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. 9,931,352
`U.S. Patent No. 10,039,774
`U.S. Patent No. 10,052,338
`____________
`
`DECLARATION OF LAWRENCE POREE, M.D., PH.D.
`
`1
`
`Grün. Exh. 1004
`PGR for U.S. Patent No.
`
`8
`
`Grün. Exh. 1004
`PGR for U.S. Patent No.
`
`10,052,338
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`Introduction .........................................................................................................1
`
`II. Qualifications ......................................................................................................2
`
`III. Scope of Work and Opinions ..............................................................................4
`
`IV. Person of Ordinary Skill in the Art .....................................................................4
`
`V. Claim Interpretation ............................................................................................6
`
`A. “A method of treating [a sign or symptom] associated with [CRPS]” .........6
`
`VI. Grounds for Unpatentability ...............................................................................8
`
`A. Obviousness of the Independent Challenged Claims....................................8
`
`1.
`2.
`3.
`
`4.
`
`Obviousness Standard......................................................................8
`The Independent Challenged Claims...............................................9
`The Prior Art Taught that Neridronate is Effective to Treat
`CRPS and its Symptoms ................................................................11
`The Prior Art Taught that the Signs and Symptoms in the
`Independent Challenged Claims Are Defining Symptoms,
`Signs, and Diagnostic Criteria of CRPS........................................16
`It Would Have Been Obvious to Administer Neridronic
`Acid to Treat Patients Suffering from the Claimed Signs and
`Symptoms Associated with CRPS.................................................26
`The Pain Intensity Limitations of the ’774 Patent Claims.............28
`6.
`B. Obviousness of the Dependent Challenged Claims ....................................30
`
`5.
`
`1.
`
`2.
`
`3.
`
`“wherein a total of about 200 mg to about 500 mg [or about
`400 mg] of the neridronic acid is administered parenterally
`to the human being”.......................................................................31
`“wherein a total of about 100 mg to about 200 mg of the
`neridronic acid is administered parenterally to the human
`being within a period of about 1 month”.......................................31
`“wherein a total of about 250 mg of the neridronic acid is
`administered parenterally to the human being within a
`period of about 1 month”...............................................................32
`i
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`2
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`

`

`4.
`
`5.
`
`6.
`
`“wherein the neridronic acid is administered in divided
`parenteral doses” and “wherein each divided parenteral dose
`contains about 10 mg to about 150 mg of the neridronic
`acid” ...............................................................................................34
`“wherein each divided parenteral dose contains about 62 mg
`to about 63 mg of the neridronic acid” ..........................................34
`“wherein the complex regional pain syndrome is associated
`with an inciting traumatic event”...................................................35
`“wherein the human being has suffered from complex
`regional pain syndrome for at least 6 months” or “for about
`6 months to about 12 months or “for about 1 year to about 2
`years” .............................................................................................36
`“wherein the human being has an age of about 30 years to
`about 40 years”...............................................................................38
`“wherein the human being has a pain intensity of at least 7
`cm [or 8 cm or 9 cm] on the 10 cm visual analogue scale
`(VAS) or at least 7 [or 8 or 9] on the 0-10 numeric rating
`scale (NRS) ....................................................................................39
`C. Indefiniteness of Claims 17-30 of the ’338 Patent......................................40
`
`7.
`
`8.
`
`9.
`
`D. Lack of Written Description for All Challenged Claims ............................42
`
`ii
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`3
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`

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`I, Dr. Lawrence Poree, hereby declare as follows:
`
`I.
`
`Introduction
`
`1.
`
`I have been retained by Venable LLP 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. 9,931,352 (Exhibit 1001, “the ’352 patent”), U.S.
`
`Patent No. 10,039,774 (Exhibit 1002, “the ’774 patent”), and U.S. Patent No.
`
`10,052,338 (Exhibit 1003, “the ’338 patent”) in view of the state of the art at the
`
`time and various references that predate those patents, all of which I refer to in this
`
`declaration.
`
`2.
`
`I understand that Grünenthal GmbH has petitioned the Patent Trial
`
`and Appeal Board (PTAB) to institute post-grant reviews (PGRs) of the ’352
`
`patent, the ’774 patent, and the ’338 patent, and has requested that the PTAB
`
`cancel the claims of those patents due to obviousness, lack of written description,
`
`and/or indefiniteness.
`
`3.
`
`I understand that this declaration is being filed as Exhibit 1004 in each
`
`of the respective PGRs against the ’352 patent, the ’774 patent, and the ’358
`
`patent. In this declaration, I refer to these three patents collectively as the
`
`“Challenged Patents.” I also refer to the totality of the claims of the Challenged
`
`Patents as the “Challenged Claims.”
`
`1
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`4
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`

