Trials@uspto.gov
`Tel: 571-272-7822
`
`
`Paper 6
`Entered: August 20, 2019
`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`GRÜNENTHAL GMBH,
`Petitioner,
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`Patent Owner.
`
`
`Case 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.
`
`
`
`
`DECISION
`
`Institution of Post-Grant Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`Tel: 571-272-7822
`
`
`Paper 6
`Entered: August 20, 2019
`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`GRÜNENTHAL GMBH,
`Petitioner,
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`Patent Owner.
`
`
`Case 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.
`
`
`
`
`DECISION
`
`Institution of Post-Grant Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`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 have authority to determine whether to institute a post-grant
`review. 35 U.S.C. § 324(c); 37 C.F.R. § 42.4(a). The standard for
`instituting a post-grant review is set forth in 35 U.S.C. § 324(a), which
`provides that a post-grant review may not be instituted unless “it is more
`likely than not that at least 1 of the claims challenged in the petition is
`unpatentable.”
`After considering the Petition and the evidence of record, we
`determine that Petitioner has shown that at least one challenged claim is
`more likely than not to be unpatentable. Accordingly, we institute a post-
`grant review.
`
`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-
`00022, and petitions are pending in PGR2018-00001,1 PGR2018-00062,
`PGR2019-00003, PGR2019-00026, and PGR2019-00027. Id.
`
`1 Since the parties identified related matters, the Board has issued a final
`written decision in PGR2018-00001. See PGR2018-00001, Paper 48.
`
`2
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`PGR2019-00028
`Patent 10,052,338 B2
`
`
`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
`Statutory
`Basis
`Challenged Claims
`Ground
`§ 103(a)
`
`Varenna 2011,3 Gatti,4 and/or
`Muratore;5 and Harden6
`
`Indefiniteness
`
`
`§ 112
`
`1–16
`
`17–30
`
`
`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
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`
`Statutory
`Ground
`§ 103(a)
`
`Basis
`
`Challenged Claims
`
`Varenna 2011, Gatti, and/or
`Muratore; Harden; and
`Drummond7
`
`Written Description
`
`
`17–30
`
`1–30
`
`§ 112
`
`D. The ’338 Patent
`The ’338 patent, titled “Neridronic Acid for Treating Complex
`Regional Pain Syndrome,” issued on August 21, 2018. Ex. 1003, at [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 [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
`associated with [complex regional pain syndrome],” which “is a debilitating
`
`
`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”).
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`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. Ex. 1003, 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:
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`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.
`Ex. 1003, 90:17–21.
`
`ANALYSIS
`A. Eligibility of the ’338 Patent for Post-Grant Review
`Petitioner states that, “during prosecution, the Examiner treated
`the ’338 patent as” originating from “an application filed on or after
`March 16, 2013 and therefore subject to the first-to-file provisions of the
`AIA.” Pet. 20 (citing Ex. 1037, 263). That fact, standing alone, tends to
`supports a finding of PGR eligibility. Petitioner further observes, correctly,
`that in this forum, a patent is eligible for post-grant review if it contains “at
`least one claim that was not disclosed in compliance with the written
`description and enablement requirements of § 112(a) in” an application filed
`prior to March 16, 2013. Id. (citation omitted).
`Petitioner avers, in that regard, “the pre-AIA applications” from
`which the ’338 patent allegedly claims priority “are devoid of any data,
`information, or other disclosures regarding the lengths of time patients have
`suffered from CRPS,” and, on that basis, contends that none supports
`claims 10–12 or 26–28. Id. at 22. Those claims require a “human being”
`suffering from CRPS “for ‘at least 6 months,’ ‘about 6 months to about 12
`
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`months,’ and ‘about 1 year to about 2 years.’” Id. at 21–22; Ex. 1003,
`89:56–90:3, 90:47–55. According to Petitioner, therefore, none of claims
`10–12 or 26–28 is supported by a pre-AIA application—a circumstance that
`supports a finding that the ’338 patent is eligible for post-grant review.
`Pet. 21–22.
