Applicant : Baldassarre et al
`12/820,866
`Serial No. :
`22JUNIO
`Filed
`8 ofl5
`Page
`
`Attorney's Docket No.: 1001-0002USC1
`
`study results, and increases the soundness of the conclusions reached in the study. Accordingly,
`
`patients with background disease sufficiently severe to overwhelm or confound an expected
`
`treatment effect are systematically
`
`identified and excluded quite
`
`independently from
`
`considerations of anticipated safety or efficacy of the test article in this particular patient group.
`
`19.
`
`For example, patients with malignancy are often excluded from non-oncologic
`
`clinical trials, not because the test agents are unsafe, pose any specific risk in this population, or
`
`will not work, but rather because the clinical results will be confounded by the wholly unrelated
`
`effects of the underlying malignancy, thereby reducing the power of the clinical trial to answer a
`
`specific hypothesis regarding the test treatment. As a specific example, exclusion of patients
`
`with malignancy or advanced heart failure from cholesterol lowering trials does not imply that
`
`statins are unsafe or ineffective in these patients, but rather that their inclusion would confound
`
`the potential effects of statins on overall mortality or cardiovascular events.
`
`20.
`
`In the specific case of Kinsella et al., it is clear that one of ordinary skill in the art
`
`would understand that the patients having fatal congenital anomalities or congenital heart disease
`
`were excluded not because of a suspected safety risk of treating these patients with inhaled NO
`
`(e.g., a risk of pulmonary edema), but rather solely because the inclusion of such patients would
`
`have made it much more difficult - if not impossible - for Kinsella et al. to interpret the target
`
`outcomes of the study (i.e., would have "confounded" the results).
`
`21.
`
`On page 9 of the Office Action, the Examiner states:
`
`Loh et a/. teach that inhaled nitric oxide in patients with left ventricular
`dysfunction may have adverse effects in patients with LV failure (Title and
`Abstract). Loh et a/. clearly teaches that patients with pulmonary artery wedge
`pressure, which is synonymous with the instantly claimed pulmonary capillary
`wedge pressure, of greater than or equal to 18mm Hg had a greater effect of
`inhaled NO due to the greater degree of reactive pulmonary hypertension
`present in such patients (p. 2784, left column). Loh et a/. state: "Since the
`degree of reactive pulmonary hypertension is generally related to the severity
`of hemodynamic compromise in patients with LV failure,
`it might be
`
`Ex. 2007-0851
`
`

`
`Applicant : Baldassarre et al
`Serial No. :
`12/820,866
`Filed
`22JUNIO
`9 of 15
`Page
`
`Attorney's Docket No.: 1001-0002USC1
`
`anticipated that patients with more severe heart failure will have a more
`marked hemodynamic response to inhaled NO. " Loh et a/. examined this
`prediction further and verified it (p. 2784, left column).
`
`The Examiner apparently neglects to consider that the acute hemodynamic effect of inhaled NO
`was studied by Loh et al. only in adult patients with New York Heart Association Class III or IV
`
`congestive failure due to coronary artery disease or dilated cardiomyopathy, not in term or near(cid:173)
`
`term neonates who were not dependent upon right-to-left shunting. Thus, their observations do
`
`not teach, or even suggest, the risk of inhaled NO in neonates or children with pulmonary
`
`hypertension and left ventricular dysfunction who are not dependent on right-to-left shunting of
`
`blood, the population that is addressed in the present claims.
`
`22.
`
`The underlying etiologies and hemodynamic characteristics of both the primary
`
`heart disease and the increased pulmonary vascular resistance are drastically different from
`
`adults, as compared to non-adults, such that one cannot readily assume or anticipate clinical
`
`results within adults to translate into neonates or children.
`
`In particular, left ventricular
`
`dysfunction in neonates with congenital heart disease is primarily due to developmental
`
`structural disease of the heart, inborn errors of metabolism that impair energy generation in the
`
`heart muscle, or viral infection. Class III or class IV congestive heart failure in adults (in
`
`contrast to congenital heart disease in neonates or children) is due to ischemic or dilated
`
`cardiomyopathy, mostly secondary to coronary artery disease and/or chronic systemic
`
`hypertension. Pulmonary hypertension associated with neonatal congenital heart disease is
`
`secondary to chronic hypoxemia, developmental abnormalities of the pulmonary blood vessels
`
`and/or pulmonary vascular damage from abnormally high blood flow and/or pressure through the
`
`pulmonary vasculature, resulting in evident disease of the lung vasculature.
