Trials@uspto.gov
`Tel: 571-272-7822
`
`Paper 25
`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.
`
`PGR2019-00028
`Patent 10,052,338 B2
`
`
`
`
`
`
`
`
`
`Before GRACE KARAFFA OBERMANN, CHRISTOPHER M. KAISER,
`and WESLEY B. DERRICK, Administrative Patent Judges.
`KAISER, Administrative Patent Judge.
`
`JUDGMENT
`Final Written Decision
`Determining All Claims Unpatentable
`35 U.S.C. § 328(a)
`
`
`
`
`
`
`
`Tel: 571-272-7822
`
`Paper 25
`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.
`
`PGR2019-00028
`Patent 10,052,338 B2
`
`
`
`
`
`
`
`
`
`Before GRACE KARAFFA OBERMANN, CHRISTOPHER M. KAISER,
`and WESLEY B. DERRICK, Administrative Patent Judges.
`KAISER, Administrative Patent Judge.
`
`JUDGMENT
`Final Written Decision
`Determining All Claims Unpatentable
`35 U.S.C. § 328(a)
`
`
`
`
`
`
`
`
`PGR2019-00028
`Patent 10,052,338 B2
`
`INTRODUCTION
`
`A. Background
`Grünenthal GmbH (“Petitioner”) filed a Petition (Paper 2, “Pet.”)
`requesting a post-grant review of claims 1–30 of U.S. Patent No. 10,052,338
`B2 (Ex. 1003, “the ’338 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 11, “PO
`Resp.”), Petitioner filed a Reply (Paper 13, “Reply”), and Patent Owner filed
`a Sur-Reply (Paper 16, “PO Sur-Reply”). Patent Owner also filed a motion
`to exclude certain evidence. Paper 21 (“Mot. Exclude”). Petitioner opposed
`this motion (Paper 22, “Opp. Mot.”), and Patent Owner filed a Reply
`(Paper 23, “Reply Mot.”). We held a hearing on April 24, 2020, the
`transcript of which has been entered into the record. Paper 24.
`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–
`30 of the ’338 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. 5–6; Paper 3, 2. Petitioner
`has, however, challenged patents related to the ’338 patent in additional
`petitions. Pet. 5; Paper 3, 2. In particular, according to the parties, the
`Board has issued final written decisions in PGR2017-00008 and PGR2017-
`
`2
`
`
`
`PGR2019-00028
`Patent 10,052,338 B2
`00022, and petitions are pending in PGR2018-00001,1 PGR2018-00062,
`PGR2019-00003, PGR2019-00026, and PGR2019-00027. Id.
`
`C. The Asserted Grounds of Unpatentability
`Petitioner contends that claims 1–30 of the ’338 patent are
`unpatentable based on the following grounds (Pet. 24–78):2
`35 U.S.C.
`References/Basis
`Challenged Claims
`§
`
`103
`
`Varenna 2011, 3 Gatti, 4 and/or
`Muratore;5 and Harden6
`
`
`1–16
`
`
`1 After the parties identified related matters, the Board issued a final written
`decision in PGR2018-00001. See PGR2018-00001, Paper 48 (PTAB
`Apr. 29, 2019).
`2 Petitioner also relies on a Declaration from Lawrence Poree, M.D., Ph.D.
`Ex. 1004.
`3 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).
`4 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”).
`5 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).
`6 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”).
`
`3
`
`
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`PGR2019-00028
`Patent 10,052,338 B2
`35 U.S.C.
`References/Basis
`§
`
`112
`
`103
`
`112
`
`Indefiniteness
`
`Varenna 2011, Gatti, and/or
`Muratore; Harden; and
`Drummond7
`
`Written Description
`
`
`Challenged Claims
`
`17–30
`
`17–30
`
`1–30
`
`D. The ’338 Patent
`The ’338 patent, titled “Neridronic Acid for Treating Complex
`Regional Pain Syndrome,” issued on August 21, 2018. Ex. 1003, code (45),
`(54). The ’338 patent relates to “[o]ral dosage forms of osteoclast inhibitors,
`such as neridronic acid, in an acid form or a salt form” that “can be used to
`treat or alleviate pain or related conditions, such as allodynia associated with
`complex regional pain syndrome.” Id. at code (57). According to the 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 1:58–63.
