955)................................................................ 16, 22
`
`In re Antor Media Corp.,
`689 F.3d 1282 (Fed. Cir. 2012) .......................................................................9
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .....................................................................18
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .....................................................................18
`
`In re Wertheim,
`541 F.2d 257 (C.C.P.A. 1976).......................................................................18
`
`Nat’l Recovery Techs., Inc. v. Magnetic Separation Sys., Inc.,
`166 F.3d 1190 (Fed. Cir. 1999) .......................................................................4
`
`iii
`
`

`

`Wojciak v. Nishiyama,
`61 U.S.P.Q.2d 1576, 1581 (B.P.A.I. 2001) .....................................................9
`
`Statutes
`
`35 U.S.C. § 112..........................................................................................................4
`
`35 U.S.C. § 326(e) .....................................................................................................9
`
`Other Authorities
`
`Manual of Patent Examining Procedure § 706 ..........................................................9
`
`Rules of Practice for Trials before the PTAB and Judicial
`Review of PTAB Decisions [Docket No. PTO-P-2011-
`0082] RIN 0651-AC70 ..................................................................................10
`
`iv
`
`

`

`I.
`
`CLAIMS 2-30 ARE NOT ENABLED
`
`A.
`
`Patent Owner’s Expert Conceded that the ’862 Patent Adds
`Nothing to the Prior Art
`
`Patent Owner asserts that “[t]he ’862 specification teaches at least two things
`
`that a POSA would not know, (1) that a dosage form of zoledronic acid with a
`
`bioavailability range of about 1.1% to about 4% is effective in treating disease, e.g.
`
`knee pain, and (2) one can achieve a dosage form within this bioavailability range
`
`without the need for enhancers.” Paper 27 (“POR”) at 5. The ’862 patent teaches
`
`neither.
`
`As to efficacy, Patent Owner’s expert, Dr. Wargin, was unable to identify
`
`anything in the specification that would allow a POSA to determine that a
`
`bioavailability range of about 1.1% to about 4% is effective; nor could Dr. Wargin
`
`identify any information in the ’862 patent as to the efficacy of oral zoledronic acid
`
`forms over what was already known in the prior art. Exh. 1083 45:17-46:7.
`
`Regarding bioavailability without enhancers, Patent Owner wrongly asserts
`
`that the testimony of Petitioner’s expert, Dr. Wilson, provides direct evidence that
`
`the claims are enabled. POR at 6-7. Although Dr. Wilson acknowledged the
`
`assertion in the ’862 patent that the disodium salt form could have increased
`
`bioavailability, he noted that “there is no actual data showing such a bioavailability
`
`was actually observed.” Exh. 1005 ¶69. As Dr. Wilson explained, a POSA as of
`
`May 2014 would not have believed that one could have obtained an oral dosage
`
`1
`
`

`

`form of zoledronic acid with a bioavailability within the claimed ranges without
`
`the use of an enhancer. Exh. 1005 ¶¶67-72. Dr. Wargin likewise testified that a
`
`POSA would have been skeptical that different salt forms could be used to achieve
`
`oral dosage forms of zoledronic acid having bioavailabilities of between about
`
`1.1% to about 4%, and could not think of anything in the ’862 patent that would
`
`have removed that speculation. Exh. 1083 113:13-114:20.
`
`Dr. Wargin elsewhere alleged “what is taught in the ’862 patent over the
`
`prior art is that the salt form of zoledronic acid improves aqueous solubility.”
`
`Exh. 1083 41:13-19; see also POR at 12. Yet, Dr. Wargin admitted that this was
`
`known in the prior art and that an increase in aqueous solubility may not
`
`necessarily result in increased bioavailability, only that it would “give one reason
`
`to test.” Id. 40:2-10, 41:20-42:16. No such testing was performed by the inventor
`
`here. As Dr. Wargin conceded, “there’s no bioavailability data in the [’862]
`
`patent.” Id. 20:20-21:1. Thus, the ’862 patent adds nothing over what was known
`
`in the prior art.
`
`B.
`
`The Specification Does Not Enable Oral Dosage Forms
`Satisfying the Bioavailability Limitations of Claims 2-30
`Without the Use of Enhancers
`
`Patent Owner incorrectly asserts that “[t]he specification, at col. 8, line 2,
`
`discloses that a disodium salt form of zoledronic acid has a bioavailability of
`
`0.015, i.e., 1.5%.” POR at 10. A POSA would have recognized that the inventor
`
`2
`
`