`
`In contrast,
`
`increased pulmonary vascular resistance in adult Class III or IV congestive heart failure is due to
`
`reactive pulmonary vasoconstriction secondary to increased sympathetic tone or circulating
`
`vasoactive molecules (Loh et al., p. 2780, left column) in otherwise structurally normal blood
`
`vessels. Therefore, the hemodynamic responses to pulmonary vasodilation by inhaled NO in
`
`children or neonates, without right-to-left shunting of blood, but with significant pulmonary
`
`hypertension and left ventricular dysfunction cannot be reasonably predicted from the
`
`hemodynamic responses to pulmonary vasodilation by inhaled NO of adults with advanced
`
`Ex. 2007-0852
`
`

`
`Applicant : Baldassarre et al
`12/820,866
`Serial No. :
`Filed
`22JUNIO
`Page
`10 ofl5
`
`Attorney's Docket No.: 1001-0002USC1
`
`atherosclerotic congestive heart failure and reactive neuro-humoral pulmonary vascular
`
`constriction (with or without pulmonary hypertension) as described by Loh et al.
`
`23.
`
`On page 10 of the Office Action, the Examiner states:
`
`"It would have been obvious to one of ordinary skill in the art at the time the
`claimed invention was made to perform the method of Atz et a/. and identify
`patients with a second condition/risk factor and administer iNO to patients
`that do not have the first or second condition/risk factors of instant claims 20-
`27 and inform the medical provider that patients with a pulmonary capillary
`wedge pressure greater than 20 mm Hg that may increase pulmonary edema,
`as suggested by Loh et a/., and Kinsella et a/., and produce the instant
`invention."
`
`24.
`
`Atz & Wessel do not recommend exercising "caution" when treating tenn or near-
`
`tenn neonates who are not dependent upon right-to-left shunting, but rather refer to two other
`
`patient populations, namely (i) neonatal patients whose systemic circulation is dependent upon
`
`right-to-left shunting of blood and who therefore might suffer from systemic circulatory collapse
`
`if given inhaled NO (a well-known contraindication for inhaled NO) and (ii) adult patients with
`
`New York Heart Association Class III-IV heart failure due
`
`to
`
`ischemic or dilated
`
`cardiomyopathy and increased neuro-humorally-mediated pulmonary vascular resistance might
`
`be hemodynamically at risk for pulmonary edema if given inhaled NO (the same population
`
`discussed by Loh et al. ).
`
`25.
`
`On page 10 of the Office Action, the Examiner states:
`
`"One of ordinary skill in the art would have been motivated to do this because:
`/) it is common sense that if the neonate is healthy then iNO therapy can be
`performed safely; 2) if the neonate is not healthy and has left ventricular
`dysfunction (LVD), then Atz eta/. clearly teach using extreme caution or not
`using NO at all in the treatment of patients with LVD which would also render
`obvious all conditions/risk factors associated with LVD; and 3) the art of
`Kinsella et a/. establishes excluding certain patients (premature neonates)
`from inhaled nitric oxide treatment if they have fatal congenital anomalies or
`congenital heart disease."
`
`Ex. 2007-0853
`
`

`
`Applicant : Baldassarre et al
`Serial No. :
`12/820,866
`Filed
`22JUNIO
`II of 15
`Page
`
`Attorney's Docket No.: 1001-0002USC1
`
`The conclusion presented by the Examiner is not clinically accurate, nor does it accurately reflect
`
`the expectations or motivations of a clinician of ordinary skill in the art at the time of the
`It is by no means "1)
`invention. Their expectation would have been quite the opposite.
`... common sense that if the neonate is healthy then iNO therapy can be performed safely; 2) if
`the neonate is not healthy and has left ventricular dysfunction (LVD), then Atz eta/. clearly teach
`
`using extreme caution or not using NO at all in the treatment of patients with LVD." Firstly,
`inhaled NO would have no utility in healthy neonates, and is safely used in very severely ill
`
`neonates on a routine basis. Secondly, Atz & Wessel teach "using extreme caution or not using
`
`NO at all" only in neonates dependent upon right-to-left shunting of blood in order to avoid
`
`systemic circulatory collapse, and makes no statement regarding neonates with left ventricular
`dysfunction who are not dependent upon right-to-left shunting. Kinsella et al. do not teach
`
`about the safe or unsafe use of inhaled NO in neonates or children, let alone term or near-term
`
`neonates not dependent upon right-to-left shunting, but merely noted that they had excluded
`
`premature babies with fatal malformations or congenital heart disease from a clinical trial of
`
`inhaled NO in premature babies suffering from the respiratory distress of prematurity. Loh et at.