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`4.
`
`I make this declaration based upon personal knowledge. I am over the
`
`age of 21 and otherwise competent to make this declaration.
`
`5.
`
`I am being compensated at the rate of $800 per hour for work
`
`performed on this matter. My compensation does not depend on the nature of my
`
`findings, the presentation of my findings in testimony, or the outcome of this
`
`proceeding.
`
`II. Qualifications
`
`6.
`
`A copy of my CV, which fully describes my qualifications as an
`
`expert in the instant matters, is submitted as Exhibit 1005 in each of the respective
`
`PGRs against the ’352 patent, the ’774 patent, and the ’358 patent. I have set forth
`
`particularly relevant qualifications to my testimony in these matters in the
`
`paragraphs that follow.
`
`7.
`
`I am a Professor of Pain Medicine and the Director of
`
`Neuromodulation at the University of California at San Francisco.
`
`8.
`
`I received my Ph.D. in Toxicology/Environmental Health Sciences
`
`from the University of California in 1988 and my M.D. from Stanford University
`
`School of Medicine in 1997. In 2002 I completed a Pain Fellowship at the
`
`University of California at San Francisco.
`
`9.
`
`I have over 20 years of experience treating patients with chronic pain
`
`and studying treatments for pain disorders including complex regional pain
`
`2
`
`5
`
`

`

`syndrome (“CRPS”). I continue to treat patients at the University of California
`
`Pain Management Center, seeing approximately 30 patients per week.
`
`10.
`
`I am currently a member of the Board of Directors for the
`
`International Neuromodulation Society, the California Society of Interventional
`
`Pain Physicians, and the North American Neuromodulation Society.
`
`11.
`
`I am an author of over 20 publications on the treatment of pain,
`
`including several papers on the treatment of CRPS in both animal models and
`
`clinical trials. I served on the editorial board for the journal Pain from 2009 to
`
`2010.
`
`12.
`
`I am currently involved in a clinical trial involving spinal cord
`
`stimulation for the management of moderate to severe chronic, intractable pain of
`
`the lower limbs due to CRPS types I and II.
`
`13.
`
`In the past 4 years, I have not provided expert testimony in deposition
`
`or at trial. On April 18, 2018, I submitted an expert declaration in support of
`
`Petitioner Grünenthal GmbH’s Petition for Post Grant Review of U.S. Patent No.
`
`9,707,245, Case PGR2018-00062. On August 21, 2018, I submitted an expert
`
`declaration in support of Petitioner’s Petition for Post Grant Review of U.S. Patent
`
`No. 9,820,999, Case PGR2018-00092. On October 16, 2018, I submitted an expert
`
`declaration in support of Petitioner’s Petition for Post Grant Review of U.S. Patent
`
`No. 9,867,839, Case PGR2019-00003.
`
`3
`
`6
`
`

`

`III.
`
`Scope of Work and Opinions
`
`14.
`
`I have been asked to consider and provide my opinions on certain
`
`topics related to Challenged Patents and the Challenged Claims:
`
`• How a POSA would interpret the Challenged Claims
`
`• Whether the Challenged Claims are obvious in view of certain prior
`
`art references
`
`• Whether, alternatively, the Challenged Claims lack sufficient written
`
`description in the Challenged Patents’ specifications
`
`• Whether certain of the Challenged Claims are indefinite
`
`15.
`
`In forming my opinions, I reviewed the documents cited in this
`
`declaration.
`
`16. My opinions are based upon my education, training, and experience in
`
`the field of pain treatment and pain management, as well as the documents I
`
`considered.
`
`17. My understanding of relevant legal standards, as discussed throughout
`
`this declaration, is based on discussions I had with Petitioner’s counsel.
`
`IV. Person of Ordinary Skill in the Art
`
`18.
`
`I understand that the opinions I provide in these PGRs must be from
`
`the perspective of a person of ordinary skill in the art that the Challenged Patents
`
`pertain to. I understand that the person of ordinary skill in the art, sometimes
`
`4
`
`7
`
`

