Paper No. 18
`Filed: May 1, 2019
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`PGR2018-00062
`U.S. Patent No. 9,707,245 B2
`____________
`
`PETITIONER’S REPLY
`
`
`Filed: May 1, 2019
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`PGR2018-00062
`U.S. Patent No. 9,707,245 B2
`____________
`
`PETITIONER’S REPLY
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`Person of Ordinary Skill in the Art .................................................................. 3
`
`Claims 1-4, 9-10, 12, 14, 16-18, 23-24, 27-29 Are Anticipated
`by Varenna 2012 .............................................................................................. 3
`
`A.
`
`B.
`
`C.
`
`D.
`
`Petitioner Has Proven that Varenna 2012 Is Prior Art .......................... 3
`
`The Challenged Claims Do Not Require Efficacy ................................ 7
`
`Varenna 2012 Expressly Discloses That Neridronate Is
`Effective ................................................................................................ 9
`
`Varenna 2012 Inherently Anticipates the Challenged
`Claims .................................................................................................. 12
`
`III. Claims 1-29 Are Obvious Based Upon Varenna 2012 Alone or
`in Combination with Bruehl and One or More of Gatti, La
`Montagna, and/or Muratore ........................................................................... 13
`
`A.
`
`B.
`
`The Prior Art Teaches or Suggests All Claim Elements ..................... 13
`
`Patent Owner Failed to Produce Evidence of Unexpected
`Results ................................................................................................. 15
`
`IV. Claims 5-8, 21, and 26 Are Obvious Over Varenna and
`Manicourt ....................................................................................................... 17
`
`V.
`
`Claim 30 Is Obvious ...................................................................................... 19
`
`VI. Alternatively, Claims 1-30 Lack Written Description .................................. 21
`
`VII. Alternatively, Claims 1-30 Are Not Enabled ................................................ 23
`
`VIII. Conclusion ..................................................................................................... 25
`
`i
`
`
`
`TABLE OF AUTHORITIES
`
`Cases
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .....................................................................18
`
`Atlas Powder Co. v. IRECO Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) .....................................................................12
`
`Dynamic Drinkware LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) ....................................................................... 6
`
`Ericsson Inc. v. Intellectual Ventures I LLC,
`IPR2014-00527, Paper 41 (P.T.A.B. May 18, 2015) ...................................... 5
`
`Ex parte Eggleston,
`159 U.S.P.Q. 692 (B.P.A.I. 1967) .................................................................22
`
`Ford Motor Co. v. Cruise Control Techs. LLC,
`IPR2014-00291, Paper 44 (P.T.A.B. June 29, 2015) ...................................... 4
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .......................................................................18
`
`Genentech, Inc. v. Novo Nordisk A/S,
`108 F.3d 1361 (Fed. Cir. 1997) .....................................................................24
`
`Hoffman-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .............................................................. 22, 24
`
`In re Efthymiopoulos,
`839 F.3d 1375 (Fed. Cir. 2016) .....................................................................19
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .....................................................................16
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .....................................................................12
`
`In re Lindner,
`457 F.2d 506 (C.C.P.A. 1972) .......................................................................16
`
`ii
`
`
`
`Provepharm Inc. v. Wista Labs. Ltd.,
`IPR2018-00182, Paper 16 (P.T.A.B. Jul. 5, 2018) .......................................... 4
`
`Rayvio Corp. v. Nitride Semiconductors Co. Ltd.,
`IPR2018-01141, Paper 14 (P.T.A.B. Dec. 4, 2018) ........................................ 4
`
`Statutes
`
`35 U.S.C. § 112 .......................................................................................................... 2
`
`Rules
`
`Fed. R. Evid. 803(17) ................................................................................................. 5
`
`Fed. R. Evid. 807 ....................................................................................................... 5
`
`Regulations
`
`37 C.F.R. § 42.64(b)(1) ..........................................................................................4, 6
`
`iii
`
`
`
`The ’245 patent is nothing more than Patent Owner’s attempt to take credit
`
`for others’ work. In November 2012, Dr. Massimo Varenna, et al. published a
`
`clinical study showing that neridronate, a bisphosphonate drug, is effective to treat
`
`CRPS. Ex. 1005. The patients Dr. Varenna treated included patients having
`
`fracture-induced CRPS.1 Id. at 536. In May 2013, after Dr. Varenna’s work was
`
`published, Patent Owner filed a patent application directed to the use of zoledronic
`
`acid, a different bisphosphonate, for the treatment of “any type of pain.” Ex. 1024
`
`at 21. That application also contained a laundry list of other bisphosphonates that
`
`could allegedly be used in the purported invention, including neridronate. Id. at
`
`20, ¶23. Later, Dr. Varenna published Varenna 2017 with several of the same co-
`
`authors as Varenna 2012. Ex. 1015. Varenna 2017 analyzed data from patients
`
`who received the same neridronic acid dosing regimen described in Varenna
`
`2012—including the Varenna 2012 patients themselves—and concluded that
`
`patients with fracture-induced CRPS were more likely to respond to that treatment
`
`than patients with CRPS triggered by other causes. Id. at 1131, 1134.
