Trials@uspto.gov
`Tel: 571-272-7822
`
`Paper 24
`Date: July 28, 2020
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`GRÜNENTHAL GMBH,
`Petitioner,
`v.
`ANTECIP BIOVENTURES II LLC,
`Patent Owner.
`
`PGR2019-00027
`Patent 10,039,774 B2
`
`
`
`
`
`
`
`
`
`Before GRACE KARAFFA OBERMANN, CHRISTOPHER M. KAISER,
`and WESLEY B. DERRICK, Administrative Patent Judges.
`OBERMANN, Administrative Patent Judge.
`
`JUDGMENT
`Final Written Decision
`Determining All Claims Unpatentable
`35 U.S.C. § 328(a)
`
`
`
`
`
`
`
`Tel: 571-272-7822
`
`Paper 24
`Date: July 28, 2020
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`GRÜNENTHAL GMBH,
`Petitioner,
`v.
`ANTECIP BIOVENTURES II LLC,
`Patent Owner.
`
`PGR2019-00027
`Patent 10,039,774 B2
`
`
`
`
`
`
`
`
`
`Before GRACE KARAFFA OBERMANN, CHRISTOPHER M. KAISER,
`and WESLEY B. DERRICK, Administrative Patent Judges.
`OBERMANN, Administrative Patent Judge.
`
`JUDGMENT
`Final Written Decision
`Determining All Claims Unpatentable
`35 U.S.C. § 328(a)
`
`
`
`
`
`
`
`
`PGR2019-00027
`Patent 10,039,774 B2
`
`
`INTRODUCTION
`
`A. Background
`Grünenthal GmbH (“Petitioner”) filed a Petition (Paper 2, “Pet.”)
`requesting a post-grant review of claims 1–29 of U.S. Patent No. 10,039,774
`B2 (Ex. 1002, “the ’774 patent”). Antecip Bioventures II LLC (“Patent
`Owner”) did not file a Preliminary Response. We instituted review of all
`challenged claims on each of the grounds asserted in the Petition. Paper 6
`(“Dec. Inst.”). Following institution, Patent Owner filed a Response (Paper
`10, “PO Resp.”), Petitioner filed a Reply (Paper 12, “Reply”), and Patent
`Owner filed a Sur-Reply (Paper 15, “PO Sur-Reply”). Patent Owner also
`filed a motion to exclude certain evidence. Paper 20 (“Mot. Exclude”).
`Petitioner opposed this motion (Paper 21, “Opp. Mot.”), and Patent Owner
`filed a Reply (Paper 22, “Reply Mot.”). We held a hearing on April 24,
`2020, the transcript of which has been entered into the record. Paper 23.
`We have jurisdiction under 35 U.S.C. § 6, and we issue this Final
`Written Decision pursuant to 35 U.S.C. § 328(a). We conclude that
`Petitioner has established by a preponderance of the evidence that claims 1–
`29 of the ’774 patent are unpatentable.
`
`B. Related Matters
`The parties do not direct us to any judicial matter that would be
`affected by the outcome of this proceeding. Pet. 4–5; Paper 3, 2. Petitioner,
`however, challenges patents related to the ’774 patent in additional
`administrative petitions for review. Pet. 4; Paper 3, 2. In particular,
`according to the parties, the Board has issued final written decisions in
`PGR2017-00008 and PGR2017-00022, and petitions are pending in
`PGR2018-00001, PGR2018-00062, PGR2019-00003, PGR2019-00026, and
`
`2
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`PGR2019-00027
`Patent 10,039,774 B2
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`PGR2019-00028. Id. After the parties identified related matters, the Board
`issued a final written decision in PGR2018-00001. See PGR2018-00001,
`Paper 48 (PTAB April 29, 2019).
`
`C. The Asserted Grounds of Unpatentability
`Petitioner contends that claims 1–29 of the ’774 patent are
`unpatentable based on the following grounds (Pet. 22–75):1
`
`35 U.S.C. §
`103
`
`References/Basis
`Varenna 2011, 2 Gatti, 3
`Muratore, 4 Harden,5
`Drummond6
`
`Challenged Claims
`1–15
`
`
`1 Petitioner also relies on a Declaration from Lawrence Poree, M.D., Ph.D.
