Paper No. ___
`Filed: December 14, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`U.S. Patent No. 9,283,239
`____________
`
`DECLARATION OF STEPHEN BRUEHL, PH.D
`
`ANTECIP EXHIBIT 2025
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2017-00022
`
`Page 1
`
`
`Filed: December 14, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`U.S. Patent No. 9,283,239
`____________
`
`DECLARATION OF STEPHEN BRUEHL, PH.D
`
`ANTECIP EXHIBIT 2025
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2017-00022
`
`Page 1
`
`
`
`I, Stephen Bruehl, Ph.D, declare as follows:
`
`I.
`
`Introduction
`1.
`I have been retained by Fitzpatrick, Cella, Harper & Scinto on behalf
`
`of Grünenthal GmbH as an independent expert to provide my opinions on the
`
`subject matter recited in the claims of U.S. Patent No. 9,283,239 (Exh. 1003, “the
`
`’239 patent”) in view of the state of the art at the time of the ’239 patent and
`
`various references that predate the ’239 patent, all of which are contained in this
`
`declaration.
`
`2.
`
`I understand that Grünenthal GmbH has petitioned the Patent Trial
`
`and Appeal Board (PTAB) to institute a post-grant review (PGR) of the ’239 patent
`
`and has requested that the PTAB cancel all claims of the ’239 patent due to lack of
`
`novelty, obviousness, lack of written description, and/or lack of enablement.
`
`3.
`
`I make this declaration based upon personal knowledge. I am over the
`
`age of 21 and otherwise competent to make this declaration.
`
`II. Qualifications
`4.
`A copy of my curriculum vitae, which fully describes my
`
`qualifications as an expert in this matter can be found at Exhibit 1002. In addition,
`
`I have set forth some particularly relevant qualifications in the paragraphs that
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`follow.
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`Page 2
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`5.
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`In 1985, I received my B.S. degree in psychology from Belmont
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`University in Nashville, TN. I received an M.A. degree in clinical psychology
`
`from the University of Kentucky in Lexington, KY in 1991. In 1994, I received a
`
`Ph.D. in clinical psychology, with a specialization in health psychology, also from
`
`the University of Kentucky. The Ph.D. is a research degree specifically training
`
`the individual to design and conduct research studies, and to read and interpret the
`
`published research literature.
`
`6.
`
`Since 2011, I have been a Professor of Anesthesiology with tenure at
`
`Vanderbilt University in Nashville, TN. I was previously an Assistant Professor at
`
`Vanderbilt from 2000 to 2005, and an Associate Professor of Anesthesiology with
`
`tenure from 2005 to 2011.
`
`7.
`
`I have studied and conducted extensive medical research on complex
`
`regional pain syndrome (CRPS; formerly known by multiple names including
`
`reflex sympathetic dystrophy and causalgia) for over 20 years. I am the co-founder
`
`and have served as co-director of both national and international Complex
`
`Regional Pain Syndrome Research Consortia that have conducted key research
`
`studies designed to improve understanding, diagnosis, and assessment of CRPS.
`
`8.
`
`I am also one of the co-creators of the “Budapest criteria” for
`
`diagnosing CRPS. These diagnostic criteria were developed between 1999 and
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`2
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`Page 3
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`2010 and, in 2012, were adopted by International Association for the Study of Pain
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`(IASP) as that organization’s worldwide standard for diagnosing CRPS.
`
`9.
`
`I have participated in several advisory and scientific panels regarding
`
`CRPS, including a CRPS panel convened by the National Institutes of Health
`
`(NIH) in 2001. I have also been invited to give presentations regarding CRPS at
`
`workshops and symposia put on by the NIH, national professional associations
`
`focused on management of pain, the IASP, and others.
`
`10.
`
`I have authored over 130 peer-reviewed publications, all of which
`
`pertain to the field of pain management. In particular, I have authored at least two
`
`dozen peer-reviewed publications and nine book chapters concerning CRPS,
`
`addressing all aspects of the condition including its pathophysiology, diagnosis,
`
`assessment, and treatment.
`
`11.
`
`I have served as the Principal Investigator on seven large pain
`
`research grants funded by the NIH, including a recent grant designed to better
`
`understand the pathophysiological mechanisms that contribute to development of
`
`CRPS after surgery.