`
`1 Petitioner follows the Board’s convention of using “fracture-induced CRPS” as
`
`shorthand for “CRPS wherein fracture was a predisposing [or precipitating] event.”
`
`See Paper 11 at 13-14.
`
`1
`
`
`
`Now, having done nothing more than file a broad patent application with no
`
`working examples pertinent to neridronate between Varenna 2012 and Varenna
`
`2017, Patent Owner claims that it owns the use of Dr. Varenna’s methods to treat
`
`fracture-induced CRPS. This cannot be correct. Indeed, the Board properly
`
`determined in its Institution Decision (“D.I.,” Paper 11) that all challenged claims
`
`were more likely than not anticipated by Varenna 2012 and/or obvious over
`
`Varenna 2012 alone or in combination with other prior art.
`
`Patent Owner’s Response (“POR,” Paper 15) does nothing to undermine the
`
`Board’s initial determinations. The Board based its Institution Decision in large
`
`part on the testimony of Petitioner’s expert Dr. Lawrence Poree, a Ph.D. and
`
`practicing M.D. with over 20 years’ experience treating and studying chronic pain
`
`disorders such as CRPS. See Ex. 1003 ¶¶5-12. Dr. Poree’s opinions stand
`
`unrebutted; Patent Owner did not submit any expert testimony and did not depose
`
`Dr. Poree. In response, Patent Owner submits only bare and unsupported attorney
`
`arguments that misconstrue the prior art, are factually incorrect for a number of
`
`reasons, and are legally baseless, as discussed below. Moreover, even if the Board
`
`were to agree with Patent Owner that the challenged claims are not anticipated
`
`and/or obvious over the prior art, the Board should then be left with no choice but
`
`to find the challenged claims unpatentable under 35 U.S.C. § 112 given the lack of
`
`disclosure over what was already known in the art.
`
`2
`
`
`
`I.
`
`Person of Ordinary Skill in the Art
`
`Patent Owner argues that Petitioner’s definition of the person of ordinary
`
`skill in the art (POSA) is incorrect because it includes experience and education in
`
`clinical psychology. Petitioner maintains that its definition is correct, but the
`
`differences between Petitioner’s and Patent Owner’s definitions have no impact on
`
`the asserted grounds here.
`
`II.
`
`Claims 1-4, 9-10, 12, 14, 16-18, 23-24, 27-29 Are Anticipated by Varenna
`20122
`
`A.
`
`Petitioner Has Proven that Varenna 2012 Is Prior Art
`
`Contrary to Patent Owner’s arguments, Petitioner adduced sufficient
`
`evidence demonstrating that Varenna 2012, Ex. 1005 filed with the Petition, is
`
`prior art to the ’245 patent. See Petition (“Pet.,” Paper 2) at 34. Patent Owner does
`
`not dispute that the ’245 patent’s earliest possible priority date is May 14, 2013.