`
`teach about the effect of inhaled NO on hemodynamic measurements in adults with advanced
`
`heart failure and secondary neuro-humorally-mediated increased pulmonary vascular resistance,
`
`and speculate that these adults may be at increased risk for pulmonary edema, but do not teach
`
`anything about the use of inhaled NO in term or near-term neonates not dependent upon right-to(cid:173)
`
`left shunting.
`
`26.
`
`On page 11 of the Office Action, the Examiner states:
`
`"Furthermore, it is already known through the teachings of Loh et al. that a
`pulmonary capillary wedge pressure (PCWP) of greater than 18 mg Hg serves
`as a guidepost for alerting the artisan to adverse events from inhaled NO.
`Thus, it is not inventive to exclude patients with a PCWP of greater than 20
`mm Hg when the art already suggests the risk of trouble of treating patients
`with a PCWP of 18 mm Hg because inhaled NO increases the wedge pressure
`as taught by Loh et a/. (see entire document). In summary, it remains the
`position of the Examiner, which is in alignment with the written opinion of the
`international search authority, that it is simply not inventive to 'inform' a
`medical provider that a neonate with L VD is at risk of adverse/serious adverse
`
`Ex. 2007-0854
`
`

`
`Applicant : Baldassarre et al
`12/820,866
`Serial No. :
`22JUNIO
`Filed
`Page
`12ofl5
`
`Attorney's Docket No.: 1001-0002USC1
`
`events from iNO therapy when the art already has established that fact and the
`ordinary artisan is alerted to this fact. /(the patient has LVD then thev are at
`risk of adverse and/or serious adverse events ftom iNO therapy and it is not
`inventive to further identify other secondary conditions/risk (actors associated
`with LVD and provide further warnings (or secondary conditions/risk factors
`that are separate and independent from the first condition/risk factor but
`nevertheless associated with LVD to the medical provider. Screening (or
`conditions that predispose the patient to adverse/serious adverse effects from
`medical treatment is obvious given the teachings above." (emphasis in
`original)
`
`It is inaccurate to represent Lob et al as "serving as a guidepost for alerting the artisan to
`
`adverse events from inhaled NO," as Lob et al. reported no adverse events during administration
`
`of inhaled NO for 10 minutes to 19 stable patients with advanced heart failure. Rather, Loh et al.
`
`speculated that a finding of an elevation in PCWP in a subgroup of such patients could pose an
`
`increased risk of pulmonary edema in adults with congestive heart failure due to ischemic or
`
`dilated cardiomyopathy. As discussed above, extrapolation of that theoretical risk to neonates
`
`and children with different forms of heart disease, different cardiovascular hemodynamics, and
`
`different pulmonary vasculature physiology, pathophysiology and pathology was not obvious, as
`
`evidenced by the fact that the members of the INOT22 Screening Committee (including Dr.
`
`Wessel) who designed the INOT22 study protocol, the approximately 18 Institutional Review
`
`Boards and/or Independent Ethics Committee, and 5 National Health Authorities (FDA and
`
`national Health Authority for United Kingdom, France, Netherlands and Spain) who reviewed
`
`and approved the INOT22 study protocol prior to its initiation, all failed to predict that any
`
`untoward effects would be caused by the administration of inhaled NO within a pediatric patient
`
`population having left ventricular dysfunction who are not dependent on right-to-left shunting of
`
`blood .. Only after being informed of the present invention did the FDA mandate a change to the
`
`drug labeling for inhaled NO to include a new warning (separate and distinct from the pre(cid:173)
`
`existing contraindication pertaining to neonates dependent on right-to-left shunting of blood)
`
`concerning the use of inhaled NO in patients with pre-existing left ventricular dysfunction.
`
`27.