`
`12.
`
`I have served as a consultant to multiple pharmaceutical companies,
`
`including Grünenthal GMBH and Thar Pharmaceuticals, Inc., among others, that
`
`are involved in the development of pharmacological CRPS treatments.
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`3
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`Page 4
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`13.
`
`In the past 4 years, I have provided expert testimony in deposition or
`
`at trial in five cases, all involving personal injury/malpractice:
`
`a) Svendsen vs. Walmart (Trial), Nashville, TN, 2013
`
`b) Candise Walker v. Logan Parker and Delta Wireless (Trial), Salt
`
`Lake City, UT, 2016
`
`c) Rodriguez vs. Wal-Mart (Deposition), New Jersey, 2015
`
`d) Stocks vs. Lowes and Woodfin Griffin (Deposition), Alabama,
`
`2014
`
`e) Senevonghachak v. Franciscan St. Anthony Health (Deposition),
`
`Illinois, 2014
`
`III.
`
`Scope of Work
`14.
`I have been asked to consider and provide my opinions on the claims
`
`of the ’239 patent, including the technical subject matter and the application of
`
`various references that are prior art to the ’239 patent. In particular, I have been
`
`asked to consider what a person of ordinary skill in the art (“POSA”) would have
`
`understood from the ’239 patent, whether references disclose or suggest the
`
`features recited in the claims of the ’239 patent, and whether a POSA would have
`
`had reason to combine certain references to arrive at the subject matter claimed by
`
`the ’239 patent. I have also been asked to consider the information and disclosures
`
`in the ’239 patent specification.
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`4
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`Page 5
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`15.
`
`I am being compensated at the rate of $400 per hour for work
`
`performed on this matter. My compensation is in no way contingent on the nature
`
`of my findings, the presentation of my findings in testimony, or the outcome of any
`
`proceeding.
`
`16.
`
`In forming my opinions, I have reviewed the following documents:
`
`a) U.S. Patent No. 9,283,239
`
`b) U.S. Patent No. 9,216,168
`
`c) U.S. Patent No. 9,408,862
`
`d) U.S. Patent No. 7,704,977
`
`e) U.S. Patent Application Publication No. 2004/0063670
`
`f) de Castro et al. (2011) article entitled “Zoledronic Acid to treat
`
`complex regional pain syndrome type I in adult”
`
`g) Zaspel et al. (2007) published abstract entitled “Treatment of early
`
`stage CRPS I – cortisone (methylprednisolone) versus bisphosphonate
`
`(zoledronic acid)”
`
`h) Manicourt et al. (2004) article entitled “Role of alendronate in
`
`therapy for posttraumatic complex regional pain syndrome type I of
`
`the lower extremity”
`
`i) Leonard et al. (2007) scientific poster presentation entitled
`
`“MER-101 tablets: a pilot bioavailability study of a novel oral
`
`5
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`Page 6
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`
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`formulation of zoledronic acid”
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`j) Schott (1997) article entitled “Bisphosphonates for pain relief in
`
`reflex sympathetic dystrophy?”
`
`l) Adami et al. (1997) article entitled “Bisphosphonate therapy of
`
`reflex sympathetic dystrophy syndrome”
`
`m) Maillefert et al. (1995) article entitled “Treatment of refractory
`
`reflex sympathetic dystrophy with pamidronate”
`
`n) Siminoski et al. (2000) article entitled “Intravenous pamidronate
`
`for treatment of reflex sympathetic dystrophy during breast feeding”
`
`p) Cortet et al. (1997) article entitled “Treatment of severe,
`
`recalcitrant reflex sympathetic dystrophy: assessment of efficacy and
`
`safety of the second generation bisphosphonate pamidronate”
`
`q) Robinson et al. (2004) article entitled “Efficacy of pamidronate in
`
`complex regional pain syndrome type I”
`
`r) Kubalek et al. (2001) article entitled “Treatment of reflex
`
`sympathetic dystrophy with pamidronate: 29 cases”
`
`s) McHugh, et al., “MER-101 Tablets: A Pilot Bioavailability Study
`
`of a Novel Oral Formulation of Zoledronic Acid,” Molecular Cancer
`
`Therapeutics, vol. 6, no. 12, pt. 2, B194, pp. 3494s-3495s (December
`
`2007)(“McHugh,” Exh. 1008).