`
`See id. at 17-22; D.I. at 7. Varenna 2012 was plainly published, i.e. made publicly
`
`available, before that date. At the top of the first page, Varenna 2012 expressly
`
`states that it is an article from the journal Rheumatology published on November
`
`30, 2012. Ex. 1005 at 534. Moreover, the copyright line at the bottom of the first
`
`page reads: “© The Author 2012. Published by Oxford University Press on behalf
`
`2 Petitioner addresses the Petition’s grounds in the order that the Board considered
`
`them in the Institution Decision.
`
`3
`
`
`
`of the British Society for Rheumatology. All rights reserved. For Permissions,
`
`please email: journals.permissions@oup.com.” Id. This indicates that Varenna
`
`2012 was published in 2012 by a well-known and reputable publisher.
`
`Patent Owner argues—for the first time in the POR—that these dates are
`
`“inadmissible hearsay.” POR at 13. But Patent Owner failed to timely object to
`
`Varenna 2012 within ten business days of the institution of trial as required by 37
`
`C.F.R. § 42.64(b)(1). See Paper No. 13. Thus, Patent Owner waived any hearsay
`
`objections to Varenna 2012, including its publication and copyright dates. Those
`
`dates are properly before the Board and, absent any evidence to the contrary, are
`
`sufficient to show that Varenna 2012 is prior art to the ’245 patent. See Ford
`
`Motor Co. v. Cruise Control Techs. LLC, IPR2014-00291, Paper 44 at 6-11
`
`(P.T.A.B. June 29, 2015) (finding reference was prior art where Patent Owner
`
`“offere[d] no rebuttal vis-à-vis the printed copyright notice” on face of reference);
`
`Rayvio Corp. v. Nitride Semiconductors Co. Ltd., IPR2018-01141, Paper 14 at 26-
`
`27 (P.T.A.B. Dec. 4, 2018) (reference’s pre-filing copyright date and statement that
`
`it was “published . . . by Oxford University Press” established it was prior art);
`
`Provepharm Inc. v. Wista Labs. Ltd., IPR2018-00182, Paper 16 at 17-18 (P.T.A.B.
`
`Jul. 5, 2018) (article’s “submitted” and “published” dates established publication
`
`date).
`
`4
`
`
`
`Even if Patent Owner had timely objected, the publication and copyright
`
`dates in Varenna 2012 would still be admissible because they meet one or more
`
`hearsay exceptions. For example, the dates fall under the Fed. R. Evid. 803(17)
`
`exception because they are “generally relied on by the public or by persons in
`
`particular occupations.” See Ericsson Inc. v. Intellectual Ventures I LLC,
`
`IPR2014-00527, Paper 41 at 10-11 (P.T.A.B. May 18, 2015). Alternatively, the
`
`dates fall under the residual exception of Fed. R. Evid. 807. See id. If Patent
`
`Owner elects to file a motion to exclude Varenna 2012 despite not having timely
`
`objected, Petitioner will address these evidentiary issues in more detail in a
`
`response.
`
`Moreover, if the Board entertains Patent Owner’s untimely objections,
`
`Petitioner will rely upon the testimony of Dr. Philip Robinson as further proof that
`
`Varenna 2012 was publicly available before May 14, 2013. Ex. 1031. Dr.
`
`Robinson testifies that he accessed, reviewed, and posted about Varenna 2012 on
`
`the social media site Twitter in February 2013, proving beyond any question that it
`
`was publicly available before the ’245 patent’s earliest possible priority date. Id.
`
`Next, Patent Owner argues—again for the first time in the POR—that
`
`Varenna 2012 “does not bear the indicia of authenticity one would expect from an
`
`actually published and disseminated article.” POR at 13. Again, to the extent
`
`5
`
`
`
`Patent Owner contests Varenna 2012’s authenticity, that objection is waived. 37
`
`C.F.R. § 42.64(b)(1); see Paper No. 13.