`Petitioner further avers that “the pre-AIA priority applications are
`devoid of any data, information, or other disclosures regarding the age of
`patients to be treated.” Id. at 23. Petitioner argues that this circumstance
`provides an independent basis for concluding that the ’338 patent is eligible
`for post-grant review. Id. Specifically, Petitioner asserts that claims 13
`and 29, which include limitations on the age of treated patients, are not
`supported by any pre-AIA application. Id. at 22–23; see Ex. 1003, 90:4–5,
`90:56–57.
`For purposes of this decision only, we accept Petitioner’s
`representations on this point, which are not opposed by Patent Owner at this
`stage of the proceeding. Based on Petitioner’s averments, we preliminarily
`find that the ’338 patent is eligible for post-grant review. Patent Owner may
`dispute that finding in a timely filed response to the Petition.
`
`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,
`
`7
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`PGR2019-00028
`Patent 10,052,338 B2
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`Inc., 200 F.3d 795, 803 (Fed. Cir. 1999). Here, Petitioner proposes that we
`interpret the preambles of all challenged claims as non-limiting. Pet. 14–16.
`On the present record, we agree with Petitioner’s proposed
`construction. “[A] preamble is not limiting ‘where a patentee defines a
`structurally complete invention in the claim body and uses the preamble only
`to state a purpose or intended use for the invention.’” Catalina Marketing
`Int’l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 808 (Fed. Cir. 2002)
`(quoting Rowe v. Dror, 112 F.3d 473, 478 (Fed. Cir. 1997)). Where a
`preamble “recites essential structure or steps, or if it is ‘necessary to give
`life, meaning, and vitality’ to the claim,” it is limiting. Id. (quoting Pitney
`Bowes, Inc. v. Hewlett-Packard Co., 182 F.2d 1298, 1305 (Fed. Cir. 1999)).
`In particular, for method-of-treatment claims, when the preamble provides
`antecedent basis for a phrase such as “a patient in need thereof” in the body
`of the claim, the preamble is limiting, but, when the preamble is merely “a
`statement of purpose and intended result,” it is non-limiting. Bristol-Myers
`Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1376 (Fed. Cir. 2001).
`The preamble of claim 1 is “[a] method of treating allodynia
`associated with complex regional pain syndrome,” and the preamble of
`claim 17 is “[a] method of treating autonomic motor change associated with
`complex regional pain syndrome.”8 Ex. 1003, 89:27–31, 90:17–21. The
`bodies of the claims, respectively, recite “parenterally administering
`
`
`8 The remaining challenged claims are all dependent claims depending
`ultimately from either claim 1 or claim 17; their preambles uniformly take
`the form of “[t]he method of claim 1” or “[t]he method of claim 17.” Id. at
`89:32–90:59. These preambles are not limiting except in the sense that they
`incorporate the limitations of the earlier claims from which they depend. 37
`C.F.R. § 1.75(c).
`
`8
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`neridronic acid in a salt form or an acid form to a human being suffering
`from allodynia associated with complex regional pain syndrome” and
`“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. In neither case does the body of the claim
`contain a vague phrase along the lines of “in need thereof” that refers back
`to the preamble for its antecedent basis.
`Moreover, to the extent that we might be inclined to treat the
`preambles of claims 1 and 17 as limiting, the present record suggests that
`limitation would be quite broad in scope. 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 affects the structure or any
`function of the body of man or other animals.” Id. at 7:43–47. Thus, for
`example, “[a] method of treating allodynia associated with complex regional
`pain syndrome” would be interpreted as 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. To the extent that this would require carrying out the method on
`a patient suffering from allodynia associated with complex regional pain
`syndrome, this is already part of the method recited in the body of the claim,
`so the preamble provides no additional limitation. To the extent that the
`preamble is interpreted as requiring some particular result to be brought
`about, that result could be the diagnosis, cure, mitigation, or prevention of
`the allodynia in question, or it could be any effect at all on the structure or
`
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`any function of the patient’s body. This is such a broad category of possible
`results as to constitute no apparent limitation at all. Accordingly, on the
`record presently before us, and for purposes of the present decision, we
`agree with Petitioner that the preambles of the challenged claims are non-
`limiting.