`
`6
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`Page 7
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`
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`t) Bennett & Xie (1988) article entitled “A peripheral
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`mononeuropathy in rat that produces disorders of pain sensation like
`
`those seen in man”
`
`u) Daemen et al. (1998) article entitled “Neurogenic inflammation and
`
`reflex sympathetic dystrophy (in vivo and in vitro assessment in an
`
`experimental model)”
`
`v) Kurvers et al. (1996) article entitled “Influence of partial nerve
`
`injury in the rat on efferent function of sympathetic and
`
`antidromically acting sensory nerve fibers”
`
`w) Seltzer et al. (1990) article entitled “A novel behavioral model of
`
`neuropathic pain disorders produced in rats by partial sciatic nerve
`
`injury”
`
`IV. Basis for Opinions
`17.
`The opinions given in this declaration are based on my education,
`
`training, experience, and the content of the materials considered. My
`
`understanding of the relevant law, as discussed below, is based on discussions I
`
`had with Petitioner’s counsel.
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`7
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`Page 8
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`A.
`18.
`
`Prior Art
`It is my understanding that patents, published patent applications, and
`
`other printed publications that were published before the priority date of a patent
`
`are prior art to the patent in a post-grant review proceeding.
`
`19.
`
`It is my understanding that the earliest priority date that any of the
`
`’239 patent claims could be entitled to is the May 14, 2012 filing date of
`
`Provisional Application No.61/646,538. Therefore, any patent or publication
`
`published before that date is prior art to the ’239 patent.
`
`B.
`20.
`
`Claim Construction
`I understand the first step in any patentability analysis by the PTAB is
`
`the construction, i.e. interpretation, of the claims of the challenged patent.
`
`21.
`
`I understand that in PGR proceedings, a claim shall be given its
`
`broadest reasonable construction in light of the specification of the patent in which
`
`it appears.
`
`22. But I also understand that a patentee may “act as his or her own
`
`lexicographer.” In other words, I understand that a patentee may give a word or
`
`phrase a specific meaning in the patent specification that is different from the
`
`ordinary and customary definition of that word or phrase in the art. Thus, I
`
`understand any definitions provided in the specification must be taken into account
`
`during claim construction.
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`8
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`C.
`23.
`
`Anticipation
`I understand that subject matter claimed in a patent is anticipated by a
`
`prior art reference if each and every claim limitation is found expressly, implicitly,
`
`or inherently in that prior art reference.
`
`D.
`24.
`
`Obviousness
`I understand that a claim may be unpatentable even if each and every
`
`claim limitation is not present or disclosed in a single prior art reference.
`
`25.
`
`I understand that a claim is obvious if the differences between the
`
`invention and the prior art are such that the subject matter as a whole would have
`
`been obvious at the time the invention was made to a person of ordinary skill in the
`
`art to which the patent pertains (POSA). The POSA is presumed to have
`
`knowledge of the relevant prior art at the time of the claimed invention.
`
`26.
`
`I understand that obviousness is based on the scope and content of the
`
`prior art, the differences between the prior art and the claimed invention, the level
`
`of ordinary skill in the art, and secondary considerations of obviousness and non-
`
`obviousness, to the extent such considerations exist.
`
`27.
`
`I understand that subject matter claimed in a patent is obvious if a
`
`POSA at the time the alleged invention was made would have been motivated to
`
`combine or modify the disclosures of one or more prior art references to arrive at
`
`the claimed subject matter, with a reasonable expectation of success. I understand
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`that, although it is not absolutely required, it can be important to identify some
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`teaching, suggestion, or motivation in the prior art that would have led a POSA to
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`modify the prior art reference to combine prior art teachings to arrive at the
`
`claimed invention.
`
`28.
`
`I understand that there is no rigid formula for determining
`
`obviousness and that various different rationales can support a conclusion of
`
`obviousness. For example, a claimed invention is obvious if it is simply a
`
`combination of known prior art methods to yield predictable results.
`
`E. Written Description
`
`29.
`
`I understand that a patent’s specification must contain a written
`
`description of the invention, and of the manner and process of making and using it,
`
`in such full, clear, concise, and exact terms as to enable a POSA to make and use
`
`the claimed invention.