`
`In the Institution Decision, the Board concluded based on the evidence
`
`before it that Petitioner made a threshold showing that it is more likely than not
`
`that Varenna 2012 is anticipatory prior art. See D.I. at 6, 10-12. At this time the
`
`burden of production shifted to Patent Owner to come forward with evidence
`
`showing that Varenna was not prior art. See Dynamic Drinkware LLC v. Nat’l
`
`Graphics, Inc., 800 F.3d 1375, 1379 (Fed. Cir. 2015). But Patent Owner presents
`
`nothing more than attorney argument that Varenna 2012 was not “actually
`
`published and disseminated.” This is simply insufficient. Varenna 2012 states on
`
`its face that it is an article from the journal Rheumatology published by Oxford
`
`University Press. Patent Owner provides no expert testimony or any other
`
`explanation as to why the words “Original Article” or “Advance Access
`
`publication” appearing on the first page of Varenna 2012 suggest that it was not
`
`disseminated and accessible. See POR at 13-14. Quite the contrary, “Original
`
`Article” and “Advance Access publication 30 November 2012” mean what they
`
`say: That Varenna 2012 is an original article published on that date. See Pet. at
`
`34; Ex. 1005 at 534.
`
`Patent Owner also takes issue with the “Varenna 2012” label Petitioner
`
`assigned to Ex. 1005 in the Petition. Yet, it was Patent Owner that coined that
`
`6
`
`
`
`moniker. In Information Disclosure Statements filed during prosecution, Patent
`
`Owner submitted this reference to the PTO with a filename “Varenna2012.pdf”
`
`and represented that it had a publication date of November 2012. Ex. 1022 at 432,
`
`440. If these statements are not binding admissions, they are at least sufficient,
`
`credible evidence that Varenna 2012 is prior art.
`
`B.
`
`The Challenged Claims Do Not Require Efficacy
`
`As to Petitioner’s anticipation ground, Patent Owner disputes only whether
`
`Varenna 2012 teaches that “neridronic acid effectively mitigates pain associated
`
`with CRPS in patients presenting with ‘bone fracture’ as a ‘predisposing event for’
`
`that condition.” POR at 15 (quoting D.I. at 11) (emphasis added). Patent Owner
`
`further argues that anticipation here requires a conclusive showing of efficacy by
`
`conducting a sufficiently large clinical trial. Id. at 19-20. Patent Owner’s
`
`arguments are misplaced.
`
`Patent Owner’s contention that “at least some level of diagnosing, curing,
`
`mitigating, or preventing pain” must “be shown” is nothing more than unsupported
`
`attorney argument. See POR at 2. Likewise, Patent Owner’s unsupported
`
`argument that anticipation requires “conclusive” evidence of efficacy from a large
`
`clinical trial is also incorrect. Id. at 19-20.
`
`Efficacy is not a limitation of any challenged claim. Pet. at 15. In fact, it is
`
`undisputed that the ’245 patent claims do not require any particular level of
`
`7
`
`
`
`efficacy. POR at 2. They “only require that one use neridronic acid to treat CRPS
`
`in patients with bone fracture as a predisposing event.” Id. at 9. Indeed, Dr.
`
`Poree’s unrebutted expert testimony establishes a POSA would interpret the claims
`
`as:
`
`requir[ing] administration of neridronic acid . . . for the
`purpose of diagnosing, curing, mitigating, and/or
`preventing pain associated with CRPS or for having
`activity that otherwise affects the structure or any
`function of the body in a human being with CRPS,
`wherein fracture was a predisposing event for
`CRPS . . . . The terms “treating” or “treatment,” as
`defined, do not require any particular measure or level of
`efficacy against pain associated with CRPS.
`
`Ex. 1003 ¶¶33-34; Pet. at 15.
`
`Consequently, consistent with Dr. Poree’s unrebutted opinions, all that the
`
`’245 patent claims require is administration of neridronic acid to a patient having
`
`fracture-induced CRPS for the purpose of treating pain associated with CRPS. Ex.
`
`1003 ¶¶33-34; Pet. at 15. Varenna 2012 plainly discloses administration of
`
`neridronic acid to such patients for the purpose of treating, among other symptoms,
`
`pain associated with CRPS. Ex. 1005 at 536; Pet. at 35-36. Thus, Patent Owner’s
`
`sole argument against anticipation is unavailing.
`
`8
`
`
`
`C.