`Ex. 1004.
`2 Massimo Varenna, The Clinical Framework of Algodystrophy (Complex
`Regional Pain Syndrome Type I), An Update, 37 IT. J. ORTHOPEDICS &
`TRAUMATOLOGY 227, 227–34 (Oct. 2011) (Ex. 1006, “Varenna 2011”)
`(English translation).
`3 Davide Gatti, Ombretta Viapiana, Luca Idolazzi, Elena Fracassi & Silvano
`Adami, Neridronic Acid for the Treatment of Bone Metabolic Diseases,
`5 EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 1305, 1305–11
`(2009) (Ex. 1008, “Gatti”).
`4 M. Muratore, F. Calcagnile, L. Cosentino, M. Serra, C. Circhetta, & E.
`Quarta, Neridronate in the Treatment of Reflex Sympathetic Hip
`Algodystrophy: Open Comparison with Clodronate, PROGRESS IN
`RHEUMATOLOGY (Apr. 2004) (Ex. 1007, “Muratore”) (English translation).
`5 R. Norman Harden, Stephen Bruehl, Roberto S.G.M. Perez, Frank
`Birklein, Johan Marinus, Christian Maihofner, Timothy Lubenow,
`Asokumar Buvanendran, Sean Mackey, Joseph Graciosa, Mila Mogilevski,
`Christopher Ramsden, Melissa Chont, & Jean-Jacques Vatine, Validation of
`Proposed Diagnostic Criteria (the “Budapest Criteria”) for Complex
`Regional Pain Syndrome, 150 PAIN 268, 268–74 (Apr. 2010) (Ex. 1009,
`“Harden”).
`6 Peter D. Drummond, Sensory Disturbances in Complex Regional Pain
`Syndrome: Clinical Observations, Autonomic Interactions, and Possible
`
`3
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`PGR2019-00027
`Patent 10,039,774 B2
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`
`35 U.S.C. §
`103
`
`112
`
`References/Basis
`Varenna 2011, Gatti,
`Muratore, Harden7
`Written Description
`
`Challenged Claims
`16–29
`
`1–29
`
`D. The ’774 Patent
`The ’774 patent, titled “Neridronic Acid for Treating Complex
`Regional Pain Syndrome,” issued on August 7, 2018. Ex. 1002, at (45),
`(54). The ’774 patent relates to “[o]steoclast inhibitors, such as neridronic
`acid, in an acid or a salt form” that “can be used to treat or alleviate pain or
`related conditions, such as complex regional pain syndrome” (“CRPS”). Id.
`at (57).
`According to the ’774 patent, “[b]isphosphonate compounds are
`potent inhibitors of osteoclast activity, and are used clinically to treat bone-
`related conditions such as osteoporosis and Paget’s disease of bone,” as well
`as “cancer-related conditions including multiple myeloma, and bone
`metastases from solid tumors,” but these compounds “generally have low
`oral bioavailability.” Id. at 1:38–43. “[O]ral dosage forms of
`bisphosphonate compounds . . . can be used to treat or alleviate pain or
`related conditions.” Id. at 1:51–54. Two of these conditions are “changes in
`skin blood flow” and “abnormal sudomotor activity” associated with CRPS,
`
`
`Mechanisms, 11 Pain Medicine 1257, 1257–66 (2010) (Ex. 1010,
`“Drummond”).
`7 This ground advances the same prior art references as the obviousness
`ground asserted against claims 1–16. We address this as a distinct ground to
`mirror the structure of the Petition.
`
`4
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`which is a “debilitating pain syndrome[] . . . characterized by severe pain in
`a limb.” Id. at 13:23–32.
`None of the figures or working examples in the specification of
`the ’774 patent relate to the use of neridronic acid. Id. at 3:21–4:13
`(describing Figs. 1–16), 49:33–65:24 (Examples 1–10); see id. at Figs. 1–16
`(all discussing the use of zoledronic acid). Nevertheless, the specification
`identifies neridronic acid as a bisphosphonate suitable for use in the
`invention and contains information pertaining to daily oral dosing of
`neridronic acid. Id. at 3:4–10, 31:40–45. The specification also refers to a
`“molecular complex comprising neridronic acid” that “is administered in an
`amount that results in” certain disclosed blood plasma concentration curves.