`

`abbreviated as a “POSA,” is a hypothetical person who is presumed to have known
`
`of all relevant prior art at the time of the invention.
`
`19. All of the Challenged Claims cover methods of treating various signs
`
`and symptoms “associated with” CRPS. For example, claims 1-16 of the ’352
`
`patent (Exhibit 1001) cover “method[s] of treating hyperalgesia associated with
`
`[CRPS].”
`
`20. CRPS is a chronic pain syndrome that often develops after trauma
`
`such as a fracture, surgery, or soft tissue injury. Exhibit 1020, Merskey, at 57.
`
`Among the main features of CRPS is pain that is disproportionately greater than
`
`would be expected by the inciting event, which is “frequently described as burning
`
`and continuous and exacerbated by movement, continuous stimulation, or stress.”
`
`Exhibit 1020, Merskey, at 57. “It is associated at some point with evidence of
`
`edema, changes in skin blood flow, abnormal sudomotor activity in the region of
`
`the pain, or allodynia or hyperalgesia.” Exhibit 1020, Merskey, at 57.
`
`21. Accordingly, because the Challenged Claims are directed to treating
`
`CRPS, a chronic pain syndrome, they concern the field of pain treatment. A POSA
`
`with respect to the Challenged Claims would have an M.D. or a Ph.D. in a pain
`
`medicine relevant discipline, such as clinical health psychology or neuroscience,
`
`and 3 to 5 years of experience in the treatment or study of chronic pain
`
`management.
`
`5
`
`8
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`22. Based on my training and experience, I am a person of greater than
`
`ordinary skill in the relevant art. As a Professor of Pain Medicine at the University
`
`of California at San Francisco, I routinely train other physicians on the treatment of
`
`pain, including CRPS. As a member of the Board of Directors of three medical
`
`societies, I also regularly provide local, national, and international lectures on the
`
`treatment of pain, including CRPS. I am therefore qualified to offer opinions from
`
`the perspective of a POSA.
`
`V.
`
`Claim Interpretation
`
`23.
`
`I was asked to offer my opinions as to how a POSA would interpret
`
`certain terms in the Challenged Patents
`
`24.
`
`I understand that claim terms are to be given their “ordinary and
`
`customary meaning,” i.e., the meaning that the term would have to a POSA as of
`
`the filing date of the patent application.
`
`25.
`
`I understand that an inventor may give a word or phrase a specific
`
`meaning in the patent, and that in such cases the inventor’s definition controls.
`
`A.
`
`“A method of treating [a sign or symptom] associated with
`[CRPS]”
`
`26. All of the Challenged Claims cover methods of treating a particular
`
`sign or symptom “associated with” CRPS. For example, claims 1-16 of the ’352
`
`patent (Exhibit 1001) cover “method[s] of treating hyperalgesia associated with
`
`6
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`9
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`

`

`[CRPS].” To the extent these terms impose limitations on the claims at all, I was
`
`asked to provide my opinion as to how a POSA would interpret them.
`
`27.
`
`Each of the Challenged Patents defines “treating” as broadly including
`
`“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.” Exhibit 1001,
`
`’352 patent, column 7, lines 43-47; Exhibit 1002, ’774 patent, column 7, lines 43-
`
`47; Exhibit 1003, ’338 patent, column 7, lines 43-47.
`
`28.
`
`I understand that, because the specification expressly defines this
`
`term, the definition in the specification must be applied. As such, this limitation of
`
`each of the claims of the Challenged Patents merely requires that neridronic acid
`
`be administered for the purpose of diagnosing, curing, mitigating, or preventing the
`
`particular claimed sign or symptom associated with CRPS, or for activity that
`
`otherwise affects the structure or any function of the body in a human being with
`
`CRPS.
`
`29. A POSA would not interpret this term, so defined, as requiring or
`
`specifying any particular degree or level of efficacy in treating CRPS, or in treating
`
`the particular claimed signs or symptoms of CRPS.
`
`7
`
`10
`
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`