`
`Varenna 2012 Expressly Discloses That Neridronate Is Effective
`
`Even if the challenged claims required efficacy, Varenna 2012 would still
`
`anticipate. See Pet. at 35-39. In Varenna 2012’s double-blind study phase, 11 of
`
`41 CRPS patients receiving neridronic acid had fracture-induced CRPS. Ex. 1005
`
`at 536; Ex. 1003 ¶84. Based on the results of that study, Varenna 2012 broadly
`
`concludes that “a course of i.v. neridronate reduces pain intensity and improves
`
`clinical signs and functional status in patients with CRPS-I at either the hand or
`
`foot.” Ex. 1005 at 538; Ex. 1003 ¶86. Varenna 2012 further states that a
`
`“[m]ultivariate regression analysis was performed to assess the potential influence
`
`of baseline variables on treatment effect [site of disease: (upper/lower limb),
`
`disease duration and precipitating event (none/trauma, surgery)].” Ex. 1005 at
`
`536; Ex. 1003 ¶87. In the multivariate regression analysis, “baseline variables
`
`except treatment assignment” did not “appear[] to influence outcome measures.”
`
`Ex. 1005 at 538; Ex. 1003 ¶87. Dr. Poree considered these statements, among
`
`others, and concluded that Varenna 2012 teaches a POSA that “the particular type
`
`of precipitating event did not influence outcomes in the study, indicating that
`
`patients with all types of precipitating events, including fractures, benefited from
`
`the neridronate treatment.” Ex. 1003 ¶88.
`
`Patent Owner tries to contest Dr. Poree’s conclusions, arguing that Varenna
`
`2012 omitted fracture patients from the analysis of the precipitating event baseline
`
`9
`
`
`
`variable because “fracture” is not listed in parentheses after “precipitating event” in
`
`the “statistical analysis” section of the article. POR at 16-18. As an initial matter,
`
`Patent Owner’s unsupported attorney argument does not and cannot refute Dr.
`
`Poree’s expert opinions concerning how a POSA would interpret Varenna 2012.
`
`But Patent Owner’s arguments are also clearly scientifically incorrect for at least
`
`three reasons.
`
`First, Varenna 2012’s statistical analysis section expressly states that “[t]he
`
`statistical analysis was carried out according to the intention-to-treat principle,
`
`including all randomized patients who received at least one dose of the study
`
`medication.” Ex. 1005 at 536 (emphasis added). Thus, fracture patients were
`
`included in the multivariate regression analysis, which ultimately concluded that
`
`no baseline variables (such as precipitating event) other than treatment assignment
`
`affected the study’s outcome measures. Ex. 1005 at 538; Ex. 1003 ¶¶87-88. In
`
`fact, Varenna 2012 affirmatively states that, other than treatment assignment, “[w]e
`
`could not identify other baseline factors influencing the outcome measures to
`
`neridronate treatment as well as the high positive response rate we observed.” Ex.
`
`1005 at 540 (emphasis added). Varenna 2012 simply did not omit fracture as a
`
`precipitating event, or any other baseline variable, from the analysis, and thus
`
`showed that treatment with neridronate was effective in fracture patients. See Ex.
`
`1003 ¶88.
`
`10
`
`
`
`Second, Varenna 2012 broadly states that the study showed “significant,
`
`clinically relevant and persistent benefit to patients with acute CRPS-I following
`
`an i.v. neridronate course, providing in our opinion conclusive evidence that the
`
`use of bisphosphonate, at appropriate doses, is the treatment of choice for CRPS-
`
`I.” Ex. 1005 at 541; Ex. 1003 ¶77. Such broad conclusions could not be reached if
`
`the investigators had omitted fracture patients from the baseline variable analysis.
`
`Third, Varenna 2012 discloses that “[d]uring the open-extension phase in the
`
`former[] placebo group the results of treatment were superimposable on those seen
`
`during the blind phase in the active group. A year later none of the patients was
`
`referring symptoms linked to CRPS-I.” Ex. 1005 at 534; Ex. 1003 ¶¶124-125.
`
`Indeed, “[a]t an investigator global assessment, the disease was considered
`
`resolved in all patients, with the remaining symptoms (pain or stiffness) not
`
`attributed to CRPS-I.” Id. at 538. Because the open-extension phase of the study
`
`included patients with fracture-induced CRPS formerly in the placebo group,
`
`Varenna necessarily discloses that neridronate is effective to treat pain in fracture-
`
`induced CRPS. Ex. 1003 ¶¶124-125; Pet. at 36, 37, 46.