`

`was simply providing a hypothetical example of how to calculate “nd”. Exh. 1076
`
`¶17. Even if this were not a hypothetical, it does not establish that the inventor
`
`was in possession of the full scope of the claimed bioavailability range. For
`
`example, inventing a dosage form with bioavailability of 1.5% does not establish
`
`that one also invented a dosage form with bioavailability more than twice as high
`
`(e.g., 3-4%).
`
`Patent Owner also incorrectly asserts that the disclosure that the “oral
`
`bioavailability of zoledronic acid can be . . . about 1.4% to about 1.5%, about 1.5%
`
`to 1.6%” provides evidence that the inventor actually demonstrated such a
`
`bioavailability. Exh. 1001 13:6-33; POR at 10. Dr. Wargin testified that it “would
`
`not be possible” for a “[POSA] using the ’862 patent to create a pharmaceutical
`
`dosage form of zoledronic acid that could . . . reliably result in a bioavailability of
`
`between 1.3 and 1.5 percent.” Exh. 1083 25:24-26:6; see also Exh. 1076 ¶18.
`
`Indeed, the ’862 patent lists bioavailabilities from 0.01% to 10% with no
`
`instructions as to how to achieve a particular bioavailability within that range. A
`
`POSA would not have understood the laundry list of bioavailability ranges in the
`
`specification to enable any particular bioavailability within that broad range. Exh.
`
`1076 ¶19.
`
`In addition, as Dr. Wargin admitted that the ’862 patent provides no specific
`
`guidance as to what non-active ingredients can be used to obtain a dosage form
`
`3
`
`

`

`within the claimed bioavailability ranges, just that “[t]here is guidance around the
`
`types of excipients that could possibly be used and so a POSA would consider . . .
`
`using those excipients” and that such general guidance was already known to a
`
`POSA. Exh. 1083 48:16-23, 58:10-23. Dr. Wargin further testified that whether
`
`any of those excipients would actually increase bioavailability of zoledronic acid
`
`by even a mere 20% (i.e., to obtain a dosage form having a bioavailability of 1.2%)
`
`“would be speculative” and “would have to be tested.” Id. 65:24-66:3.
`
`Dr. Wargin continued: “I think having information about the target
`
`bioavailabilities and the possible formulations outlined in Column 14 and the
`
`possible excipients in Column 14, I think that would give the POSA a starting
`
`point[ ] recognizing that it may be an iterative process, that [a]n 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. However, it is not
`
`enough for the specification to “provide[ ] a starting point from which one of skill
`
`in the art can perform further research in order to practice the claimed invention”
`
`to satisfy § 112. Nat’l Recovery Techs., Inc. v. Magnetic Separation Sys., Inc., 166
`
`F.3d 1190, 1198 (Fed. Cir. 1999).
`
`4
`
`

`

`C.
`
`Dr. Wargin Admitted That the ‘669 Publication Does Not
`Demonstrate That the Bioavailability of the Disodium Salt Is
`Within the Claimed Range
`
`Patent Owner asserts that a POSA would look to Example 7 of the ’669
`
`publication as a demonstration that the inventors were in possession of dosage
`
`forms with bioavailabilities in humans of 1.46% and 1.84%. POR at 10-11. But
`
`Dr. Wargin disagrees, noting that the “objective of this study was to obtain the
`
`relative bioavailability of the disodium salt to zoledronic acid” and that there was
`
`no “intent to try to . . . assess the absolute bioavailability.” Exh. 1083 106:7-25.
`
`As such, he “wouldn’t want to try to extrapolate specifically the data [to] humans
`
`in a quantitative sense.” Id. As such, Dr. Wargin admitted 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.
`
`Dr. Wargin further admitted that as of 2014, a POSA would not have
`
`believed bioavailability data in dogs correlates well to humans and that if a POSA
`
`were to determine the bioavailability of a particular zoledronic acid dosage form
`
`was between 1.1 and 2.3% in dogs it is “probably unlikely” that a POSA would get
`
`the same number in humans. Id. 34:4-19, 35:1-10. Dr. Wargin testified that “dog
`
`bioavailability studies . . . may be less than 50 percent predictive of what will
`
`happen in humans” because of “differences in the physiology . . . of the GI tract”
`
`between dogs and humans and possibly due to gastric pH differences that would be
`
`5
`
`