`VI. Grounds for Unpatentability
`
`A.
`
`30.
`
`Obviousness of the Independent Challenged Claims
`
`I understand that the Challenged Patents’ earliest possible priority
`
`filing date is May 14, 2012. I was asked to offer my opinion as to whether each of
`
`the independent Challenged Claims would have been obvious to a POSA as of that
`
`date.
`
`31.
`
`For the reasons discussed below, it is my opinion that the independent
`
`Challenged Claims would have been obvious to a POSA as of May 14, 2012.
`
`1.
`
`Obviousness Standard
`
`32.
`
`I understand that a claim may be unpatentable even if each and every
`
`element of the claim is not present or disclosed in a single prior art reference.
`
`33.
`
`I understand that even if each and every element of a claim is not
`
`found expressly or inherently in a single prior art reference, that claim may still be
`
`unpatentable if the differences between the invention and the prior art are such that
`
`the subject matter as a whole would have been obvious to a POSA at the time the
`
`invention was made. The POSA is presumed to have knowledge of all relevant
`
`prior art at the time of the claimed invention.
`
`34.
`
`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 any objective indicia of obviousness and
`
`nonobviousness, to the extent such indicia exist.
`8
`
`11
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`

`

`35.
`
`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
`
`that, although it is not absolutely required, it can be important to identify some
`
`teaching, suggestion, or motivation in the prior art that would have led a POSA to
`
`modify the prior art reference to combine or modify prior art teachings to arrive at
`
`the claimed invention.
`
`36.
`
`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.
`
`2.
`
`The Independent Challenged Claims
`
`37. All of the independent Challenged Claims cover a method of treating
`
`a particular sign or symptom of CRPS by parenterally administering neridronic
`
`acid to a patient suffering from that particular sign or symptom of CRPS. Each of
`
`the independent Challenged Claims is reproduced in the table below, with the
`
`particular claimed sign or symptom of CPRS bolded and underlined:
`
`9
`
`12
`
`

`

`Claim No.
`’352 patent (Exhibit
`1001) Claim 1
`
`’352 patent (Exhibit
`1001) Claim 17
`
`’774 patent (Exhibit
`1002) Claim 1
`
`’774 patent (Exhibit
`1002) Claim 16
`
`Claim Text
`A method of treating hyperalgesia 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
`hyperalgesia associated with complex regional pain
`syndrome
`A method of treating edema 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 edema
`associated with complex regional pain syndrome.
`
`A method of treating changes in skin blood flow
`associated with complex regional pain syndrome,
`comprising parenterally administering neridronic acid
`in a salt or an acid form to a human being suffering
`from changes in skin blood flow associated with
`complex regional pain syndrome, wherein the human
`being has a pain intensity of at least 7 cm on the 10
`cm visual analogue scale (VAS) or at least 7 on the 0-
`10 numerical rating scale (NRS).
`A method of treating abnormal sudomotor activity
`associated with complex regional pain syndrome,
`comprising parenterally administering neridronic acid
`in a salt or an acid form to a human being suffering
`
`10
`
`13
`
`

`

`’338 patent (Exhibit
`1003) Claim 1
`
`’338 patent (Exhibit
`1003) Claim 17
`
`from abnormal sudomotor activity associated with
`complex regional pain syndrome, wherein the human
`being has a pain intensity of at least 7 cm on the 10
`cm visual analogue scale (VAS) or at least 7 on the 0-
`10 numerical rating scale (NRS).
`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.
`A method of treating autonomic motor change
`associated with complex regional pain syndrome
`(CRPS), comprising administering neridronic acid in
`a salt form or an acid form to a human being suffering
`from autonomic motor change associated with
`CRPS.
`
`3.
`
`The Prior Art Taught that Neridronate is Effective to Treat
`CRPS and its Symptoms
`
`38. A POSA would have known that neridronate is effective to treat
`
`CRPS and its symptoms based on at least three prior art articles published in
`
`scientific journals before May 14, 2012.
`
`39.
`
`The first is M. Varenna, “L’inquadramento clinico della sindrome
`
`algodistrofica (Complex Regional Pain Syndrome di tipo I). Recenti Acquisizioni,
`
`11
`
`14
`
`