`
`C. Alleged Obviousness over Harden and One or More of Varenna
`2011, Gatti, and Muratore
`Petitioner argues that claims 1–16 of the ’338 patent would have been
`obvious over the combination of Harden and one or more of Varenna 2011,
`Gatti, and Muratore. Pet. 24–49.
`
`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.
`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,
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`
`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 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
`Gatti 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
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`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%.” 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
`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
`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 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).
`Harden teaches that significant numbers of CRPS patients self-reported or
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`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
`a. Claim 1
`Claim 1 recites “[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. Because we interpret the preamble of this claim as non-limiting,
`the scope of claim 1 is defined by its body as “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.” Id.
`Petitioner argues that a person of ordinary skill in the art “would have
`been motivated to administer neridronic acid to [patients suffering from
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`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. Petitioner argues further that, having been so
`motivated, the person of ordinary skill in the art would have “look[ed] to
`other references like Varenna 2011 and Harden, which describe the
`diagnostic criteria, signs, and symptoms of [CRPS].” Id. Because these
`references teach that allodynia is a common symptom of CRPS, Petitioner
`argues that the person of ordinary skill in the art “would have had a
`reasonable expectation that neridronic acid or one of its salts could
`successfully be administered to a patient suffering from allodynia associated
`with CRPS.” Id. On the present record, we agree with Petitioner’s
`arguments.
`Varenna 2011 teaches that neridronate9 “seems to possess an excellent
`efficacy profile” in treating CRPS. Ex. 1006, 233. In the context of
`reporting the use of “[n]eridronic acid for the treatment of bone metabolic
`diseases,” Gatti teaches that “[i]ntravenous high doses of bisphosphonates
`are increasingly used for the treatment of [CRPS].”10 Ex. 1008, 1305, 1308.
`
`
`9 At this stage of the proceeding, we accept Petitioner’s view that
`“neridronate” is the salt form of neridronic acid. Ex. 1004 ¶ 43.
`10 Gatti uses the terms “reflex sympathetic dystrophy syndrome” and
`“algodystrophy.” Ex. 1008, 1308. On the present record, we interpret both
`of these terms as synonymous with “complex regional pain syndrome,”
`“CRPS,” “complex regional pain syndrome type I,” “CRPS I,” “reflex
`sympathetic algodystrophy,” “reflex sympathetic dystrophy,” and
`“causalgia.” Ex. 1006, 227 (equating “algodystrophy,” “complex regional
`pain syndrome type I,” and “CRPS I”); Ex. 1007, 89 (using the term “reflex
`sympathetic algodystrophy”); Ex. 1019, 713 (equating “complex regional
`pain syndrome,” “CRPS,” “reflex sympathetic dystrophy,” and “causalgia”).
`
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`Gatti also reports that a clinical trial of neridronic acid “is underway.” Id.
`Muratore teaches that neridronate was “efficacious in the treatment of
`[CRPS].” Ex. 1007, 89. Thus, on the present record, each of these
`references sufficiently teaches the efficacy of neridronic acid or its salt in
`treating CRPS, suggesting that a person of ordinary skill in the art would
`have been motivated to use neridronic acid in treating CRPS.
`With respect to the limitation of claim 1 requiring that the neridronic
`acid be “parenterally administer[ed],” each of Varenna 2011, Gatti, and
`Muratore teaches intravenous administration of neridronic acid. Ex. 1006,
`233; Ex. 1007, 89; Ex. 1008, 1308. There is evidence of record that
`intravenous administration is a type of parenteral administration. Ex. 1004
`¶ 44.
`
`Harden teaches that the Budapest Criteria are used as “clinical
`diagnostic criteria for CRPS” and include allodynia. Ex. 1009, 274
`(Appendix II). Further, Harden teaches that 70.5% of patients diagnosed
`with CRPS were observed on examination to exhibit allodynia. Id. at 271
`(Table 2). Thus, Harden teaches that a patient with CRPS is likely to suffer
`from allodynia. On the present record, because Varenna 2011, Gatti, and
`Muratore teach that neridronic acid is effective in treating CRPS, the
`combination of any of those references with Harden would have suggested
`to a person of ordinary skill in the art that neridronic acid would be effective
`in alleviating allodynia associated with CRPS.