`Id. at 26:30–43. Moreover, the specification contains other general
`information pertaining to the dosing of neridronic acid. For example,
`the ’774 patent describes the administration of “[a]ny suitable amount of an
`osteoclast inhibitor, including a bisphosphonate,” from a list that includes
`“neridronic acid” and identifies broad dosing ranges (from about 0.005 mg
`to about 2000 mg). Id. at 33:25–57. The ’774 patent also describes the
`administration of “any amount of osteoclast inhibitor” that is “in a range
`bounded by, or between, any of these values.” Id. at 34:12–13. The
`specification compares oral forms of bisphosphonates to “parenteral modes
`of administration, such [as] intravenous or subcutaneous” modes. Id.
`at 26:57–61. The specification explains that “[c]ommonly used measures of
`pain intensity include the visual analog scale (VAS) and the numerical rating
`scale (NRS).” Id. at 10:9–11.
`
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`E. Illustrative Claims
`Claims 1–29 of the ’774 patent are challenged. Claims 1 and 16 are
`independent and illustrative; they recite:
`1. A method of treating changes in skin blood flow associated
`with complex regional pain syndrome, comprising
`parenterally administering neridronic acid in a salt form or
`an acid form to a human being suffering from changes in
`skin blood flow associated with complex regional pain
`syndrome, wherein the human being has a pain intensity of
`at least 7 cm on the 10 cm visual analogue scale (VAS) or at
`least 7 on the 0–10 numerical rating scale (NRS).
`Ex. 1002, 90:33–40.
`16. A method of treating abnormal sudomotor activity
`associated with complex regional pain syndrome,
`comprising parenterally administering neridronic acid in a
`salt form or an acid form to a human being suffering from
`abnormal sudomotor activity associated with complex
`regional pain syndrome, wherein the human being has a pain
`intensity of at least 7 cm on the 10 cm visual analogue scale
`(VAS) or at least 7 on the 0–10 numerical rating scale
`(NRS).
`Id. at 91:14–21.
`
`ANALYSIS
`A. Eligibility of the ’774 Patent for Post-Grant Review
`Post-grant reviews are available only for patents “described in section
`3(n)(1)” of the Leahy-Smith America Invents Act (“AIA”), Pub L. No. 112-
`29, 125 Stat. 284 (2011). AIA § 6(f)(2)(A). These patents are those that
`issue from applications “that contain[] or contained at any time . . . a claim
`to a claimed invention that has an effective filing date as defined in section
`100(i) of title 35, United States Code, that is on or after” “the expiration of
`the 18-month period beginning on the date of the enactment of” the AIA.
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`6
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`Id. § 3(n)(1). Because the AIA was enacted on September 16, 2011, post-
`grant reviews are available only for patents that issue from applications that
`at one point contained at least one claim with an effective filing date on or
`after March 16, 2013, with “effective filing date” having the definition given
`to it by 35 U.S.C. § 100(i). The effective filing date of an application for a
`patent on an invention is “the filing date of the earliest application for which
`the . . . application is entitled, as to such invention, to a right of priority
`under section 119, 365(a), 365(b), 386(a), or 386(b) or to the benefit of an
`earlier filing date under section 120, 121, 365(c), or 386(c).” 35 U.S.C.
`§ 100(i)(1)(B).
`Petitioner argues that, although the ’774 patent claims priority to
`several applications filed before March 16, 2013, it nevertheless is eligible
`for post-grant review because it “contains . . . at least one claim that was not
`disclosed in compliance with the written description and enablement
`requirements of § 112(a) in the” applications to which it claims priority.
`Pet. 19 (quoting Inguran, LLC v. Premium Genetics (UK) Ltd., PGR2015-
`00017, Paper 8 at 11 (PTAB Dec. 22, 2015)). Specifically, Petitioner argues
`that none of the applications to which the ’774 patent claims priority
`sufficiently describes claims 10–13 or 25–28. Id. at 20–22. Those claims
`recite limitations regarding the age of patients being treated or the duration
`of the patient’s suffering from complex regional pain syndrome. Ex. 1002,
`90:65–91:8, 92:16–26. According to Petitioner, none of the priority
`applications describe these limitations. Pet. 20–22.