`

`The clinical framework of algodystrophy (Complex Regional Pain Syndrome type
`
`I). An Update,” GIOT Ottobre 2011;37:227-234 (Exhibit 1006, “Varenna 2011”).
`
`40. Varenna 2011 is an article published in volume 5, October 2011 of
`
`“Giornale Italiano di Ortopedia e Traumatologia” (GIOT), which translates as the
`
`“Italian Journal of Orthopedics and Traumatology.” Exhibit 1006. An electronic
`
`copy of Varenna 2011 can also be found on the GIOT which confirms its original
`
`publication date. Exhibit 1038. Based on the publication date printed on Varenna
`
`2011, which is confirmed by the website, a POSA would have concluded that
`
`Varenna 2011 was published no later than October 2011. Because Varenna 2011
`
`was originally published in the Italian language, I reviewed a certified English
`
`translation of Varenna 2011, which I understand was filed as part of Exhibit 1006.
`
`41. Varenna 2011 teaches that intravenously administered
`
`bisphosphonates such as clodronate, pamidronate, and alendronate showed efficacy
`
`in treating CRPS in randomized, double-blind clinical trials. Exhibit 1006,
`
`Varenna 2011, at 233.
`
`42. Varenna also teaches that, “[w]ithin this pharmacological family [of
`
`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.” Exhibit 1006, Varenna 2011, at 233 (emphasis added).
`
`12
`
`15
`
`

`

`43. A POSA would have known that the term “neridronate” indicates that
`
`a salt form of neridronic acid was used to treat CRPS, as permitted by the
`
`independent Challenged Claims.
`
`44. A POSA also would have known that the intravenous route of
`
`administration is one type of “parenteral” administration, as recited in claim 1.
`
`45. Based on Varenna 2011, a POSA would have concluded that
`
`parenteral administration of a neridronic acid salt is effective for treating CRPS.
`
`46.
`
`The second reference is D. Gatti et al., Neridronic acid for the
`
`treatment of bone metabolic diseases, EXPERT OP. ON DRUG METABOLISM &
`
`TOXICOLOGY 5(10):1305-11 (Sept. 2009) (Exhibit 1008, “Gatti”). Based on the
`
`publication date printed on Gatti, a POSA would have concluded that Gatti was
`
`published no later than September 2009. Gatti also concerns the use of neridronate
`
`to treat CRPS and confirms Varenna 2011’s teachings.
`
`47. Gatti teaches that neridronic acid treats various bone conditions. In
`
`particular, intravenous doses of bisphosphonates were “increasingly used for the
`
`treatment of reflex sympathetic dystrophy syndrome or algodystrophy,” which a
`
`POSA would understand refers to CRPS. Exhibit 1008, Gatti, at 1308; see Exhibit
`
`1019, Bruehl 2010, at 713.
`
`48.
`
`In Gatti’s Phase II clinical trial, it was shown “that the most effective
`
`dose is 100 mg diluted in 250 ml of saline solution given intravenously over 4
`
`13
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`16
`
`

`

`days. With this treatment regimen, the proportion of patients experiencing rapid
`
`(in 7 – 12 days) > 70% symptomatic improvements is close to 80%.” Exhibit
`
`1008, Gatti, at 1308.
`
`49. Gatti states that “[o]n the basis of these preliminary observations, 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.” Exhibit 1008, Gatti, at 1308.
`
`50.
`
`The third publication is M. Muratore et al., Il neridronato nel
`
`trattamento dell’algodistrofia simpatica riflessa dell’anca: confronto in aperto con
`
`il clodronato,, PROGRESSI IN REUMATOLOGIA, ABSTRACT BOOK VII CONGRESSO
`
`NAZIONALE COLLEGIO DEI REUMATOLOGI OSPEDALIERI 5(Suppl. 1):89 (April 16-
`
`18, 2004) (Exhibit 1007, “Muratore”). Based on the publication date printed on
`
`Muratore, a POSA would have concluded that it was published no later than April
`
`2004. Because Muratore was originally published in the Italian language, I
`
`reviewed a certified English translation of Muratore, which I understand was filed
`
`as part of Exhibit 1007.
`
`51. Muratore teaches that “[r]eflex sympathetic algodystrophy represents
`
`a syndrome characterized by the presence of localized pain, severe functional
`
`limitation, regional vasomotor disturbances, localized secondary osteoporosis,
`
`[and] possible dystrophic alterations of the skin. The pain, prevalently of a
`
`14
`
`17
`
`