`

`expected to affect bioavailability. Id. 32:13-33:14. In fact, despite “working in the
`
`field for 30 years” and “see[ing] a lot of dog data,” Dr. Wargin has “come to the
`
`conclusion that, for the most part, it’s better to go directly into humans [to] get the
`
`data you need.” Id. 35:11-36:6. Indeed, Dr. Wargin was unaware of any
`
`circumstances where bioavailability data in dogs correlated well to humans. Id.
`
`34:20-25.
`
`Moreover, Dr. Wargin explained that these opinions are not inconsistent
`
`with the statements cited by Patent Owner from the ’435 application (Exh. 2021) at
`
`POR 11-12. Id. 42:17-43:21; see also Exh. 1076 ¶¶30. Dr. Wargin’s opinions
`
`here are also consistent with those of Dr. Wilson who explains that even if a POSA
`
`were to consider the degree of improvement observed for the disodium salt form
`
`over the bioavailability of the free acid form, there is no data regarding the
`
`unenhanced bioavailability of zoledronic acid in the prior art except disclosures
`
`that it is less than 1%. Exh. 1076 ¶¶27-29. The ’862 patent discloses that the
`
`unenhanced bioavailability of zoledronic acid could be as low as 0.01%. Exh.
`
`1001 at 13:11-14. Thus even a dosage form with an 84% improvement may not
`
`have a bioavailability in the claimed ranges. Exh. 1076 ¶29; Exh. 1083 80:21-
`
`81:20.
`
`6
`
`

`

`D.
`
`Patent Owner Cannot Rely on the Prior Art for Enablement
`
`Patent Owner alleges that the novel aspect of the invention (even though
`
`absent from the claims) is that the ’862 allegedly teaches a POSA how to achieve a
`
`dosage form of zoledronic acid with a bioavailability of about 1.1% to about 4%.
`
`Patent Owner admits, however, that the specification does not explicitly say that a
`
`bioavailability of 3-4% can be achieved without an enhancer, only that it “believes
`
`that this is possible.” POR at 13. That Patent Owner believes it possible for a
`
`POSA to achieve such a formulation is not enough to enable the full scope of the
`
`claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244 (Fed. Cir. 2003).
`
`In light of the lack of guidance in the ’862 patent, Patent Owner points to the
`
`prior art for enablement of the full range of the claims: “a POSA could use the
`
`knowledge in the prior art to enhance the achievable bioavailability of the
`
`disodium salt or other enhanced forms of zoledronic acid to obtain a higher
`
`bioavailability within the recited range of about 1.1% to about 4%.” POR at 23.
`
`Although the specification need not disclose what is well known in the art, “that
`
`general, oft-repeated statement is merely a rule of supplementation, not a substitute
`
`for a basic enabling disclosure.” Genentech, Inc. v. Novo Nordisk A/S, 108 F.3d
`
`1361, 1366 (Fed. Cir. 1997). “It is the specification, not the knowledge of [a
`
`POSA], that must supply the novel aspects of an invention in order to constitute
`
`7
`
`