`In our Decision on Institution, based on Petitioner’s representations,
`we preliminarily found that the ’774 patent was eligible for post-grant
`review. Dec. Inst. 8–9. We observed that “Patent Owner may dispute that
`
`7
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`finding in a timely-filed response to the Petition.” Id. at 9. Patent Owner
`did not dispute our finding or otherwise argue that the ’774 patent was
`ineligible for post-grant review in its Response. PO Resp. 1–25.
`Accordingly, we find that the ’774 patent is eligible for post-grant review.
`
`B. Claim Construction
`In a post-grant review, we construe claim terms in an unexpired patent
`“in accordance with the ordinary and customary meaning of such claim as
`understood by one of ordinary skill in the art and the prosecution history
`pertaining to the patent,” as the claims would be construed “in a civil action
`under 35 U.S.C. 282(b).” 37 C.F.R. § 42.200(b) (2018). Only terms which
`are in controversy need to be construed, and then only to the extent
`necessary to resolve the controversy. Vivid Techs., Inc. v. Am. Sci. & Eng’g,
`Inc., 200 F.3d 795, 803 (Fed. Cir. 1999). On the question of claim
`construction, the sole dispute is whether the preambles of the challenged
`claims should be treated as limiting the scope of those claims. Pet. 15–18;
`PO Resp. 2–4; Reply 1–2; PO Sur-Reply 1. We agree that no other
`limitation requires express discussion for our purposes here.
`Claim 1 recites “[a] method of treating changes in skin blood flow
`associated with complex regional pain syndrome.” Ex. 1002, 90:33–40.
`Claim 16 similarly recites “[a] method of treating abnormal sudomotor
`activity associated with complex regional pain syndrome.” Id. at 91:14–21.
`Petitioner argues that these preambles should not be interpreted as limiting
`the scope of the challenged claims. Pet. 13–18; Reply 1–2. Patent Owner
`disagrees, arguing that the preambles should be construed as limiting.
`PO Resp. 2–4; PO Sur-Reply 1.
`
`8
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`The result of Petitioner’s unpatentability challenges would not change
`regardless of whether the preambles are limiting. Even if the preambles are
`limiting, their scope is so broad as to be hardly different from no limitation
`at all. The specification of the ’774 patent defines “treating” as “includ[ing]
`any kind of treatment activity, including the diagnosis, cure, mitigation, or
`prevention of disease in man or other animals, or any activity that otherwise
`affects the structure or any function of the body of man or other animals.”
`Ex. 1002, 7:43–47. This definition exhibits “reasonable clarity,
`deliberateness, and precision” and is “‘set out . . . within the patent
`disclosure’ so as to give one of ordinary skill in the art notice of the change”
`in meaning. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994) (quoting
`Intellicall, Inc. v. Phonometrics, Inc., 952 F.2d 1384, 1387–88 (Fed. Cir.
`1992)). Accordingly, we give effect to this definition of “treating.”
`Under the definition of “treating” in the specification of the ’774
`patent, “[a] method of treating” changes in skin blood flow (claim 1) or
`abnormal sudomotor activity (claim 16) “associated with complex regional
`pain syndrome” means a method of diagnosing, curing, mitigating, or
`preventing that condition associated with complex regional pain syndrome,
`or otherwise affecting the structure or any function of the body of someone
`suffering from the condition associated with complex regional pain
`syndrome. To the extent that this requires carrying out the method on a
`patient suffering from changes in skin blood flow (claim 1) or abnormal
`sudomotor activity (claim 16) associated with complex regional pain
`syndrome, this is already part of the method recited in the body of the
`claims, Ex. 1002, 90:33–40, 91:14–21, so the preambles provide no
`additional limitation. To the extent that the preambles require some
`
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`Patent 10,039,774 B2
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`particular result to be brought about, that result could be the diagnosis, cure,
`mitigation, or prevention of the symptom in question, or it could be any
`effect at all on the structure or any function of the patient’s body. Thus,
`even when construed as limiting, the preambles provide little, if any, further
`restriction on the scope of the challenged claims beyond that set forth in the
`body of the claims.