`“[O]ral dosage forms of bisphosphonate compounds . . . can be used to treat
`or alleviate pain or related conditions.” Id. at 2:3–5. One of these
`conditions is “allodynia . . . after a precipitating event such as fracture that is
`
`
`7 Peter D. Drummond, Sensory Disturbances in Complex Regional Pain
`Syndrome: Clinical Observations, Autonomic Interactions, and Possible
`Mechanisms, 11 Pain Medicine 1257, 1257–66 (2010) (Ex. 1010,
`“Drummond”).
`
`4
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`PGR2019-00028
`Patent 10,052,338 B2
`associated with [complex regional pain syndrome],” which “is a debilitating
`pain syndrome” that “is characterized by severe pain in a limb that can be
`accompanied by edema, and autonomic, motor and sensory changes.” Id. at
`3:19–24, 13:23–26.
`None of the figures or working examples in the specification of
`the ’338 patent relate to the use of neridronic acid. Id. at 3:28–4:18, 49:15–
`63:18, 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 3:19–24, 31:26–31. 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 26:16–29. Moreover, the specification contains other general
`information pertaining to the dosing of neridronic acid. For example, the
`’338 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 33:12–44. The 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. The specification
`compares oral forms of bisphosphonates to “parenteral modes of
`administration, such [as] intravenous or subcutaneous” modes. Id. at 26:43–
`47.
`
`E. Illustrative Claims
`Claims 1–30 of the ’338 patent are challenged. Claims 1 and 17 are
`independent and illustrative; they recite:
`
`5
`
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`PGR2019-00028
`Patent 10,052,338 B2
`1. A method of treating allodynia 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 allodynia associated with
`complex regional pain syndrome.
`Ex. 1003, 89:27–31.
`17. A method of treating autonomic motor change associated
`with complex regional pain syndrome, comprising
`administering neridronic acid in a salt form or an acid form
`to a human being suffering from autonomic motor change
`associated with complex regional pain syndrome.
`Id. at 90:17–21.
`
`ANALYSIS
`A. Eligibility of the ’338 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.
`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
`
`6
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`PGR2019-00028
`Patent 10,052,338 B2
`earlier filing date under section 120, 121, 365(c), or 386(c).” 35 U.S.C.
`§ 100(i)(1)(B).
`Petitioner notes that the ’338 patent claims priority to several
`applications filed before March 16, 2013, but argues that 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. 20 (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 ’338 patent claims priority
`sufficiently describes claims 10–13 or 26–29. Id. at 21–23. 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. 1003,
`89:56–90:5, 90:47–57. According to Petitioner, none of the priority
`applications describe these limitations. Pet. 21–23.
`In our Decision on Institution, based on Petitioner’s representations,
`we preliminarily found that the ’338 patent was eligible for post-grant
`review. Dec. Inst. 6–7. We noted that “Patent Owner may dispute that
`finding in a timely-filed response to the Petition.” Id. at 7. Patent Owner
`did not dispute our finding or otherwise argue that the ’338 patent was
`ineligible for post-grant review in its Response. PO Resp. 1–27.
`Accordingly, we find that the ’338 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
`
`7
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`PGR2019-00028
`Patent 10,052,338 B2
`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).
`The parties propose construing two terms. First, the parties dispute
`whether the preambles of the challenged claims should be treated as limiting
`the scope of those claims. Pet. 16–19; PO Resp. 2–5; Reply 1–2; PO Sur-
`Reply 1. Second, the parties disagree about how we should interpret the
`phrase “autonomic motor change” in claims 17–30. PO Resp. 4–5; Reply 3;
`PO Sur-Reply 1–2.
`
`1. Preambles of the Challenged Claims
`Claim 1 of the ’338 patent recites “[a] method of treating allodynia
`associated with complex regional pain syndrome.” Ex. 1003, 89:27–31.