`

`adequate enablement.” Id. Here, the ’862 specification fails to provide any
`
`enabling disclosure.
`
`Furthermore, if Patent Owner’s arguments concerning the prior art are
`
`correct, they show that the ’862 patent claims are not inventive. Patent Owner
`
`contends that Aronhime (Exh. 1035) already 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 come to the claimed invention. POR at 13. The ’862 patent does
`
`not actually disclose the bioavailability of any particular salt form disclosed in
`
`Aronhime. Yet, if Patent Owner is correct that a routine bioavailability test of the
`
`salt forms described in Aronhime would reveal the claimed bioavailability ranges,
`
`claims 17-30 are plainly anticipated by Aronhime or obvious over Aronhime and
`
`Leonard. It is not inventive to discover a new property (bioavailability) of a
`
`known substance through routine testing. Atlas Powder Co. v. IRECO Inc., 190
`
`F.3d 1342, 1347 (Fed. Cir. 1999).
`
`II.
`
`CLAIMS 17-30 ARE ANTICIPATED BY OR OBVIOUS OVER
`LEONARD
`
`A.
`
`Patent Owner—Not Petitioner—Has the Burden to Prove
`Leonard Is Not Enabling
`
`Patent Owner incorrectly asserts that Petitioner has the burden to prove that
`
`Leonard’s disclosure is enabling. POR at 25-26. Although it is true that a prior art
`
`8
`
`

`

`reference does not anticipate a claimed invention “if the allegedly anticipatory
`
`disclosures cited as prior art are not enabled,” the very same case law Patent
`
`Owner cites in support of this proposition establishes that the burden is on the
`
`Patent Owner to prove that Leonard is not enabling. See POR at 26. “Both
`
`claimed and unclaimed materials disclosed in a [prior art] patent are presumptively
`
`enabling.” In re Antor Media Corp., 689 F.3d 1282, 1287 (Fed. Cir. 2012). This
`
`“presumption applies in the district court as well as the PTO, placing the burden on
`
`the patentee to show that [claimed or] unclaimed disclosures in a prior art patent
`
`are not enabling.” Id. at 1288.
`
`In a PGR, Petitioner’s burden is to establish anticipation by a preponderance
`
`of the evidence, the same standard applied during patent examination and lower
`
`than the clear and convincing evidence standard applied in litigation. See Manual
`
`of Patent Examining Procedure § 706; 35 U.S.C. § 326(e). It would make no sense
`
`for a PGR Petitioner—unlike the patent examiner or a party accused of
`
`infringement—to have the burden to affirmatively establish prior art references
`
`were enabling. Patent Owner’s contention (at POR 26-27) that Petitioner must
`
`satisfy this “burden” by submitting “an affidavit by an individual having first-hand
`
`knowledge of how the data was generated” applies to Patent Owners to prove the
`
`veracity of data to establish unexpected results, invention dates, or the like. See
`
`Wojciak v. Nishiyama, 61 U.S.P.Q.2d 1576, 1581 (B.P.A.I. 2001); Rules of
`
`9
`
`

`

`Practice for Trials before the PTAB and Judicial Review of PTAB Decisions
`
`[Docket No. PTO-P-2011-0082] RIN 0651-AC70, 48623-24. Patent Owner cites
`
`no legal authority for the proposition that a Petitioner must submit an affidavit
`
`proving the veracity of presumptively enabling disclosures in a prior art patent.
`
`Moreover, Patent Owner’s proposed standard of proof for Leonard stands in
`
`stark contrast to its own arguments concerning enablement. Patent Owner
`
`questions the veracity of Leonard’s human bioavailability study data and contends
`
`that it does not support a bioavailability of 2.5% and a bioavailability range of
`
`from 2.5% to 13% as recited in Leonard claim 2. Yet at the same time, Patent
`
`Owner contends that the ’862 patent specification—which contains no
`
`bioavailability data whatsoever—enables the ranges recited in the claims. The
`
`’862 patent provides no information as to how the many recited bioavailability
`
`ranges were experimentally determined and calculated. Patent Owner cannot
`
`demand more of the prior art than it contends is required in its own specification.
`
`Hoffman-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014).
`
`Even if Patent Owner’s arguments regarding anticipation were correct,
`
`“[u]nder § 103 . . . a reference need not be enabled; it qualifies as a prior art,
`
`regardless, for whatever is disclosed therein.” Amgen Inc. v. Hoechst Marion
`
`Roussel, Inc., 314 F.3d 1313, 1357 (Fed. Cir. 2003). Petitioner relies on Leonard
`
`10
`
`