`

`mechanical nature, limits movements, preventing load.” Exhibit 1007, Muratore,
`
`at 89. Muratore confirms that it was already well known in the art that
`
`bisphosphonates could be used to treat CRPS, stating that “[m]ost of the studies in
`
`the literature, reported positive results following the use of powerful antiresorptive
`
`drugs, such as bisphosphonates.” Exhibit 1007, Muratore, at 89.
`
`52. Muratore also reports results of a study comparing 100 mg
`
`intravenous neridronic acid every 4 days with 300 mg/day intravenous clodronate
`
`for 12 days in patients with femoral head algodystrophy. Exhibit 1007, Muratore,
`
`at 89.
`
`53. A POSA would have understood that CRPS has been identified by
`
`many names over the years, and that, for example, “algodystrophy,” “reflex
`
`sympathetic dystrophy,” and “reflex sympathetic algodystrophy” are synonyms for
`
`CRPS. See Exhibit 1019, Bruehl 2010, at 713.
`
`54.
`
`In Muratore’s study, neridronic acid caused a “significant well-
`
`correlated reduction of VAS” in the patients. Exhibit 1007, Muratore, at 89.
`
`55. Muratore concludes that 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, reduction of bone reabsorption markers and restoration
`
`to the original condition of the femoral head was demonstrated to be statistically
`
`15
`
`18
`
`

`

`more significant in patients treated with Neridronate.” Exhibit 1007, Muratore, at
`
`89.
`
`56.
`
`Thus, Varenna 2011, Gatti, and/or Muratore, alone or in combination
`
`with one another, teach a POSA that neridronic acid can be administered
`
`parenterally to treat CRPS and the symptoms of CRPS. A POSA would have been
`
`motivated to combine the teachings of Varenna 2011, Gatti, and Muratore because
`
`all three references concern—and share the common goal of—using neridronic
`
`acid to treat CRPS. A POSA reading Varenna 2011, for example, would be
`
`motivated to look to Gatti and Muratore for additional information and further
`
`examples of the use of neridronic acid to treat CRPS.
`
`4.
`
`The Prior Art Taught that the Signs and Symptoms in the
`Independent Challenged Claims Are Defining Symptoms,
`Signs, and Diagnostic Criteria of CRPS
`
`57. CRPS is a syndrome characterized by severe, continuing, regional
`
`pain wherein the pain is disproportionately greater in intensity or duration to the
`
`pain that would normally be expected to result from the triggering event. CRPS
`
`often develops after trauma, most often after fracture, surgery, or soft tissue injury.
`
`58. CRPS diagnosis is clinical, i.e., CRPS is defined by and diagnosed
`
`based upon the signs and symptoms it produces in affected patients. Exhibit 1031,
`
`de Castro, at 71.
`
`16
`
`19
`
`

`

`59. A physician determines whether a patient does or does not have CRPS
`
`using clinical diagnostic criteria set forth by the International Association for the
`
`Study of Pain (IASP). A POSA would have known that the IASP diagnostic
`
`criteria for CRPS were originally developed in 1994 and required:
`
`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.
`Exhibit 1020, Merskey, at 57-58 (emphasis added); Exhibit 1032, Bruehl 1999, at
`
`147.
`
`60. Revised IASP criteria known as the “Budapest Criteria” were
`
`published at least as early as 2010 and were adopted and generally accepted by
`
`2012 to improve the specificity of CRPS diagnoses. See Exhibit 1032, Bruehl
`
`1999; Exhibit 1009, Harden.
`
`61.
`
`The “Budapest Criteria” for diagnosing CRPS are reported in both
`
`Varenna 2011 (Exhibit 1006) and Harden, et al., Validation of proposed diagnostic
`
`17
`
`20
`
`

`

`criteria (the “Budapest Criteria”) for Complex Regional Pain Syndrome, PAIN 150
`
`(2010) 268–274 (Exhibit 1009, “Harden”). The Budapest Criteria for CRPS are:
`
`-
`
`-
`
`(1) Continuing pain, which is disproportionate to any
`inciting event
`(2) Must report at least one symptom in three of the four
`following categories:
`-
`Sensory: reports of hyperesthesia 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,
`nail, 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
`
`-
`
`-
`
`18
`
`21
`
`