`Claim 17 similarly recites “[a] method of treating autonomic motor change
`associated with complex regional pain syndrome.” Id. at 90:17–21.
`Petitioner argues that these preambles should not be interpreted as limiting
`the scope of the challenged claims. Pet. 16–18; Reply 1–2. Patent Owner
`disagrees, arguing that the preambles should be construed as limiting. PO
`Resp. 2–5; PO Sur-Reply 1.
`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 ’338 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
`
`8
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`PGR2019-00028
`Patent 10,052,338 B2
`affects the structure or any function of the body of man or other animals.”
`Ex. 1003, 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 ’338
`patent, “[a] method of treating allodynia associated with complex regional
`pain syndrome” means a method of diagnosing, curing, mitigating, or
`preventing allodynia associated with complex regional pain syndrome, or
`otherwise affecting the structure or any function of the body of someone
`suffering from allodynia associated with complex regional pain syndrome. 8
`To the extent that this requires carrying out the method on a patient suffering
`from allodynia (or autonomic motor change) associated with complex
`regional pain syndrome, this is already part of the method recited in the body
`of the claims, Ex. 1003, 89:27–31, 90:70–21, so the preambles provide no
`additional limitation. To the extent that the preambles require some
`particular result to be brought about, that result could be the diagnosis, cure,
`mitigation, or prevention of the allodynia (or autonomic motor change) in
`question, or it could be any effect at all on the structure or any function of
`
`
`8 Similarly, “[a] method of treating autonomic motor change associated with
`complex regional pain syndrome” means a method of diagnosing, curing,
`mitigating, or preventing autonomic motor change associated with complex
`regional pain syndrome, or otherwise affecting the structure or any function
`of the body of someone suffering from autonomic motor change associated
`with complex regional pain syndrome.
`
`9
`
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`PGR2019-00028
`Patent 10,052,338 B2
`the patient’s body. Thus, even when construed as limiting, the preambles
`impose 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. 9 Thus, regardless of whether we treat the preambles as
`limiting or not, we would resolve this case the same way. Given this, we
`treat the preambles of the challenged claims as limiting, and we give them a
`meaning consistent with the specification’s definition of “treating.”
`
`2. “Autonomic Motor Change”
`Claim 17 recites the phrase “autonomic motor change.” Ex. 1003,
`90:17–21. Petitioner did not originally argue that we should construe
`“autonomic motor change,” but Petitioner did argue that a person of ordinary
`skill in the art would not have been able to understand the meaning of the
`phrase. Pet. 14–19, 50–52. Specifically, Petitioner argued that “‘autonomic’
`changes and ‘motor’ changes are actually two different types of changes”
`and that a person of ordinary skill in the art would not have understood
`“whether the ‘autonomic motor change’ of claims 17–30 covered . . .
`autonomic changes associated with CRPS, motor changes associated with
`CRPS, or both.” Id. at 51–52. Patent Owner argues that, to the contrary, a
`person of ordinary skill in the art would have known that “autonomic motor
`
`
`9 The asserted grounds of unpatentability other than obviousness can be
`resolved without deciding whether the preambles of the challenged claims
`are limiting.
`
`10
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`PGR2019-00028
`Patent 10,052,338 B2
`change” meant “changes such as changes in skin blood flow, changes in
`temperature, such as temperature asymmetry, and sweating changes.”
`PO Resp. 4–5. In the Reply, Petitioner argues that there is no record
`evidence to support Patent Owner’s proposed construction and that the
`phrase “autonomic motor change” should be construed as “autonomic
`dysfunction associated with CRPS, motor changes associated with CRPS, or
`both.” Reply 3.
`The parties’ arguments thus present us with two choices for the proper
`construction of “autonomic motor change.” First, we could construe the
`term as “autonomic dysfunction associated with CRPS, motor changes
`associated with CRPS, or both,” as Petitioner argues. Alternatively, we
`could construe the phrase as “changes such as changes in skin blood flow,
`changes in temperature, such as temperature asymmetry, and sweating
`changes,” as Patent Owner argues. We agree with Patent Owner.