`Moreover, as discussed below with respect to the asserted grounds of
`obviousness, Petitioner directs us to evidence that the prior art teaches or
`suggests the subject matter of the preambles, even when those preambles are
`construed as limiting in accordance with the meaning of “treating” provided
`in the specification. 8 Thus, whether or not we treat the preambles as
`limiting, the outcome does not change. Given this circumstance, we treat the
`preambles of the challenged claims as limiting and assign them a meaning
`consistent with the specification’s definition of “treating.”
`
`C. Asserted Obviousness of Claims 1–15 over Harden, Drummond,
`and One or More of Varenna 2011, Gatti, and Muratore
`Petitioner argues that the subject matter of claims 1–15 would have
`been obvious over the combination of Harden, Drummond, and one or more
`of Varenna 2011, Gatti, and Muratore. Pet. 22–50.
`
`1. Varenna 2011
`Varenna 2011 relates to “[t]he Clinical Framework of
`Algodystrophy,” which is also referred to as “Complex Regional Pain
`Syndrome Type I” or “Algodystrophic Syndrome.” Ex. 1006, 227, 228.
`
`
`8 The asserted ground of unpatentability based on lack of written description
`support can be resolved without deciding whether the preambles of the
`challenged claims are limiting.
`
`10
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`According to Varenna 2011, the “Budapest Criteria” are “used for the
`diagnosis of” CRPS:
`1. Continuous pain disproportionate to the triggering
`event
`2. Patient must report the presence of at least one
`symptom in three of the following four categories:
`• Sensory changes: hyperesthesia and/or
`allodynia
`• Vasomotor changes: asymmetry of warmth
`when touched and/or change and/or asymmetry
`of skin color
`• Sudomotor changes/edema: edema and/or
`perspiration anomalies and/or asymmetry
`• Motor/trophic changes: reduced range of
`motion and/or motor anomalies (hyposthenia,
`tremors, dystonia) and/or trophic changes (skin,
`nails, hair follicles)
`3. At least one sign in two or more of the following
`categories must be objectivized:
`• Sensory changes: hyperalgesia and/or allodynia
`• Vasomotor changes: evidence of asymmetry in
`contact with heat and/or change and/or
`asymmetry of skin color
`• Sudomotor changes/edema: evidence of . . .
`edema and/or perspiration anomalies and/or
`asymmetry
`• Motor/trophic changes: evidence of: reduced
`range of motion and/or motor anomalies
`(hyposthenia, tremors, dystonia) and/or trophic
`changes (skin, nails, hair follicles)
`4. Absence of alternative diagnostic interpretation
`Id. at 228 (Table 1).
`
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`In addition, Varenna 2011 teaches that “various studies . . . seem to
`demonstrate the efficacy of Bisphosphonates administered intravenously at
`high dosages” in treating CRPS. Id. at 233. Among these bisphosphonates,
`“the molecule that has most recently demonstrated efficacy is Neridronate
`which seems to possess an excellent efficacy profile when administered
`intravenously at a dosage of 100 mg per four infusions every fourth day.”
`Id.
`
`2. Gatti
`Gatti9 reports that “[i]ntravenous high doses of bisphosphonates are
`increasingly used for the treatment of reflex sympathetic dystrophy
`syndrome or algodystrophy,” which is another term for CRPS. Ex. 1008,
`1308; supra 10. According to Gatti, “the most effective dose is 100 mg
`diluted in 250 ml of saline solution given intravenously over 4 days,” and,
`“[w]ith this treatment regimen, the proportion of patients experiencing rapid
`(in 7 – 12 days) > 70% symptomatic improvements is close to 80%.”
`Ex. 1008, 1308. Because of these “preliminary observations,” Gatti reports
`that “the first formal registrative randomized double-blind clinical trial
`comparing 400 mg neridronic acid to placebo in patients with foot or
`forearm algodystrophy syndrome has been designed and is underway.” Id.
`
`3. Muratore
`Muratore reports the results of a comparison of neridronate and
`clodronate “in the treatment of reflex sympathetic hip algodystrophy.”
`Ex. 1007, 89. The purpose of the study was “[t]o evaluate the therapeutic
`
`
`9 Gatti originally was written in Italian, but we refer to the English
`translation Petitioner submitted.