`
`On page 12 of the Office Action the Examiner states:
`
`Ex. 2007-0855
`
`

`
`Applicant : Baldassarre et al
`12/820,866
`Serial No. :
`22JUNIO
`Filed
`13 of 15
`Page
`
`Attorney's Docket No.: 1001-0002USC1
`
`Respectfully, the instantly claimed method steps are in the realm of common
`sense and not in the realm of invention because it is already known in the art
`that patients with pre-existing LVD are at risk of adverse effects from iNO. It is
`obvious to the ordinary artisan that if the neonate has LVD with or without any
`number of conditions/risk factors, then in order to avoid the risk of adverse or
`serious adverse events associated with iNO, to then exclude the neonate from
`iNO therapy. In other words, given the art as a whole, determination o.ffurther
`conditions/risk factors that would exclude the neonate fi·om iNO therapy is
`obvious given the teachings in the art as discussed above which direct the
`artisan to screen neonates about to undergo treatment with NO by inhalation
`and to exclude those with L VD from such treatment. In light of the forgoing
`discussion, the Examiner concludes that the subject matter defined by the
`instant claims would have been obvious within the meaning of 35 USC 103(a).
`From the teachings of the references, it is apparent that one of ordinary skill in
`the art would have had a reasonable expectation of success in producing the
`claimed invention. Therefore, the invention as a ·whole was prima facie
`obvious to one of ordinary skill in the art at the time the invention was made,
`as evidenced by the references, especially in the absence of evidence to the
`contrary. "
`
`The arguments by which this conclusion is supported are both medically and scientifically
`
`unsound. To summarize, the teaching of Atz & Wessel is inaccurately portmyed by the
`
`Examiner due to his confusion of the known risk of systemic vascular collapse if inhaled NO is
`
`administered to neonates dependent upon right-to-left shunting of blood, and the opposite case of
`
`adults where inhaled NO may be less effective than in children. The Examiner misconstrues
`
`Kinsella et al. 's clinical trial inclusion/exclusion criteria as a teaching of risk associated with
`
`inhaled NO administration, rather than as a routine pmctical measure in the design of clinical
`
`trials to minimize confounding factors and heterogeneity in the study population. Lastly, the
`
`Examiner grossly over-interprets the hemodynamic findings of Loh et al. in adults with ischemic
`
`or dilated cardiomyopathy and congestive heart failure (a disease process differing in etiology,
`
`physiology, pathophysiology and pathology from childhood congenital heart disease) as "a
`
`guidepost to the artisan" regarding the use of inhaled NO in children and neonates with
`
`pulmonary hypertension and left ventricular dysfunction, but not dependent on right-to-left
`
`shunting of blood. These inaccurate and erroneous interpretations of all three supporting
`
`publications cited by the Examiner lead the Examiner to draw incorrect conclusions regarding
`
`what is or is not taught or suggested by the prior art.
`
`Ex. 2007-0856
`
`

`
`Applicant :
`Serh1l No.
`Filed
`Page
`
`Bakkmsarr~ l.lt al
`! 2Jg2Q,S66
`22JI3--i !0
`!4 of 15
`
`28.
`
`On June 28, 20! l, l met \vith Dr, David L WesseL the chair of the ! NOT22
`
`Steering Cornrnithx~ and tht.~ senior author of /1/z & ll"cssd (S'eminars in Perinawlogy !997,
`21(5). pp ,j.IJ--455. During our discussion, I inf(H·mcd Dr. \Vessel of the 12/820,866 and
`12/820,980 patent applications~ and th<:~ l~1ct that in both pending patent applk:ations, the
`Exmnlncr \V~ls citing i\lz & Wt.~sstd to alk!gt:! that h 'vou!d hnvc b~:-1:.n ohvim1s lo predict the
`
`adverse t.~\·i..~nts and outcmm~s of the !NOT22 studv that lend to t!K~ invenlions c!uhned in
`
`<'
`
`12/S20J566 and 12/820,980.
`
`29.
`
`Dr. \Vessel di::;agn:.•ed \vith the Examint:r's allegation and limnd it ironic that his
`O\Vn publication \Vould l:H.~ cit<:xi to suggn>l the obviousncs;;; of the une.'<.perted outcomes of the
`n..:;crr'1:2 study, when Dr. We::;sd hims~:.~tC the senior author of Atz & \VesseL hiled to predict
`that neonatal and child p<rticnts \\·ith left vcntricuhlr dysfunction ~;vho ar'~ not dependent on right(cid:173)
`to-left shunting of blood \.VOUkl be at llK:r('tJ::>t~J rhk of adV!:.fSC events \Vhcn administered inhaled
`
`NO.