`
`30.
`
`I understand that to satisfy the written description requirement, the
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`specification must describe the claimed invention in sufficient detail such that a
`
`POSA could reasonably conclude that the inventor was in possession of the
`
`claimed invention.
`
`31.
`
`It is my understanding that when a range of values is recited by a
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`claim, the full scope of the range must be supported by the written description in
`
`the specification.
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`10
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`F.
`32.
`
`Enablement
`I understand that a patent’s specification must also satisfy the
`
`“enablement” requirement. I understand that the test of enablement is whether a
`
`POSA could make or use the invention from the disclosures in the patent, coupled
`
`with information known in the art, without undue experimentation.
`
`33.
`
`I understand that the enablement requirement is separate and distinct
`
`from the written description requirement.
`
`V.
`
`Person of Ordinary Skill in the Art for the ’239 Patent
`34.
`The ’239 patent, entitled “Compositions for Oral Administration of
`
`Zoledronic Acid or Related Compounds for Treating Complex Regional Pain
`
`Syndrome,” issued on March 15, 2016. (Exh. 1003).
`
`35.
`
`The ’239 patent is directed to methods of treating CRPS by orally
`
`administering zoledronic acid. Specifically, the patent is directed to methods of
`
`treating or alleviating pain in patients with CRPS by orally administering
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`zoledronic acid. (Exh. 1003 claims 1-2; abstract; col. 1, ll. 35-37).
`
`36. As explained in detail in the paragraphs below, CRPS is a condition
`
`characterized by severe, continuing, regional pain.
`
`37.
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`For the ’239 patent, a POSA would have an M.D. or a Ph.D. in a pain
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`medicine relevant discipline, such as clinical health psychology or neuroscience,
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`11
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`and 3 to 5 years of experience in the treatment or study of chronic pain
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`management.
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`38. Based on my training and experience, I am (and was as of May 14,
`
`2012) a person of greater than ordinary skill in the relevant art, which permits me
`
`to give an opinion about the qualifications of one of ordinary skill at the time of the
`
`invention. I teach and have taught medical students, medical residents, Ph.D.
`
`students, and fellows in the area of pain medicine for more than 20 years.
`
`VI.
`
`Scientific Background
`
`A.
`
`Complex Regional Pain Syndrome (CRPS)
`
`39. CRPS is a condition characterized by severe, continuing, regional pain
`
`following an injury or other triggering event wherein the pain is disproportionate in
`
`intensity or duration to the pain that would normally be expected to result from the
`
`triggering event. (Exh. 1045 p. 713.)
`
`40. CRPS develops after trauma, most often after fracture, surgery, or soft
`
`tissue injury. There are two subtypes of CRPS, similar in all clinical
`
`characteristics except whether there is (CRPS Type II) or is not (CRPS Type I)
`
`evidence for major peripheral nerve injury. (Exh. 1006 p. 71; Exh 1044 pp. 40-
`
`43).
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`12
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`Diagnosis and Characterization of CRPS
`1.
`41. CRPS diagnosis is clinical. CRPS is defined by and diagnosed solely
`
`based upon the signs and symptoms it produces in affected patients. (Exh. 1006 p.
`
`71). Whether a patient has CRPS is determined using clinical diagnostic criteria
`
`set by the International Association for the Study of Pain (IASP). The IASP
`
`criteria were originally developed in 1994 by a consensus group of pain medicine
`
`experts and have since been validated through clinical research studies.
`
`42.
`
`The 1994 IASP criteria are:
`
`1) The presence of an initiating noxious event or a cause of
`immobilization.
`2) Continuing pain, allodynia, or hyperalgesia with which the pain is
`disproportionate to any inciting event.
`3) Evidence at some time of edema, changes in skin blood flow, or
`abnormal sudomotor activity in the region of pain.
`4) This diagnosis is excluded by the existence of conditions that
`would otherwise account for the degree of pain and dysfunction.
`
`(Exh.1044 p. 42).
`
`43.