`
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`efficacy of Neridronate.” Id. One group of patients in the study “was
`administered neridronate 100 mg, intravenously diluted in 250 cc of saline
`solution every 4 days 4 times.” Id. Both neridronate and clodronate
`“demonstrated being efficacious in the treatment of Reflex Sympathetic
`Algodystrophy” (that is, CRPS (Pet. 31–32)), “but the speed of improvement
`of pain symptoms with recovery of functional/motor capability . . . was
`demonstrated to be statistically more significant in patients treated with
`Neridronate.” Ex. 1007, 89.
`
`4. Harden
`Harden reports the results of a study that “sought to compare the
`relative diagnostic efficiency of [the Budapest Criteria and an alternative,
`older set of diagnostic criteria] in discriminating between CRPS and non-
`CRPS neuropathic pain patients.” Ex. 1009, 269. The Budapest Criteria are
`listed in Harden; they are similar, with minor differences in wording, to the
`Budapest Criteria reported in Varenna 2011. Id. at 274 (Appendix II).
`Harden teaches that significant numbers of CRPS patients self-reported or
`were observed to exhibit changes in skin blood flow (such as skin color
`asymmetry) and abnormal sudomotor activity (such as sweating asymmetry).
`Id. at 271 (Table 2). In particular, Harden teaches that:
`• 69.4% of CRPS patients exhibited symptoms of temperature
`asymmetry on examination;
`• 83.9% of CRPS patients exhibited symptoms of skin color
`asymmetry on examination;; and
`• 43.8% of CRPS patients exhibited sweating asymmetry on
`examination.
`
`Id.
`
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`5. Drummond
`Drummond reports a review of “mechanisms that might contribute to
`sensory disturbances and sympathetically-maintained pain in complex
`regional pain syndrome (CRPS).” Ex. 1010, 1257. Drummond teaches that
`“CRPS is associated with a range of . . . autonomic abnormalities.” Id.
`According to Drummond, these “[a]utonomic disturbances . . . range from
`signs of sympathetic deficit (warmth and loss of vasoconstrictor reflexes) to
`sympathetic overactivity (sweating and coldness).” Id. at 1260. This effect
`can “spread beyond the CRPS-affected limb.” Id. “‘Vasomotor’ refers to
`changes in the diameter of blood vessels, namely the dilation or constriction
`of blood vessels.” Pet. 27 (citing Ex. 1004 ¶ 71). Drummond demonstrates
`“that the vasomotor signs and symptoms listed in the Budapest Criteria are
`related to changes in skin blood flow.” Id.; see id. at 28–29 (quoting
`Ex. 1010, 1260 and citing Ex. 1004 ¶¶ 70–73).
`
`6. Analysis
`Petitioner argues that claims 1–15 of the ’774 patent would have been
`obvious over the combined teachings of Harden, Drummond, and one or
`more of Varenna 2011, Gatti, and Muratore. Pet. 22–50.
`Patent Owner argues, with respect to claims 1–15, that the evidence of
`record does not show that a person of ordinary skill in the art would have
`had a reasonable expectation of success in treating complex regional pain
`syndrome with neridronic acid. PO Resp. 17–24; PO Sur-Reply 4–13.
`Patent Owner also argues that none of the asserted references qualifies as a
`printed publication under 35 U.S.C. § 102. PO Resp. 4–17; PO Sur-Reply
`14–21. Finally, with respect to claim 12, Patent Owner argues that none of
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`the asserted references teaches or suggests the duration of symptoms recited
`in the claim. PO Resp. 20–24; PO Sur-Reply 13–14.
`
`a. Reasonable Expectation of Success
`Patent Owner argues that Petitioner has not shown that a person of
`ordinary skill in the art would have had “a reasonable expectation of success
`in treating complex regional pain syndrome by administering neridronic
`acid.” PO Resp. 17. Specifically, Patent Owner argues that none of
`Petitioner’s asserted references provides data showing efficacy (namely, that
`administering neridronic acid improves the symptoms of CRPS). Id. at 17–
`18. Patent Owner also argues that the failure of Petitioner’s Phase III
`clinical trials of neridronic acid for treating CRPS demonstrates the lack of
`any reasonable expectation of success. Id. at 19–20. Despite these
`arguments, we are persuaded that Petitioner has shown by a preponderance
`of the evidence the reasonable expectation of success necessary to support
`the obviousness of claims 1–15.