`

`for what it teaches a POSA, not for the truth of the matters asserted. Thus, no
`
`affidavit is required.
`
`B.
`
`Leonard Expressly Discloses Bioavailability Overlapping the
`Claimed Ranges
`
`Patent Owner’s argument that the “Leonard data does not expressly disclose
`
`bioavailability ranges” is also wrong. POR at 26. First, Leonard claim 2 clearly
`
`and expressly discloses a zoledronic acid dosage form with bioavailability of from
`
`2.5-13%, which overlaps the claimed ranges and is presumed enabled regardless of
`
`the bioavailability data presented in Example 17. Second, a POSA would have
`
`known that bioavailability percentages can be easily and directly calculated from
`
`urinary excretion data for drugs that are not extensively metabolized, like
`
`zoledronic acid. Exh. 1076 ¶33. The urinary excretion values in Example 17 of
`
`Leonard necessarily and directly correspond to particular bioavailability
`
`percentages. Id.. In this case, the urinary excretion data corresponds to values
`
`including 2.54% and 12.99%. Id.; Exh. 1005 ¶¶100-101 In fact, Leonard’s
`
`inventor actually used the Example 17 data in precisely the same way as Dr.
`
`Wilson did to calculate the bioavailability percentage range recited in claim 2.
`
`Exh. 1076 ¶33; Exh. 1039 at 7.
`
`Dr. Wargin does not dispute Dr. Wilson’s calculation of bioavailability
`
`percentages from the urinary excretion data reported in Leonard Example 17. He
`
`merely makes the unremarkable observation that the Leonard dosage forms have a
`
`11
`
`

`

`different, but overlapping bioavailability range compared to the range recited in
`
`claims 17-30. This is insufficient to defeat anticipation where, as here, there are no
`
`unexpected results associated with the claimed range. Exh. 1076 ¶41.
`
`C.
`
`Leonard’s Bioavailability Range Does Not Operate Differently
`than the Claimed Ranges
`
`Patent Owner states that the bioavailability ranges of claims 17-30 are
`
`sdifferent from Leonard because they are “the novel range at which a
`
`therapeutically effective oral dosage form of zoledronic acid is likely to be
`
`achievable without needing an enhancer.” POR at 32 (emphasis added). But
`
`Patent Owner’s after-the-fact attempt to characterize achieving therapeutic efficacy
`
`in the absence of enhancers as critical to its alleged invention is meritless. Claims
`
`17-30 broadly cover zoledronic acid dosage forms having a particular
`
`bioavailability and are devoid of any limitations regarding the presence or absence
`
`of enhancers or efficacy against any particular condition. The specification also
`
`expressly states that “some dosage forms may have ingredients added to enhance
`
`the bioavailability.” Exh. 1001 at 13:7-8. In fact, Patent Owner concedes that the
`
`specification does not say that bioavailability at the upper end of the claimed range
`
`can be achieved without an enhancer. POR at 13. Thus, obtaining particular
`
`bioavailabilities in the absence of enhancers is not a feature of the alleged
`
`invention at all, let alone a distinguishing feature over Leonard.
`
`12
`
`

`

`Nor is it true that the inventor established that zoledronic acid is
`
`therapeutically effective at bioavailabilities of about 1.1% to about 4%. Patent
`
`Owner’s assertion appears to be based on the flawed logic that since a POSA
`
`would have understood that a dosage form of zoledronic acid below 1.1% would
`
`not be expected to be therapeutically effective, that a POSA would, therefore, in
`
`turn expect any dosage form of zoledronic acid with a bioavailability higher than
`
`1.1% to be therapeutically effective. That is clearly not true. In fact, there is no
`
`such thing as a particular bioavailability percentage at which a dosage form
`
`becomes therapeutically effective to treat a particular condition. Exh. 1076 ¶¶38-
`
`41. Whether a drug has therapeutic efficacy depends on the total amount of drug
`
`that must reach its site of action in order to exert a therapeutic effect, which in turn
`
`depends on the potency of the drug compound. Id. ¶¶38-39. The amount of drug
`
`that reaches the site of action depends on the amount of drug in the dosage form
`
`and the drug’s bioavailability in that dosage form. A 100 mg dosage with 2%
`
`bioavailability and a 50 mg dosage with 4% bioavailability would deliver
`
`approximately the same amount of drug to the systemic circulation—2 mg. Exh.
`
`1076 ¶40. If 2 mg is enough to exert a therapeutic effect, both dosage forms would
`
`be therapeutically effective.
`
`13
`
`