`
`The revised 2012 IASP criteria were originally proposed in 1999 (See
`
`Exh. 1046) to improve diagnostic specificity, with minor refinements made
`
`through 2010. (Exh. 1047). I was one of the co-creators of these revised CRPS
`
`criteria (aka the “Budapest Criteria”) that were formally adopted as the worldwide
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`13
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`standard for diagnosis of CRPS by the IASP in 2012. The Budapest Criteria for
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`diagnosing a patient with CRPS are as follows:
`
`1) Continuing pain, which is disproportionate to any
`inciting event.
`
`2) Must report at least one symptom in at least three of
`the four following categories:
`Sensory: Reports of hyperalgesia and/or allodynia.
`Vasomotor: Reports of temperature asymmetry and/or
`skin color changes and/or skin color asymmetry.
`Sudomotor/Edema: Reports of edema and/or sweating
`changes and/or sweating asymmetry.
`Motor/Trophic: Reports of decreased range of motion
`and/or motor dysfunction (weakness, tremor,
`dystonia) and/or trophic changes (hair, nails, skin).
`
`3) Must display at least one sign at time of evaluation in
`two or more of the following categories:
`Sensory: Evidence of hyperalgesia (to pinprick) and/or
`allodynia (to light touch and/or deep somatic
`pressure and/or joint movement).
`Vasomotor: Evidence of temperature asymmetry and/or
`skin color changes and/or asymmetry.
`Sudomotor/Edema: Evidence of edema and/or sweating
`changes and/or sweating asymmetry.
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`Motor/Trophic: Evidence of decreased range of motion
`and/or motor dysfunction (weakness, tremor,
`dystonia) and/or trophic changes (hair, nails, skin).
`
`4) There is no other diagnosis that better explains the
`signs and symptoms
`
`(Exh. 1047 p.274).
`
`44.
`
`The two subtypes of CRPS are diagnosed using exactly the same
`
`diagnostic criteria referenced above. The only distinction made between these two
`
`subtypes is whether or not there is evidence for major peripheral nerve injury.
`
`(Exh. 1044 pp. 40-43).
`
`45.
`
`The clinically predominant manifestation of CRPS, particularly in the
`
`initial phase, includes a mostly continuous pain, allodynia or hyperalgesia that is
`
`disproportionate to the triggering event, and prominent signs of inflammation
`
`(edema, red/warm skin). (Exh. 1007 p. 1). Both the original 1994 IASP criteria
`
`and the revised 2012 criteria identified continuing pain, allodynia and hyperalgesia
`
`as hallmark symptoms of CRPS. (Exh. 1047 p. 274; Exh. 1044 pp. 42).
`
`46. Based on his or her experience and education, a POSA would know
`
`that allodynia is the sensation of pain as a result of stimuli that are not normally
`
`painful. (Exh. 1044 p. 210). Hyperalgesia is an increased sensitivity or response
`
`to stimuli that are normally painful, which may be caused by local alterations to
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`nociceptors or peripheral nerves. (Exh. 1044 p. 211). Both allodynia and
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`hyperalgesia are related to local pro-inflammatory changes in the affected area and
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`plastic changes in the spinal cord in response to ongoing pain.
`
`47. Because CRPS is defined by pain, hyperalgesia, and allodynia, A
`
`POSA would seek to treat CRPS by treating that pain, hyperalgesia, and allodynia.
`
`Thus, a POSA would know that treatments that alleviate the underlying pain and
`
`symptoms of CRPS would be useful in treating CRPS. (See, e.g., Exh. 1007 p.
`
`1)(bisphosphonates used to treat CRPS because of “their direct analgesic
`
`potential”).
`
`CRPS Mechanisms
`2.
`48. CRPS is a multifactorial condition. The mechanisms underlying
`
`CRPS are not completely understood. A POSA would know, however, that CRPS
`
`has both inflammatory nociceptive pain and neuropathic pain components. (Exh.
`
`1045 pp. 713, 715, 717).
`
`49.
`
`The ‘239 patent confirms this understanding. It states that “CRPS is a
`
`type of inflammatory pain. CRPS can also have a neuropathic component.” (Exh.
`
`1003 col. 4, ll. 57-59). It also states that “zoledronic acid or another
`
`bisphosphonate may be administered orally to relieve inflammatory pain, including
`
`musculoskeletal pain, arthritis pain, and complex regional pain syndrome.” (Exh.