`
`/\ copy of a June 29, 20 ll klter from Dr. \Vessel to rm~ st;=Hing this opinion is attached
`
`h.~.:.~r;;.~to as Exhibit 2.
`
`3(L
`
`""
`
`I herebv de1..:!arc that all stm~:rnrnts rnmlc hen .. dn of mv n'>vn knowkdu.e: an.~ t.n.w
`..
`and that ali staternents rnade on inf()rmation ;:u1d belief are beHe:ved to be true: and further that
`
`........
`
`these statements \Ven:. made \vith the knov;ledge that <vil!fu! thlsc stmt~ments and tlx; Hh~ ~o
`rnade arc punishable by fine or imprisonment, or both, tHHJer Stx:tion !00 l of Titlt.: 18 of the
`
`United States G.xk and that such w1l!fn! C1lw~ stalcnJt'.!rlt~ rnay jeopan.lil.e the va!idl.ty of the '359
`
`patent
`
`Ex. 2007-0857
`
`

`
`Applicant :
`Serial No. :
`Filed
`Page
`
`Baldassarre et al
`12/820,866
`22JUNIO
`IS of IS
`
`Attorney's Docket No.: 1001·0002USC1
`
`EXHIBIT 1
`
`(curriculum vitae)
`
`Ex. 2007-0858
`
`

`
`.•
`
`PERSONAL DATA
`
`Name:
`
`EDUCATION
`
`High School
`
`Undergraduate
`
`()
`
`0
`
`CURRICULUM VITAE
`
`Douglas Alan Greene, M.D.
`
`Columbia High School, South Orange, NJ, 1962
`
`·Princeton University, Princeton, NJ, BA Biology(cum laude), 1962·1966
`
`Graduate/Professional
`
`Johns Hopkins School of Medicine, Bnltimorc, MD, M.D., 1966-1970
`
`POSTDOCTORAL TRAINING
`
`Medical Internship:
`
`Department of Medicine, Johns Hopkins, Baltimore, MD. 1970-1971
`
`Medical Residency:
`
`Depnrtment of Medicine, Johns Hopkins, Baltimore, MD, 1971-1972
`
`Fellowship:
`
`Medical Fellowship, Department of Medicine, Johns Hopkins University,
`School of Medicine, Baltimore, MD, 1970-1972
`
`Post-doctoral Research Fellow, Diabetes, GeorgeS. Cox Medical
`Research Institute; Hospital of the University of Pennsylvania.
`Phila~elphia, PA (Dr. Albert I. Winegrad, preceptor), 1972-1975
`
`Medical Fellowship, Department of Medicine, University of
`Pennsylvania, School of Medicine, Philadelphia, PA, 1972-1975
`
`NON·ACADEMJC EMPLOYMENT
`
`2000-2003
`
`Executive Vice President, Clinical Sciences and Product Development
`(CSPD), Merck Research Laboratories, Rahway, New Jersey, and
`Corpomte Officer, Merck, Inc. Supervised and directly managed all
`clinical research, regulatory affairs, clinical and non-clinical quality
`assunmce and pharmaco-vigilance ut Merck Research Laboratories.
`
`2003-2006 Vice President, Head Corporate Regulatory Development, Sanofi-Aventis, Bridgewater,
`NJ. Overseeing all aspects of corporate regulatory development of all pre-clinical and clinical
`development projects/life-cycle products in Research & Development.
`
`2006-2009 Senior Vice Prcseident, Chief Medical Officer, Sanon-Aventis, Bridgewater, NJ.
`Overseeing medical, regulatory, phannocovigilance, risk management, education and medical
`communications for US region, Member US Executive Committee, Member Committee
`Operntional de Development, International Clinical Development.
`
`2009-present Senior Vice President, Senior Scientific Advisor, Sanofi-Aventis, Bridgewater, New
`Jersey. Mentber Corporate Portfolio Valuation Process and Drug Development Commiuees. The
`position at the interface between the Research and Development nnd Phannaceutical Operations is
`responsible for providing key scientific and medical guidance for sanofi-aventis' scientific
`strategy within U.S. and global contexts to enhance the quality and effectiveness of the company's
`research and product portfolio, including assessment and guidance or internal R&D product
`pipeline and franchise portfolio and external commercial and academic Innovation opportunities.