`Thus, on the present record, the combination of Harden and one or
`more of Varenna 2011, Gatti, and Muratore sufficiently teaches or suggests
`all the limitations of claim 1. Moreover, at least on the present record,
`Petitioner has shown sufficiently that a person of ordinary skill in the art
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`would have had reason to combine the teachings of one or more of Varenna
`2011, Gatti, and Muratore with those of Harden in order to determine the
`symptoms of CRPS that could be improved by the treatment. Ex. 1004 ¶ 85.
`Accordingly, we conclude that Petitioner has shown that it is more likely
`than not that claim 1 would have been obvious over the combination of
`Harden and one or more of Varenna 2011, Gatti, and Muratore.
`
`b. Claims 2 and 3
`Claim 2 of the ’338 patent depends from claim 1 and adds a limitation
`requiring that “a total of about 200 mg to about 500 mg of the neridronic
`acid [be] administered parenterally to the human being.” Ex. 1003, 89:32–
`34. Claim 3 depends from claim 1 and adds a limitation requiring that “a
`total of about 400 mg of the neridronic acid [be] administered parenterally to
`the human being.” Ex. 1003, 89:35–37. Petitioner argues that both Varenna
`2011 and Muratore teach these limitations.
`On the present record, it is not clear that Varenna 2011 teaches or
`suggests a total dose of either about 400 mg or between about 200 mg and
`about 500 mg. Instead, Varenna 2011 teaches administering neridronate
`“intravenously at a dosage of 100 mg per four infusions every fourth day.”
`Ex. 1006, 233. This disclosure suggests that a total of 100 mg was
`administered over the course of four separate infusions, with the infusions
`occurring every fourth day (i.e., 25 mg on day 1, 25 mg on day 5, 25 mg on
`day 9, and 25 mg on day 13). Accordingly, we do not agree with Petitioner
`that, on the present record, Varenna 2011 teaches the limitations of claims 2
`and 3.
`Muratore, however, appears to teach administering 100 mg of
`neridronate per infusion, with one infusion occurring every four days until
`
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`four total infusions have been administered. Ex. 1007, 89. This is a total of
`400 mg of neridronate, which both falls within the recited range of claim 2
`and is the specific amount recited in claim 3. Thus, on the present record,
`Petitioner has shown that the combination of Harden and at least one of
`Varenna 2011, Gatti, and Muratore teaches or suggests the limitations of
`claims 2 and 3.
`
`c. Claim 4
`Claim 4 depends from claim 1 and adds a limitation requiring that “a
`total of about 100 mg to about 200 mg of the neridronic acid [be]
`administered parenterally to the human being within a period of about 1
`month.” Ex. 1003, 89:38–41. Petitioner argues that Gatti teaches this
`limitation. On the present record, we agree.
`Gatti teaches that “the most effective dose is 100 mg diluted in 250 ml
`of saline solution given intravenously over 4 days.” Ex. 1008, 1308. This
`statement in Gatti may refer to “bisphosphonates” generally, rather than to
`neridronic acid specifically, because the paragraph in which this statement
`appears begins with a reference to “high doses of bisphosphonates.” Id. The
`following paragraph, however, states that, because of the efficacy of the
`specified dose, a clinical trial of neridronic acid “is underway.” Id. This
`suggests that the specific bisphosphonate for which “the most effective dose
`is 100 mg diluted in 250 ml of saline solution given intravenously over 4
`days” is neridronic acid. Id. Moreover, the entirety of Gatti discusses
`“[n]eridronic acid for the treatment of bone metabolic diseases,” which also
`suggests that the particular bisphosphonate in question is neridronic acid. Id.