`
`1003 col. 4, ll. 18-21).
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`50. A POSA would know, based on experience and education, that
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`nociceptive pain is pain caused by irritation, injury, or damage to body tissues. It
`
`is caused by, for example, cuts, burns, bruises, or other injuries. In nociceptive
`
`pain, specialized nerves ending in sensors called nociceptors detect tissue injury
`
`and transmit pain signals to the brain. (Exh. 1044 p. 210-211).
`
`51.
`
`Inflammatory pain can persist even after the removal of a pain-
`
`causing stimulus and continue until the inflammatory state remits.
`
`52. Neuropathic pain occurs when the nerves are injured, damaged, or
`
`malfunctioning. Instead of being associated with the sensation of a painful
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`stimulus deriving solely from activation of nociceptors, it is associated with
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`abnormal firing patterns with the nerves themselves. (Exh. 1044 p. 210-211).
`
`53.
`
`In sum, a POSA would know that CRPS frequently combines
`
`elements of both inflammatory nociceptive and neuropathic pain mechanisms that
`
`fail to “turn off” over time as is the case in normal healing after injury.
`
`B.
`
`Bisphosphonates
`
`54. Bisphosphonates are a class of drugs that inhibit bone resorption, that
`
`is, the destruction of bone by osteoclasts. They are commonly used to treat or
`
`prevent various diseases that involve the loss of bone mass or the weakening or
`
`fragility of bone, including osteoporosis and Paget’s disease. (Exh. 1006 p. 72).
`
`17
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`55. By 2012, bisphosphonates were in widespread, commercial use for the
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`treatment of osteoporosis and other diseases involving bone resorption problems.
`
`For example, Merck’s Fosamax® tablets (alendronate sodium) were approved by
`
`the FDA in 1995 and Roche’s Boniva® tablets were approved in 2003.
`
`56. Bisphosphonates had shown efficacy in treating CRPS across multiple
`
`clinical trials, case series, and case reports dating at least as far back as 1995 (See,
`
`e.g., Exh. 1036; Exh. 1037; Exh. 1038; Exh. 1039; Exh. 1041; Exh. 1042; Exh.
`
`1043).
`
`57.
`
`It was known that oral bisphosphonates should be taken on an empty
`
`stomach and that patients (including those with CRPS) should refrain from
`
`drinking food and water for at least 30 minutes after taking oral bisphosphonates.
`
`(E.g., Exh. 1005 p. 3691).
`
`VII. Post Grant Review Eligibility
`58.
`I understand that the ’239 patent claims priority to ten provisional
`
`patent applications that pre-date March 16, 2013. I understand that March 16,
`
`2013 is the effective date of the American Invents Act. I further understand that a
`
`patent that issues from an application filed after March 16, 2013 but claims priority
`
`to an application filed before March 16, 2013 (such as the ’239 patent) is eligible
`
`for PGR if the patent contains at least one claim that was not disclosed in
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`18
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`compliance with the written description and enablement requirements in the pre-
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`March 16, 2013 applications.
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`59.
`
`In my opinion, the pre-March 16, 2013 applications to which the ’239
`
`patent claims priority do not describe or enable the full scope of the dosing
`
`regimen limitation recited in claim 1.
`
`60. Claim 1 of the ’239 patent requires administration of “about 80 to
`
`about 500 mg zoledronic acid within a period of six months.” However, none of
`
`the pre-March 16, 2013 applications to which the ’239 patent claims priority
`
`provide information from which a POSA would conclude that such a dosing
`
`regimen is part of the invention.
`
`61.
`
`Provisional application number 61/726,225 (Exh. 1016) filed on
`
`February 7, 2013 includes what appears to be part of a clinical study synopsis
`
`including a Phase 1 study directed at determining bioavailability and a Phase 2
`
`study directed at determining the safety and efficacy of the oral administration of
`
`zoledronic acid. (Exh. 1016 at 31-32.) There is no indication that these studies
`
`had been completed at the time the application was filed and thus no reason a
`
`POSA would have concluded that at this point in time any invention included a
`
`dosing regimen. Furthermore, in order to arrive at a dosing regimen made up of an
`
`amount and time period, a POSA would have to assume that the dosing amounts
`
`used in the Phase 1 clinical study focused on bioavailability (which does not
`
`19
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`Page 20
`
`
`
`specify dosing frequency or period) should be used in the Phase 2 clinical study
`
`focused on safety and efficacy (which does not specify dosing amount to be used).