`
`Ex. 2007-0859
`
`

`
`0
`
`()
`
`Douglas A. Greene, M.D.
`updated OS/28//0
`
`ACADEMIC APPOINTMENTS
`
`1915-1980
`
`1980·1986
`
`1986-2000
`
`Assistant Professor of Medicine, University of Pennsylvania, School of
`Medicine, Philadelphia, Pennsylvania
`
`Associate Professor of Medicine, Director, General Clinical Research
`Center and Diabetes Research Labomtories, University of Pittsburgh,
`School of Medicine
`
`Professor or Internal Medicine, Director, Michigan Diabetes Research
`and Tmining Center, University of Michigan School of Medicine
`
`Chief, Division of Endocrinology & Metabolism, University of Michigan
`School or Medicine
`
`2000-Prcsent
`
`Adjunct Professor, Internal Medicine. Division of Endocrinology &
`Metabolism, University of Michigan. School of Medicine
`
`SELECTED SCIENTIFIC ACTIVITIES
`
`1988-1994
`
`Chairman, Endocrinologic and Metabolic Drug Advisory Board, Food
`und Drug Administration. Washington D.C (Chair, 1990-1994)
`
`1994-2000
`
`ChaJnnan, Merck Scientific Board of Advisors
`
`SELECTED SCIENTIFIC PRIZES AND AWARDS
`
`1986
`
`1987
`
`1987
`
`1988
`
`1989
`
`1994
`
`1996
`
`1996
`
`1998
`
`First Annual Raymond A. and Robert L. Kroc Lecturer, Eisenhower Medical
`Center, Palm Springs, California
`
`Moore Award, The American As.'!ocintion of Neuropnthologists, Seattle,
`Washington
`
`Carol Sinicki Manuscript Award (The Diabetes Educator). American Association
`of Diabetes Educators. Chicago, Illinois
`
`Kellion Lecture, International Diabetes Federation, Sydney, Australia
`
`Banting and Best Lecture. Toronto General Ho.'lpital, Toronto, Canada
`
`Charles H. Best Lecturer, Toronto Diabetes Association, Toronto, Canada
`
`Invited Speaker. Seventy-tifth Anniversary Celebrating the Discovery of Insulin,
`Toronto, Canada
`
`First Alan Robinson Lecturer, University of Pittsburgh
`
`Outstanding Foreign Investigator Award, Japan Society of Diabetic
`Complications
`
`2
`
`Ex. 2007-0860
`
`

`
`..
`
`()
`
`SELBCfED BIBLIOGRAPHY
`
`..
`
`()
`
`Douglas A. Orccnc, M.D.
`updated 051281/0
`
`Pee,...Reviewed PubUc11tlons (Selected from over 110 peer-reviewed tuticles):
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`J 3.
`
`Greene DA, DeJesus PV. Winegmd AI: Effect of insulin and dietary Myo-Inositol on impaired
`peripheral motor nerve conduction velocity in acute streptozotocin diabetes. J. Clln. Invest.
`55:1326-1336, 1975.
`
`Wlnegrad AI, Greene DA: Diabetic polyneuropathy: The importance of insulin deficiency,
`hyperglycemia and nllemtions in myoinositol metabolism in Its pathogenesis. N. Engl. J. Med.
`295:1416-1420, 1976.
`
`Greene DA, Lattimer SA: Sodium- and energy dependent uptake of myo-inosltol by rabbit
`peripheral nerve. Competitive inhibition by glucose and lack or an insulin effect. J. Clin. Invest.
`70:1009-1018, 1982.
`
`OreeneDA, Lattimer SA: Impoired rat sciatic nerve sodium-potassium ATPase in acute
`streptozocin diabetes and its correlation by dietary myo-inositol supplementation. J. Clin. Invest.
`72:1058-1063, 1983.
`
`Greene DA, Lattimer SA: Impaired energy utilization and Na-K-ATPase in diabetic peripheral
`nerve. Am. J. Physiol. 246:E311-E318, 1984.