`
`Patent Owner’s other contention, that Varenna 2012’s results are not
`
`“conclusive evidence of efficacy” for fracture-induced CRPS, is legally unsound.
`
`POR at 19-20. Even if the claims required efficacy—they do not—“conclusive
`
`evidence” from a 20+ participant clinical trial would not be required. Moreover,
`
`11
`
`
`
`Varenna 2012’s treatment group comprised 41 patients with precipitating events as
`
`follows: 11 fracture, 10 trauma, 5 surgery, and 15 unknown. None of the
`
`precipitating events were represented by more than 20 participants. Ex. 1005 at
`
`536. According to Patent Owner’s tortured logic, Varenna can “conclusively”
`
`conclude that neridronate is effective to treat CRPS without regard to precipitating
`
`event, but provides no evidence regarding whether pain was effectively mitigated
`
`for any one of them. This is neither technically nor legally supportable.
`
`D.
`
`Varenna 2012 Inherently Anticipates the Challenged Claims
`
`To the extent Varenna does not expressly disclose the effective treatment of
`
`fracture-induced CRPS, it does so inherently. It is not inventive to discover an
`
`inherent property of that which was already known in the art. See Atlas Powder
`
`Co. v. IRECO Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999); In re Kao, 639 F.3d
`
`1057, 1070 (Fed. Cir. 2011). Patent Owner cites to Varenna 2017 as evidence of
`
`purported “unexpected results,” but it actually demonstrates that the challenged
`
`claims are anticipated by Varenna 2012. Varenna 2017 describes “a retrospective
`
`data analysis of patients with a diagnosis of CRPS-I referred to our unit in the last
`
`five years for treatment with bisphosphonate infusions.” Ex. 1015 at 1132. It
`
`further discloses that some of these “patients were treated with neridronate 100mg
`
`every third day for four occasions [10].” Id. at 1133. This is exactly the same
`
`dosing regimen that was used in Varenna 2012, and footnote “[10]” is Varenna
`
`12
`
`
`
`2012. Id. at 1133, 1137; Ex. 1005 at 535. Based on the data analysis, Varenna
`
`2017 concludes that patients with fracture-induced CRPS were more likely to
`
`respond to this treatment regimen. Ex. 1015 at 1134-35. At minimum, then,
`
`Varenna 2017 establishes that at least some patients with fracture-induced CRPS in
`
`the Varenna 2012 study necessarily benefitted from the treatment.3 Thus, the
`
`challenged claims are inherently anticipated.
`
`***
`
`In sum, none of Patent Owner’s arguments against anticipation have merit.
`
`The Board should maintain its conclusion that claims 1-4, 9-10, 12, 14, 16-18, 23-
`
`24, 27-29 are anticipated by Varenna 2012.
`
`III. Claims 1-29 Are Obvious Based Upon Varenna 2012 Alone or in
`Combination with Bruehl and One or More of Gatti, La Montagna,
`and/or Muratore
`
`A.
`
`The Prior Art Teaches or Suggests All Claim Elements
`
`Patent Owner argues, without explanation or support, that Varenna 2012,
`
`Gatti, La Montagna, and Muratore do not disclose treating pain associated with
`
`3 If Patent Owner contends that Varenna 2017 does not establish that at least some
`
`patients with fracture-induced CRPS necessarily benefitted from Varenna 2012’s
`
`treatment regimen, then it clearly cannot support any “unexpected results.” See
`
`Section III.B below.
`
`13
`
`
`
`fracture-induced CRPS as claimed. POR at 20-21. Patent Owner is incorrect. As
`
`discussed above, Varenna 2012 expressly teaches that neridronate was
`
`administered to patients having fracture-induced CRPS for the purpose of treating
`
`pain associated with CRPS. See Section II above; Pet. at 35-39; Ex. 1003 ¶¶75-88.
`
`Thus, that element is plainly disclosed in Varenna 2012.