`

`Thus, Leonard’s overlapping bioavailability range would be expected to
`
`confer the same efficacy as the claimed dosage forms provided an appropriate dose
`
`is chosen. There is simply no distinction between the two dosage forms.
`
`D.
`
`Leonard Discloses Dosage Forms Where Zoledronic Acid Is the
`Sole Active Ingredient
`
`Contrary to Patent Owner’s arguments, Leonard discloses dosage forms
`
`having zoledronic acid as the only active ingredient as required by the ’862 patent
`
`claims. A POSA would understand that in any description of a dosage form, all
`
`active ingredients would be listed and none would be omitted from the description.
`
`Id. ¶34. Leonard instructs that the dosage forms used in Example 17 may be
`
`formulated in accordance with Examples 6, 8, and 13, which disclose the
`
`preparation of dosage forms containing only one active ingredient. Id. For
`
`example, a dosage form of Example 17 formulated according to Example 6 would
`
`replace the parnaparin sodium in that example with zoledronic acid as taught by
`
`Example 17. Thus, a POSA would have clearly recognized that Leonard discloses
`
`dosage forms having only zoledronic acid as an active ingredient. Patent Owner
`
`has provided no evidence that dosage forms formulated in accordance with
`
`Examples 6, 8, and 13 would not have the bioavailability reported in Example 17
`
`and therefore has failed to meet its burden to show that Leonard is not enabling for
`
`all it discloses.
`
`14
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`

`

`E.
`
`Leonard Anticipates or Renders Obvious Claims 21-22, 25
`
`Claims 21-22 additionally require that the dosage form contain from “about
`
`50 mg to about 100 mg” and from “about 100 mg to about 200 mg” zoledronic
`
`acid. As Patent Owner admits, Leonard discloses that “[t]he amount of drug
`
`compound may suitably be in the range of from about 0.5 µg to about 1000 mg,”
`
`which completely overlaps the ranges of claims 21-22. Ex. 1009 at 9:49-51; POR
`
`at 35. Leonard specifically lists “zoledronate” as an example of a “drug” referred
`
`to by the recited range. Id. at 6:37. Patent Owner’s contention that a POSA would
`
`not have understood the range in Leonard as applying to zoledronic acid is
`
`incorrect and unsupported by any evidence. In fact, the ’862 specification states
`
`that an even broader range of from about 0.005 mg to 2,000 mg of zoledronic acid
`
`may be used. Exh. 1001 at 11:10-33.
`
`Patent Owner’s contention that Leonard does not disclose claim 25’s
`
`requirement that the dosage form be at least 10% by weight zoledronic acid is
`
`without merit. Leonard expressly teaches that the zoledronic acid dosage forms of
`
`its Example 17 may be formulated in accordance with the methods of Examples 6,
`
`8, and 13. A zoledronic acid tablet formulated in accordance with Example 8, for
`
`instance, would contain 37% by weight zoledronic acid. Paper 2 (“Pet.”) at 43-45;
`
`Exh. 1005 ¶¶132-133.
`
`15
`
`