`

`-
`
`Motor/trophic: evidence of decreased range of
`motion and/or motor dysfunction (weakness,
`tremor, dystonia) and/or trophic changes (hair,
`nail, skin)
`(4) There is no other diagnosis that better explains the
`signs and symptoms
`
`Exhibit 1006, Varenna 2011, at 228; Exhibit 1009, Harden, at 274.
`
`62. Hyperalgesia, which is recited in ’352 patent claim 1, is “[a]n
`
`increased response to a stimulus which is normally painful.” Exhibit 1020,
`
`Merskey, at 227. The related term hyperesthesia is “[i]ncreased sensitivity to
`
`stimulation, excluding the special senses,” and includes hyperalgesia and
`
`allodynia. Exhibit 1020, Merskey, at 227.
`
`63. Hyperalgesia is expressly listed in both the 1994 IASP criteria and the
`
`Budapest Criteria as a defining sign and symptom of CRPS.
`
`64.
`
`Edema, which is recited in ’352 patent claim 17, clinically manifests
`
`as swelling, often of a limb, due to the accumulation of excessive fluid in the
`
`tissue. Exhibit 1039, Stedman’s Medical Dictionary, 28th ed., at 612. In CRPS,
`
`“[e]dema is usually present and may be soft or firm.” Exhibit 1020, Merskey at
`
`57.
`
`65.
`
`Edema is expressly listed in both the 1994 IASP criteria and the
`
`Budapest Criteria as a defining sign and symptom of CRPS.
`
`19
`
`22
`
`

`

`66. Allodynia, which is recited in ’338 patent claim 1, is “[p]ain due to a
`
`stimulus which does not normally provoke pain.” Exhibit 1020, Merskey, at 226.
`
`67. Allodynia is expressly listed in both the 1994 IASP criteria and the
`
`Budapest Criteria as a defining sign and symptom of CRPS.
`
`68.
`
`“Sudomotor activity” refers to stimulation of the sweat glands and
`
`sweating. Exhibit 1039, Stedman’s Medical Dictionary, 28th ed., at 1861.
`
`“Abnormal sudomotor activity,” which is recited in ’774 patent claim 16, therefore
`
`refers to abnormal sweating changes or sweating asymmetry in the body parts
`
`affected by CRPS.
`
`69. Abnormal sudomotor activity, specifically sweating changes and/or
`
`sweating asymmetry, are expressly listed in the 1994 IASP criteria and the
`
`Budapest Criteria as defining signs and symptoms of CRPS.
`
`70.
`
`“Changes in skin blood flow,” which is recited in ’774 patent claim 1,
`
`are one of the symptoms expressly listed in the 1994 IASP diagnostic criteria for
`
`CRPS.
`
`71. Changes in skin blood flow are not expressly listed in the Budapest
`
`Criteria. However, the Budapest Criteria do include “vasomotor” signs and
`
`symptoms, including reports or evidence “of temperature asymmetry and/or skin
`
`color changes and/or asymmetry.” “Vasomotor” refers to changes in the diameter
`
`20
`
`23
`
`

`

`of blood vessels, namely the dilation or constriction of blood vessels. Exhibit
`
`1039, Stedman’s Medical Dictionary, 28th ed., at 2093.
`
`72. A POSA would have known that the vasomotor signs and symptoms
`
`listed in the Budapest Criteria are related to changes in skin blood flow. For
`
`example, Drummond, Sensory Disturbances in Complex Regional Pain Syndrome:
`
`Clinical Observations, Autonomic Interactions, and Possible Mechanisms, PAIN
`
`MEDICINE 11:1257-1266 (2010) (Exhibit 1010, “Drummond”) teaches that:
`
`Autonomic disturbances in the symptomatic limb of
`patients with CRPS range from signs of sympathetic
`deficit (warmth and loss of vasoconstrictor reflexes) to
`sympathetic overactivity (sweating and coldness). In a
`cross-sectional study of 25 CRPS patients, Wasner et al.
`found that whole-body cooling and warming provoked
`three distinct vascular patterns: increased skin blood flow
`and warmth in the symptomatic limb irrespective of body
`temperature; decreased flow and coolness in the
`symptomatic limb irrespective of body temperature; and
`an intermediate type where the symptomatic limb was
`warmer or cooler than the contralateral limb at different
`body temperatures. In contrast, changes in limb
`temperature and blood flow during body heating and
`cooling were symmetrical in healthy subjects and in
`patients with limb pain not associated with features of
`CRPS.
`
`21
`
`24
`
`

`

`Exhibit 1010, Drummond, at 1260.
`
`73. Based on Drummond and his or her knowledge and experience, a
`
`POSA would have known that changes in skin blood flow are observed in CPRS
`
`patients, and that the vasomotor symptoms of temperature and skin color
`
`asymmetry are associated with changes in skin blood flow. Thus, changes in skin
`
`blood flow, and related temperature and skin colo