`Petitioner’s position, that “autonomic motor change” must mean
`something like “autonomic change or motor change” is based on two pieces
`of evidence. First, Petitioner directs us to a statement in the specification of
`the ’338 patent that refers to “autonomic, motor and sensory changes.”
`Ex. 1003, 13:23–26. According to Petitioner, this phrase suggests three
`possible types of change: autonomic changes, motor changes, and sensory
`changes. Under this interpretation, the phrase “autonomic motor change”
`represents a combination of the first two types. Second, Petitioner directs us
`to the testimony of Dr. Poree, who states that a person of ordinary skill in the
`art “would have known that . . . CRPS is associated with both autonomic
`changes . . . and somatic motor changes” and would not have known
`whether claims 17–30 covered “autonomic changes associated with CRPS,
`
`11
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`Patent 10,052,338 B2
`somatic motor changes associated with CRPS, or both.” Ex. 1004 ¶¶ 136–
`137.
`
`Patent Owner, by contrast, directs us to evidence that supports
`knowledge in the art of a biological system called the “autonomic motor
`system.” Ex. 2002, 1056–57. Specifically, the evidence shows that the
`“autonomic motor system regulates gland cells as well as smooth and
`cardiac muscle, maintains constant body temperature, and controls eating,
`drinking, and sexual behavior.” Id. at 1056. “The autonomic motor system
`is distinct from the somatic motor system, which controls skeletal muscle.”
`Id. Petitioner’s proposed construction is inconsistent with the knowledge in
`the art of the “autonomic motor system,” because it ignores the existence of
`such a system. Given that a person of ordinary skill in the art would have
`known of the “autonomic motor system,” it seems reasonable to conclude
`that person would have given the phrase “autonomic motor change” its plain
`meaning by interpreting it as “changes in the autonomic motor system.”
`This leaves the question of whether interpreting “autonomic motor
`change” in this way is consistent with Petitioner’s evidence. It clearly is
`consistent with the statement in the specification of the ’338 patent that
`refers to “autonomic, motor and sensory changes.” Ex. 1003, 13:23–26. If
`“autonomic motor change” is interpreted as “changes in the autonomic
`motor system,” then “autonomic, motor and sensory changes” may be
`interpreted as “changes in the autonomic motor system, somatic motor
`system, or sensory system.” See Ex. 1004 ¶¶ 135–137 (associating “somatic
`motor changes” with the “motor . . . changes” mentioned in the specification
`of the ’338 patent); Ex. 2002, 1056 (distinguishing the autonomic motor
`system from the somatic motor system). To the extent that this
`
`12
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`interpretation is inconsistent with the testimony of Petitioner’s declarant,
`Dr. Poree, that a person of ordinary skill in the art “would not have
`understood with reasonable certainty what the claimed ‘autonomic motor
`change’ associated with CRPS refers to,” Ex. 1004 ¶ 137, we note that
`Dr. Poree does not cite any evidence in support of this conclusion.
`Accordingly, this testimony is unhelpful in resolving the meaning of the
`phrase. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281,
`294 (Fed. Cir. 1985) (a lack of objective support for an expert opinion “may
`render the testimony of little probative value”).
`After considering the evidence of record and the parties’ arguments,
`we conclude that a person of ordinary skill in the art would have understood
`“autonomic motor change” to mean “changes in the autonomic motor
`system.” Patent Owner argues that these changes include “changes in skin
`blood flow, changes in temperature, such as temperature asymmetry, and
`sweating changes.” PO Resp. 4–5. This statement is supported by evidence
`of record. Ex. 2002, 1056 (phenomenon of “palms becom[ing] sweaty” is
`“mediated by the autonomic motor system”; “the autonomic motor
`system . . . maintains constant body temperature”), 1057 (describing control
`of “vascular resistance to blood flow” as “mediated by hypothalamic control
`of the autonomic motor system”). Accordingly, we construe “autonomic
`motor change” as “changes in the autonomic motor system, such as changes
`in skin blood flow, changes in temperature, such as temperature asymmetry,
`and sweating changes.”