`As discussed below with respect to claim 1, Petitioner’s position is
`that a person of ordinary skill in the art “would have been motivated to
`administer neridronic acid to [patients suffering from CRPS] based on the
`disclosures of Varenna 2011, Gatti, and/or Muratore, which teach that
`neridronic acid is effective for treating CRPS and its symptoms.” Pet. 36.
`There is evidence in each of these references that supports a finding that a
`person of ordinary skill in the art reasonably would have expected neridronic
`acid to treat CRPS successfully. Varenna 2011 describes “Neridronate”10 as
`having “recently demonstrated efficacy” and as “seem[ing] to possess an
`
`
`10 “Neridronate” is the salt form of neridronic acid. Ex. 1004 ¶ 43.
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`excellent efficacy profile” in treating CRPS. Ex. 1006, 233. Muratore
`describes the treatment of CRPS using “Neridronate” as resulting in faster
`“improvement of pain symptoms with recovery of functional/motor
`capability, reduction of bone reabsorption markers,” and “statistically more
`significant” bone condition restoration, when compared with other drugs.
`Ex. 1007, 89. Gatti discloses that a Phase II clinical trial has shown that
`neridronic acid, used for treating CRPS, resulted in “close to 80%” of
`patients “experiencing rapid (in 7 – 12 days) > 70% symptomatic
`improvements.” Ex. 1008, 1308. Because each of these disclosures
`suggests successful treatment of CRPS and its symptoms with neridronic
`acid, we credit Dr. Poree’s testimony that a person of ordinary skill in the art
`“would have known that neridronate is effective to treat CRPS and its
`symptoms.” Ex. 1004 ¶ 38.
`Against this evidence, Patent Owner first argues that none of
`Petitioner’s asserted references provides data showing that administering
`neridronic acid improves the symptoms of CRPS. PO Resp. 17–18. But
`“[o]bviousness does not require absolute predictability of success. . . . [A]ll
`that is required is a reasonable expectation of success.” In re O’Farrell, 853
`F.2d 894, 903–904 (Fed. Cir. 1988). It is sufficient that Varenna 2011,
`Gatti, and Muratore would have informed the ordinarily skilled artisan that
`successful treatment of CRPS and its symptoms was likely; there is no
`requirement that Petitioner show that the prior art taught that success was
`certain.
`Moreover, even if Petitioner’s references insufficiently demonstrate
`that administering neridronic acid improves the symptoms of CRPS, it
`would be immaterial to the question of whether Petitioner had shown a
`
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`PGR2019-00027
`Patent 10,039,774 B2
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`reasonable expectation of success. To show the reasonable expectation of
`success necessary to prove obviousness, Petitioner need only show that a
`person of ordinary skill in the art would have had “a reasonable expectation
`of achieving what is claimed in the patent-at-issue.” Intelligent Bio-Systems,
`Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367 (Fed. Cir. 2016).
`Here, the claims at issue recite “[a] method of treating changes in skin blood
`flow” or “treating abnormal sudomotor activity” that is “associated with
`complex regional pain syndrome.” Ex. 1002, 90:33–40, 91:14–21. It might
`be possible to interpret the phrases “treating changes in skin blood flow” or
`“treating abnormal sudomotor activity” to require some improvement in
`those specified symptoms of CRPS, but, as discussed above, that is not the
`definition the ’774 patent provides. Instead, as defined in the specification
`of the ’774 patent, “[a] method of treating” a symptom associated with
`CRPS means a method of diagnosing, curing, mitigating, or preventing a
`symptom associated with complex regional pain syndrome, or otherwise
`affecting the structure or any function of the body of someone suffering
`from that symptom. Ex. 1002, 7:43–47. The disclosures of Varenna 2011,
`Gatti, and Muratore certainly suggest that the administration of neridronic
`acid to CRPS patients produced some effect in the structure or function of
`the patients’ bodies, including structure and function affected by CRPS.