`

`Even if Leonard did not anticipate claims 21-22 and 25, it nevertheless
`
`would have been obvious for a POSA to determine the appropriate amount and
`
`concentration of zoledronic acid to use in the sodium caprate dosage forms
`
`disclosed in Leonard. Exh. 1005 ¶128. “[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).
`
`III. CLAIMS 17-30 ARE OBVIOUS BASED ON LEONARD AND THE
`MERRION POSTER
`
`A.
`
`The Merrion Poster Is Prior Art
`
`The Merrion Poster was presented at the American Cancer Society Breast
`
`Cancer Symposium in San Francisco, CA in October 2009. Exh. 1040; Exh. 1003
`
`¶41; Exh. 1005 ¶106. This date is corroborated by Exhibit 1064 which is an
`
`abstract with the same title, authors, and poster number, which states that the
`
`poster was presented at General Poster Session B.
`
`Moreover, even assuming that the Merrion Poster was not a printed
`
`publication as of the date of its presentation, it was available online at least as early
`
`as March 2, 2011. Exh. 1081 at 6; see also id. at 1 ¶¶5-6. The Merrion Poster was
`
`archived on this date by the Wayback Machine, which uses programs known as
`
`crawlers to compile copies of web files, “preserving these files as they exist at the
`
`point of time of capture” and thereby provides access to archived records for a
`16
`
`

`

`given URL. Exh. 1081 at 1 ¶¶2-4. Thus, the Merrion Poster was publicly
`
`available online no later than March 2011.
`
`The Board has generally accepted documentary evidence generated by the
`
`Wayback Machine as prior art in patent cases. See, e.g., Elec. Arts Inc. v. White
`
`Knuckle IP, LLC, IPR2015-01595, Paper 38 at 11-12 (P.T.A.B. Jan. 12, 2017). A
`
`POSA could have located and accessed the Merrion Poster at least as of March 2,
`
`2011, because “web pages locatable by crawlers of the Wayback Machine would
`
`have been locatable to interested persons using typical search engines.” Creston
`
`Elecs., Inc. v. Intuitive Building Controls, Inc., IPR2015-01460, Paper 14 at 14
`
`(P.T.A.B. January 14, 2016). The Merrion Poster also does not constitute hearsay
`
`because it is not being offered to prove the truth of the matters discussed therein,
`
`only to prove that statements were made at least one year before the critical date.
`
`See id. at 15-16.
`
`B.
`
`Claims 17-30 Do Not Exclude Dosage Formulations That
`Include an Enhancer
`
`Patent Owner alleges that “the range [in claims 17-30] is distinct from and
`
`nonobvious over Leonard” allegedly because the claimed range defines a range “at
`
`which a therapeutically effective oral dosage form of zoledronic acid is likely to be
`
`achievable without the use of an enhancer.” POR at 39-40. However, claims 17-
`
`30 are not limited to dosage forms that do not include an enhancer. Thus, Patent
`
`17
`
`

`

`Owner’s alleged distinction over Leonard is irrelevant to the question of
`
`obviousness.
`
`C.
`
`A POSA in May 2014 Would Have Been Motivated to Formulate
`Zoledronic Acid in an Oral Dosage Form Having a
`Bioavailability Below 2.5% Based on Leonard and the Merrion
`Poster
`
`Patent Owner’s principal argument supporting its nonobviousness assertion
`
`is its claim that a POSA would not modify the dosage form in Leonard to lower
`
`bioavailability. As an initial matter, a POSA need not modify Leonard’s dosage
`
`form to lower bioavailability, which overlaps the claimed range and therefore
`
`renders it prima facie obvious. In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir.
`
`2003); In re Wertheim, 541 F.2d 257, 267 (C.C.P.A. 1976). Patent Owner has not
`
`come forward with any evidence of criticality of the claimed range in rebuttal.
`
`See, e.g., In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997).
`
`Moreover, Patent Owner primarily relies on testimony from Petitioner’s
`
`expert Dr. Bruehl, who admitted that he is not an expert in bioavailability. Exh.
`
`2026 9:17-10:11. Patent Owner’s own expert on bioavailability, on the other hand,
`
`disagrees with its position. Dr. Wargin testified that a POSA would have
`
`understood that since 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
`
`18
`
`

`

`“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 without the
`
`need of adding an enhancer, that might be preferrable [sic] to a dosage form having
`
`a bioavailability of 3 percent including an enhancer.” Id. 69:17-23. Here, Patent
`
`Owner has taken the position that, without any supporting data in the ’862 patent, a
`
`zoledronic acid dosage form having a bioavailability between about 1.1