`
`Even if a POSA were to make this assumption, it would have been expected that a
`
`patient should receive at least 600 mg of zoledronic acid within three months (50
`
`mg per week; administered for 12 weeks).
`
`62.
`
`Provisional application number 61/764,563 included data showing
`
`administration of zoledronic acid in rats. (Exh. 1017 at 7.) Those data failed to
`
`specify a duration of administration. Those data also provided a significant range
`
`of doses from 0.1 mcg/kg/day to 600 mcg/kg/day; from 2.5 mcg/kg once to
`
`100,000 mcg/kg once; and from 0.7 mcg/kg once weekly to 42,000 mcg/kg once
`
`weekly. If a POSA were to extrapolate the rat doses to human doses, the range
`
`disclosed would be broader than the range claimed. Furthermore, there is no
`
`information regarding whether any of the doses tested were effective at treating
`
`CRPS and thus no way for a POSA to conclude that a particular dosing regimen
`
`was part of the claimed invention at this time.
`
`63.
`
`Similarly, the 61/767,647 (Exh. 1018) and 61/767,676 (Exh. 1019)
`
`(which have substantially the same disclosure) include only broad descriptions of
`
`dosing regimens comprised of dosing amounts, dosing frequency and dosing
`
`periods. Thus, a POSA would not have understood the claimed invention to
`
`include the particular range of dosing regimens claimed.
`
`20
`
`Page 21
`
`
`
`64. Additionally, the pre-March 16, 2013 applications do not properly
`
`enable a POSA to practice the broad range of dosing regimens claimed in the ’239
`
`patent. First, the claimed range of dosing regimens allows administration of a
`
`single doses of 80, 81, 82 . . . to 498, 499, 500 mg of zoledronic acid given once
`
`within a six-month period. Similarly, daily doses ranging from approximately 0.4
`
`mg to 2.8 mg given every day within a six month period would also fall within the
`
`dosing limitation as would weekly doses ranging from 3.3 to 20.8 mg given every
`
`week for six months. Indeed the number of possible dosing regimens that would
`
`fall within the claimed range is virtually infinite. Additionally, the claim
`
`encompasses dosing regimens of varying amounts at different durations, for
`
`instance, dosing that occurs for from “2 to 15 days” which could be reproduced
`
`monthly, bimonthly, quarterly or occur only once within six months. There is
`
`nothing in the pre-March 16, 2013 applications explaining to a POSA which of
`
`these would effectively treat CRPS.
`
`65.
`
`Provisional applications numbers 61/646,538; 61/647,478; 61/654,292
`
`and 61/655,541 provide only the following statement about the appropriate dosing
`
`regimen: “In some embodiments the daily oral dose of zoledronate is about 0.005
`
`mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, or
`
`about 0.2 mg to about 5 mg” and provides no working examples whatsoever. (See,
`
`e.g., Exh. 1010, page 2.) This disclosure does not provide any information from
`
`21
`
`Page 22
`
`
`
`which a POSA might determine how long to administer zoledronic acid in order to
`
`treat CRPS.
`
`66.
`
`Similarly, the disclosure in provisional applications numbers
`
`61/655,541 and 61/655,527 add only a broad description of ranges appropriate for
`
`weekly dosing but provide no information about the duration of weekly dosing and
`
`again provide no working examples whatsoever. (Exh. 1014, Exh. 1015.) A
`
`POSA still would not be able to determine how long to administer zoledronic acid
`
`in order to treat CRPS.
`
`67. As discussed in paragraph 61 above, the ’225 application, includes a
`
`synopsis of a clinical study. Exh. 1016 at 31-32. However, as described above,
`
`the only dosing regimens possibly described in the clinical study synopsis fall
`
`outside the claimed range. Thus, a POSA would be directed away from the
`
`claimed range.
`
`68.
`
`Provisional application number 61/764,563 provides data showing
`
`administration of zoledronic acid with details related to dosing amounts based on
`
`weight and dosing frequency. This application does not provide any information
`
`about the duration of dosing or the relative success of the different doses tested. A
`
`POSA would not have known how long to administer zoledronic acid or at what
`
`frequency such dosing was required.