`Given the ’774 patent’s broad definition of “treating,” there is no
`requirement that the neridronic acid produces any particular effect, much
`less achieves any particular degree of efficacy in improving the symptoms of
`CRPS.
`Patent Owner next argues that the failure of Petitioner’s Phase III
`clinical trials of neridronic acid for treating CRPS demonstrates the lack of
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`PGR2019-00027
`Patent 10,039,774 B2
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`any reasonable expectation of success. PO Resp. 19–20. We are not
`persuaded by this argument. The record shows that, in 2019, Petitioner
`“decided to discontinue its two ongoing Phase III clinical trials of
`Neridronate . . . in patients with Complex Regional Pain Syndrome” because
`the “trials were unlikely to meet the primary endpoint.” Ex. 2001, 1–2. At
`best, this evidence demonstrates that, in 2019, neridronic acid was known to
`be unlikely to achieve some specific result (that is, the primary endpoint of
`the trials) when used to treat CRPS. As discussed above, however,
`Petitioner need not show that neridronic acid would have been understood to
`bring about any particular result; the challenged claims require the
`neridronic acid only to produce any effect at all on the structure or function
`of a CRPS patient’s body. Thus, the failure to achieve some specific result
`weighs little in the reasonable-expectation-of-success inquiry. In addition,
`even if we accept that the claims of the ’774 patent require some particular
`effect, the record contains no explanation of what was the primary endpoint
`of Petitioner’s Phase III clinical trials, much less any evidence that that
`endpoint was the same effect required by the challenged claims. For this
`reason too, the failure of the Phase III clinical trials to achieve some
`particular unspecified result is of little probative value in the reasonable-
`expectation-of-success inquiry. In the alternative, even if the failure of the
`clinical trials to achieve their endpoint is somehow relevant to the question
`of whether a person of ordinary skill in the art reasonably would have
`expected success, that failure speaks only to what would have been expected
`in 2019, years after the date of the invention of the ’774 patent. Bristol-
`Myers Squibb Co. v. Teva Pharm., Inc., 752 F.3d 967, 976 (Fed. Cir. 2014)
`(“[T]he skilled artisan’s reasonable expectation of success is measured ‘as of
`
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`PGR2019-00027
`Patent 10,039,774 B2
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`the date of the invention.’” (quoting Amgen Inc. v. Hoffman–La Roche, 580
`F.3d 1340, 1362 (Fed. Cir. 2009).)).
`Accordingly, based on the evidence of record, we find that a person of
`ordinary skill in the art at the time of the invention reasonably would have
`expected to achieve success in attaining the result claimed in the ’774 patent
`(namely, any effect at all on the structure or function of a CRPS patient’s
`body due to the administration of neridronic acid).
`
`b. Printed-Publication Status
`Patent Owner argues that none of Petitioner’s asserted references
`qualifies as a printed publication under 35 U.S.C. § 102. PO Resp. 4–16;
`PO Sur-Reply 14–21. “To qualify as a printed publication, a reference ‘must
`have been sufficiently accessible to the public interested in the art.’” Blue
`Calypso, LLC v. Groupon, Inc., 815 F.3d 1331, 1348 (Fed. Cir. 2016)
`(quoting In re Cronyn, 890 F.2d 1158, 1160 (Fed. Cir. 1989)). “A reference
`will be considered publicly accessible if it was disseminated or otherwise
`made available to the extent that persons interested and ordinarily skilled in
`the subject matter or art exercising reasonable diligence, can locate it.” Id.
`(quoting Kyocera Wireless Corp. v. Int’l Trade Comm’n, 545 F.3d 1340,
`1350 (Fed. Cir. 2008)) (internal quotation marks omitted). Thus, there are
`two ways to show that a reference was sufficiently accessible: show it was
`disseminated or show it was “otherwise made available to the extent that”
`interested people of ordinary skill in the art could have located it after
`exercising reasonable diligence. Id. Here, according to Petitioner, the
`asserted references “are articles published in periodical journals by an
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`Patent 10,039,774 B2
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`identified and reputable publisher.” Reply 3. 11 Petitioner argues that the
`references were “disseminated on the[ir] stated publication date[s].” Id. at 5.
`We agree.
`Varen
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