`
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`C. Asserted Obviousness over Harden and One or More of Varenna
`2011, Gatti, and Muratore
`Petitioner argues that the subject matter of claims 1–16 would have
`been obvious to a person of ordinary skill in the art given the teachings of
`Harden and one or more of Varenna 2011, Gatti, and Muratore. Pet. 24–49.
`
`1. Varenna 2011
`Varenna 201110 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.
`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:
`
`
`10 Varenna 2011 originally was written in Italian, but we refer to the English
`translation Petitioner submitted.
`
`14
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`PGR2019-00028
`Patent 10,052,338 B2
`• 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 di
`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 I).
`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
`Gatti11 reports that “[i]ntravenous high doses of bisphosphonates are
`increasingly used for the treatment of reflex sympathetic dystrophy
`syndrome or algodystrophy.” Ex. 1008, 1308. 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
`
`
`11 Gatti originally was written in Italian, but we refer to the English
`translation Petitioner submitted.
`
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`proportion of patients experiencing rapid (in 7 – 12 days) > 70%
`symptomatic improvements is close to 80%.” Id. 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
`Muratore12 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
`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 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.” Id.
`
`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).
`
`12 Muratore originally was written in Italian, but we refer to the English
`translation Petitioner submitted.
`
`16
`
`
`
`PGR2019-00028
`Patent 10,052,338 B2
`Harden teaches that significant numbers of CRPS patients self-reported or
`were observed to exhibit allodynia, motor changes, temperature asymmetry,
`and sweating asymmetry. Id. at 271 (Table 2). In particular, Harden teaches
`that:
`
`• 70.5% of CRPS patients exhibited allodynia on examination;
`• 88.3% of CRPS patients self-reported motor changes;
`• 79.3% of CRPS patients exhibited motor changes on
`examination;
`• 86.6% of CRPS patients self-reported temperature asymmetry;
`• 69.4% of CRPS patients exhibited temperature asymmetry on
`examination;
`• 62.5% of CRPS patients self-reported sweating asymmetry; and
`• 43.8% of CRPS patients exhibited sweating asymmetry on
`examination.
`
`Id.
`
`5. Analysis
`Petitioner argues that a person of ordinary skill in the art would have
`had reason to combine Harden’s teachings with those of Varenna 2011,
`Gatti, and/or Muratore and that those combined teachings teach or suggest
`every limitation of claims 1–16. Pet. 24–49.
`Patent Owner argues, with respect to claims 1–16, 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. 18–22; PO Sur-Reply 5–14.
`Patent Owner also argues that none of the asserted references qualifies as a
`printed publication under 35 U.S.C. § 102. PO Resp. 6–18; PO Sur-Reply
`
`17
`
`
`
`PGR2019-00028
`Patent 10,052,338 B2
`15–22. Finally, with respect to claim 12, Patent Owner argues that none of
`the asserted references teach or suggest the duration of symptoms recited in
`the claim. PO Resp. 22–25; PO Sur-Reply 14–15.
`
`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. 19. Specifically, Patent Owner argues that none of
`Petitioner’s asserted references provides data showing that administering
`neridronic acid improves the symptoms of complex regional pain syndrome
`(“CRPS”). Id. at 19–20. 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 20–
`22. 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 1–16.
`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. 37.
`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”13 as
`
`
`13 “Neridronate” is the salt form of neridronic acid. Ex. 1004 ¶ 43.
`
`18
`
`
`
`PGR2019-00028
`Patent 10,052,338 B2
`having “recently demonstrated efficacy” and as “seem[ing] to possess an
`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 argues first that none of
`Petitioner’s asserted references provides data showing that administering
`neridronic acid improves the symptoms of CRPS. PO Resp. 19–20. 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 taught 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 demonstrated
`that administering neridronic acid resulted in an improvement in the
`symptoms of CRPS, it would be immaterial to the question of whether
`
`19
`
`
`
`PGR2019-00028
`Patent 10,052,338 B2
`Petitioner had shown a 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 Cambr
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