`
`To the extent Patent Owner contends that Varenna 2012 does not disclose
`
`“efficacy,” this, too, is wrong because efficacy is not a limitation of any challenged
`
`claim. Nonetheless, as discussed above and contrary to Patent Owner’s arguments,
`
`Varenna 2012 did include fracture in its statistical analysis and does expressly
`
`disclose patients with fracture-induced CRPS benefitted from treatment. See
`
`Section II.C. And it is undisputed that Varenna 2012, Gatti, La Montagna, and
`
`Muratore each disclose the use of neridronate to treat CRPS generally without
`
`reference to precipitating event. Ex. 1003 ¶¶129-139. This, at a minimum,
`
`suggests that neridronate would be effective to treat fracture-induced CRPS, which
`
`according to Bruehl is among the most common CRPS-precipitating events. Id.
`
`¶131. As such, no elements are missing from the prior art.
`
`Patent Owner further contends, without support, that Varenna would not
`
`motivate a POSA to select patients with fracture-induced CRPS for neridronate
`
`treatment. POR at 21. Not so. Dr. Poree’s thorough, detailed, and unrebutted
`
`opinions on obviousness establish that:
`
`14
`
`
`
`1. Varenna 2012 teaches that neridronate was effective to treat CRPS
`
`generally in a study that included fracture-induced CRPS patients (Ex.
`
`1003 ¶¶124-128);
`
`2. Gatti, Muratore, and La Montagna all teach that neridronic acid is
`
`effective to treat CRPS generally (Id. ¶139);
`
`3. Bruehl teaches that fracture is among the most common CRPS-
`
`precipitating events (Id. ¶140);
`
`4. Nothing in the prior art suggests that, contrary to the general
`
`teachings, pain associated with fracture-induced CRPS in particular
`
`could not be effectively treated with neridronate (Id. ¶143-144);
`
`5. A POSA would have been motivated to combine these references and
`
`would have had a reasonable expectation of success in using
`
`neridronate to treat pain associated with CRPS triggered by a fracture
`
`(Id. ¶¶141-42).
`
`Patent Owner’s attorney argument does not and cannot disturb Dr. Poree’s
`
`conclusions. Consequently, nothing in the POR negates Petitioner’s prima facie
`
`obviousness case.
`
`B.
`
`Patent Owner Failed to Produce Evidence of Unexpected Results
`
`Patent Owner has not established that the results presented in Varenna 2017
`
`are, in fact, unexpected. Patent Owner cites to nothing in Varenna 2017 suggesting
`
`15
`
`
`
`that the authors found their results surprising or unexpected in view of their earlier
`
`work in Varenna 2012. Without offering any expert testimony, Patent Owner
`
`simply argues that the results are “unexpected.” See POR at 22-28. But “[m]ere
`
`lawyers’ arguments unsupported by factual evidence are insufficient to establish
`
`unexpected results.” In re Lindner, 457 F.2d 506, 508 (C.C.P.A. 1972); see also In
`
`re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) (“attorney argument” is “not the
`
`kind of factual evidence that is required to rebut a prima facie case of
`
`obviousness”). Thus, Dr. Poree’s expert opinion that a POSA would not find the
`
`results to be unexpected stands unrebutted. Ex. 1003 ¶¶174-178; Pet. at 62-67.
`
`Moreover, Patent Owner cannot show that its alleged unexpected results are
`
`unexpected over the prior art. Patent Owner states that the claimed method “is
`
`unexpectedly effective as compared to treatment of CRPS in patients with
`
`precipitating events other than bone fracture.” POR at 22. But this is the wrong
`
`comparison—the prior art does not only teach treatment of patients with other
`
`precipitating events to the exclusion of fracture. It discloses the use of neridronate
`
`to treat CRPS generally, without regard to precipitating event, and Varenna 2012
`
`expressly teaches administration of neridronate to patients having fracture-induced
`
`CRPS. Ex. 1003 ¶¶124-128. Based on these disclosures, Dr. Poree testified “data
`
`showing that fracture patients respond better than patients with other predisposing
`
`events does not change the fact that a POSA would have reasonably expected that
`
`16
`
`
`
`neridronic acid could be used to treat pain associated with CRPS triggered by a
`
`fracture.” Ex. 1003 ¶177. Thus, Patent Owner has not shown that the claimed
`
`methods have unexpected results compared to the prior art.