`at 1305. Thus, on the present record, Gatti teaches or suggests the
`administration of 100 mg of neridronic acid. Accordingly, on the present
`
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`Patent 10,052,338 B2
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`record, Petitioner has shown that the combination of Harden and at least one
`of Varenna 2011, Gatti, and Muratore teaches or suggests the limitations of
`claim 4.
`
`d. Claim 5
`Claim 5 depends from claim 1 and adds a limitation requiring that “a
`total of about 250 mg of the neridronic acid [be] administered parenterally to
`the human being within a period of about 1 month.” Ex. 1003, 89:42–44.
`Petitioner argues that the claimed dose falls within the range of doses that
`the prior art describes as effective and that a person of ordinary skill in the
`art would have been motivated and able to arrive at the optimum dose of
`neridronic acid. Pet. 39–41. On the present record, we agree.
`Gatti teaches that a dose of 100 mg of neridronic acid is effective in
`treating CRPS. Ex. 1008, 1308 (this dose reduces symptoms of CRPS by
`more than 70% in “close to 80%” of patients). Muratore teaches that a dose
`of 400 mg of neridronate is effective in treating CRPS. Ex. 1007, 89
`(improvement in several symptoms occurred faster with this dose of
`neridronate than in groups treated with other drugs). The 250-mg dose of
`claim 5 falls between these two prior-art values, and there is evidence of
`record that a person of ordinary skill in the art would have been motivated
`and able to find an optimum dose of neridronic acid within the prior-art
`range. Ex. 1004 ¶¶ 102–103. Given this, “it is not inventive to discover the
`optimum or workable ranges by routine experimentation.” In re Aller, 220
`F.2d 454, 456 (CCPA 1955). Accordingly, on the present record, Petitioner
`has shown that the combination of Harden and at least one of Varenna 2011,
`Gatti, and Muratore teaches or suggests the limitations of claim 5.
`
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`e. Claims 6 and 7
`Claim 6 depends from claim 2 and adds a limitation requiring that
`“the neridronic acid [be] administered in divided parenteral doses.”
`Ex. 1003, 89:45–46. Claim 7 depends from claim 6 and adds a limitation
`requiring that “each divided parenteral dose contain[] about 10 mg to about
`150 mg of the neridronic acid.” Id. at 89:47–49. Petitioner argues that both
`Varenna 2011 and Muratore teach these limitations.
`On the present record, Varenna 2011 appears to teach or suggest a
`divided parenteral dose in which each division falls between 10 mg and 150
`mg of neridronate. Ex. 1006, 233 (teaching that neridronate is “administered
`intravenously at a dosage of 100 mg per four infusions every fourth day”).
`This clearly teaches dividing a total dose into “four infusions.” Id.
`Regardless of whether the total dose is 100 mg, as is apparent from the text
`of Varenna 2011, or 400 mg, as Petitioner argues, the division into four
`infusions means that each infusion contains an amount of neridronate
`between 10 mg and 150 mg.
`Similarly, Muratore appears to teach administering 100 mg of
`neridronate per infusion, with one infusion occurring every four days until
`four total infusions have been administered. Ex. 1007, 89. This clearly
`teaches dividing a total dose of 400 mg into four infusions. Id. Thus,
`Muratore teaches both the limitation of claim 6 and, because the divided
`doses contain 100 mg each, the limitation of claim 7.
`Accordingly, on the present record, Petitioner has shown that the
`combination of Harden and at least one of Varenna 2011, Gatti, and
`Muratore teaches or suggests the limitations of claims 6 and 7.
`
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`
`f. Claim 8
`Claim 8 depends from claim 6 and adds a limitation requiring that
`“each divided parenteral dose contain[] about 62 mg to about 63 mg of the
`neridronic acid.” Id. at 89:50–52. Petitioner argues that the claimed dose
`falls within the range of doses that the prior art describes as effective and
`that a person of ordinary skill in the art would have been motivated and able
`to arrive at the optimum dose of neridronic acid. Pet. 42–44. On the present
`record, we agree.
`There is evidence of record that a person of ordinary skill in the art
`would have been motivated and able to find an optimum dose of neridronic
`acid. Ex. 1004 ¶
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