`
`22
`
`Page 23
`
`
`
`69.
`
`The last two pre-March 16, 2013 applications add only a general
`
`description of possible embodiments. Some of these embodiments fall outside the
`
`claimed range and some fall within. A POSA would not have known how to make
`
`full use of the claimed range based on this disclosure.
`
`70.
`
`The pre-March 16, 2013 applications also do not describe or enable
`
`the duration of pain relief limitation found in claim 2 or the amount of zoledronic
`
`acid limitation found in claim 17 because they do not even mention anything
`
`related to duration of pain relief or the percentage of zoledronic acid that is to be
`
`present in the dosage form.
`
`VIII. Ground 1: Lack of Written Description for Claims 1-17
`
`A.
`
`Claims 1-17: “about 80 to about 500 mg zoledronic acid within a
`period of six months”
`71. Claim 1 of the ’239 patent requires administration of “about 80 to
`
`about 500 mg zoledronic acid within a period of six months.” Claims 2-17 all
`
`depend from claim 1 and therefore also contain this limitation.
`
`72.
`
`It is my opinion that claims 1-17 are invalid for lack of written
`
`description because the ’239 patent specification does not describe the claimed
`
`range limitation in sufficient detail such that a POSA could reasonably conclude
`
`that the inventor was in possession of the claimed invention.
`
`23
`
`Page 24
`
`
`
`73.
`
`The claimed range does not appear anywhere in the ’239 patent
`
`specification. The only place in the ’239 patent where the phrase “about 80 to
`
`about 500 mg zoledronic acid within a period of six months” appears is in claim 1.
`
`74.
`
`The specification instead lists various different dosage ranges, each of
`
`which is much broader than the claimed range. For example, “in some
`
`embodiments the weekly oral dose of zoledronic acid is about 1 mg to about 1000
`
`mg,” and “in some embodiments, the monthly dose of zoledronic acid…is about
`
`5000 mg or less.” (Exh. 1003 col. 11, ll. 18-61).
`
`75.
`
`In addition to the many broad ranges listed, “any monthly dose in a
`
`range bounded by, or between, any of these values” may be employed. (Id. col. 11,
`
`ll. 46-47, 59-61).
`
`76.
`
`The specification also states that the “effective amount of zoledronic
`
`acid or another bisphosphonate will vary depending on various factors known to
`
`the treating physicians.” (Id. col. 10, ll. 10-16).
`
`77.
`
`The only example of CRPS treatment in the ’239 patent employs
`
`zoledronic acid amounts falling outside the claimed range. Example 3 is a rat
`
`model of CRPS in which the rats were given the equivalent of a human dose of
`
`29.62 mg/day over 28 days, which, according to the ’239 patent, is equivalent to a
`
`monthly human dose of about 800-900 mg.
`
`(Id. col. 17, ll. 32-39; col. 18 ll. 50-
`
`55. These amounts fall outside the range of Claim 1).
`
`24
`
`Page 25
`
`
`
`78.
`
`In the rat model of “inflammatory pain” studied in Example 1, the rats
`
`were given the equivalent of 800-900 mg monthly human dose. (Id. col. 16, ll. 21-
`
`24. These amounts also fall outside the range of Claim 1).
`
`79.
`
`The specification discloses dosage ranges and embodiments that
`
`specify the amount of zoledronic acid administered in about 1 month, about 3
`
`months, about 6 months, about 1 year, or one month or less. See, e.g., id. at col.
`
`25-26, embodiments 46, 47, 48, 49, 51, 62. To the extent the specification does
`
`describe periods of six months, it does not specify the administration of the
`
`amounts recited in claim 1 over six months.
`
`80. Based upon my review of the file history, I understand that the
`
`claimed dosage range was actually created during prosecution to avoid prior art
`
`that, according to the examiner, “show[ed] that intravenous bisphosphonates
`
`including zoledronic acid have been used to treat [CRPS].” (Exh.1009 at 426.)
`
`Claim 1 originally did not recite any particular amount of zoledronic acid.
`
`(Exh.1009 at 66.) But in response to the examiner’s rejection, claim 1
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