`
`And even if the Board accepts Patent Owner’s incorrect attorney argument,
`
`the results are still insufficient to support the patentability of the challenged claims.
`
`Patent Owner does not even attempt to respond to Petitioner’s arguments that the
`
`alleged unexpected results (1) are at best a difference in degree, not a difference in
`
`kind, and (2) are not commensurate with the scope of the claims. See Pet. at 64-66.
`
`Consequently, Patent Owner has failed to establish unexpected results.
`
`IV. Claims 5-8, 21, and 26 Are Obvious Over Varenna and Manicourt
`
`Patent Owner advances two arguments against Ground 5 and both are
`
`meritless. Patent Owner’s first argument, that Varenna teaches a POSA to
`
`“disregard Manicourt,” is simply false. POR at 29. Citing to Manicourt, Varenna
`
`2012 states that “[p]ositive results have also been reported in . . . randomized
`
`clinical trials using . . . 40 mg daily oral alendronate for 12-16 weeks.” Ex. 1005 at
`
`540 (emphasis added). And Varenna 2012 used Manicourt’s oral alendronate
`
`dosage to determine the intravenous neridronate dosage to use in its own study. Id.
`
`A reference teaches away only if a POSA, “upon reading the reference, would be
`
`discouraged from following the path set out in the reference, or would be led in a
`
`direction divergent from the path that was taken.” Galderma Labs., L.P. v.
`
`17
`
`
`
`Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013). A reference that “does not
`
`criticize, discredit, or otherwise discourage investigation into” the alleged
`
`invention does not teach away. Id. Varenna 2012’s use of Manicourt’s oral
`
`dosage amount and description of Manicourt’s results as “[p]ositive” but not
`
`“conclusive” is hardly discrediting or discouraging. Thus, Varenna does not
`
`“teach[] a POSA to disregard Manicourt” as Patent Owner contends. POR at 29.
`
`Patent Owner cites no legal authority for its second argument that the prior
`
`art must expressly disclose an oral neridronic acid dosage form that a POSA could
`
`import into Varenna 2012’s method. See POR at 29-30. Obviousness imposes no
`
`such requirement and a POSA need not combine prior art references in any
`
`particular order or way to arrive at the claimed invention. See Alcon Research,
`
`Ltd. v. Apotex Inc., 687 F.3d 1362, 1368 (Fed. Cir. 2012) (POSA’s reasoning or
`
`motivation need not match the inventor’s in arriving at the alleged invention). Dr.
`
`Poree’s unrebutted expert testimony establishes that the POSA would have arrived
`
`at the alleged inventions of the challenged claims in a different way than the
`
`strawman rationale Patent Owner has set up. Ex. 1003 ¶¶153-163. Rather than
`
`taking a preexisting oral neridronic acid dosage form and importing it into Varenna
`
`2012, Dr. Poree explains that the POSA would have been motivated by
`
`Manicourt’s disclosure of “effective” and “well-tolerated” oral dosage forms to
`
`take Varenna 2012’s intravenous neridronic acid—demonstrated to be effective—
`
`18
`
`
`
`and administer it as an oral dosage form, as described in Manicourt. Id. ¶¶159-
`
`162; see In re Efthymiopoulos, 839 F.3d 1375, 1376-78 (Fed. Cir. 2016) (claims to
`
`treating influenza with orally inhaled zanamivir obvious over reference teaching
`
`influenza treatment with zanamivir combined with reference teaching influenza
`
`treatment with oral inhalation of a compound similar to zanamivir). There is no
`
`requirement that Petitioner’s obviousness arguments follow Patent Owner’s chosen
`
`rationale. Thus, as the Board previously concluded, claims 5-8, 21, and 26 are
`
`obvious. D.I. at 14.
`
`V.
`
`Claim 30 Is Obvious
`
`It is apparently undisputed that a POSA would have had a reasonable
`
`expectation of success in treating CRPS II with neridronate, as required by claim
`
`30. See POR at 33. And Patent Owne
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