`
`Greene DA, Yagihashi S, Lnttimer SA, Sima AAF: Nerve Na"'+K+·ATPasc, conduction and
`myo-inositol in the insulin deficient BB rat. Am J Physiol241:BS34-BS39, 1984.
`
`Greene DA, Lattimer SA: Protein kinase C agonists acutely normalize decreased ouabain(cid:173)
`inhibitable respiration in diabetic rabbit nerve: Implications for [Na,K]-ATPase regulation and
`diabetic complicntions. Diabetes 35:242-245, 1986.
`
`Sima AAP,I..auimer SA, Yagihashi S, Greene DA: 'Axo-glial dysjunction' a novel structural
`lesion that accounts for poorly-reversible slowing of nerve conduction in the spontameously
`diabetic BB·rat. J. Clin. /nve.vt. 77:474-484, 1986.
`
`Greene DA: A sodium-pump defect in diabetic peripheral nerve corrected by sorbinll
`administration: Relntionshlp to myo-inositol metabolism and nerve conduction slowing.
`Metabolism 35:60-66, 1986.
`
`Greene DA, Mackway AM: Decreased myo-inositol content and Na•-K•-A'l'Pase uctivity in
`superior cervical ganglion of STL·diabetic rat and prevention by aldose reductase inhibition.
`Dlabetts35:1l06-1108, 1986.
`
`Carroll PB, Thornton BM, Greene DA: Glutathione redox state is not the link between polyol
`Ralhway activity and diminished (Nn,K)-ATPase activity in experimental diabetic neuropathy.
`Diabetes 35:1282-1285, 1986.
`
`Greene DA, Lattimer SA, Simn AAF: Sorbitol, phosphoinosilides and the sodium-potassium
`ATPase in the pathogenesis of diabetic complications. N. EnsL J. Med. 316:599-606, 1987.
`
`Greene DA, Chakmbartl S, Lattimer SA, Sima AAF: Role of sorbitol accumulation and myo(cid:173)
`inositol depletion in pumnodal swelling of large myelinated nerve fibers in the insulin-deficient
`spontaneously diabetic bio-breeding mt: Reversal by insulin replacement, on aldose reductase
`inhibitor, and myo-inositol. J. C:lln. Invest. 79:1479-1485, 1987.
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`Sima AAF. Nathaniel V, Bril V, McEwen T AJ, Greene DA: Histopathological heterogeneity of
`neuropathy in Insulin-dependent and non-insulin-dependent diabetes, and demonstrntion of axe(cid:173)
`glial dysjunction in human diabetic neuropathy. J. Clin.lnvesl. 81:349-364, 1988.
`
`Greene OA, Lattimer SA, Sima AAF: Perspectives in diabetc.~: Are disturbances of sorbitol,
`phosphoinosilide, and Nn•-K'•·ATPase regulation involved in pathogenesis or diabetic
`neuropnlhy? /Jiabetes37:688-693, 1988.
`
`Oreene DA, Lattimer SA, Sima AA: Pathogenesis und prevention of diabetic neuropathy.
`Diabetes Metab Rav 4:201-221, 1988.
`
`Lattimer SA, Sima AAF, Oreene DA: In Vitro correction of impaired Na•-Kt·ATPase in diabetic
`nerve by protein kinase C ngonists. Am. J. Physiol. 256 (Bndocrinol. Metab. 19):B264-B269.
`1989.
`
`Greene DA, Lattimer SA, Sima AAF: Pathogenesis or diabetic neuropathy: Role of altered
`phosphoinosltide metabolism. CRC Critical Reviews in Ne11roblology (J. Nelson, cd., CRC Press,
`Inc.), pp. 143-219, 1989.
`
`Greene DA, Lattimer SA, Carroll PB, Fernstrom JD, Finegold DN: A defect in sodium(cid:173)
`dependent amino acid uptake in diabetic mbbit peripheral nerve: Correction by an aldose
`reductase inhibitor or myo-inositol administration. J. Clin. Jnve.vt. 85:1657-1665, 1990.
`
`Greene DA, Sima AF, Pfeirer MA. Albers JW. Diabetic Neuropathy. Annu Rev Med 41:303-
`317, 1990.
`
`Sima AAF. Prashar A, Zhang W -X, Chakrabnrti S, Greene DA: Preventive effect of long-term
`aldose reductase inhibition (Ponalrestnl) on nerve conduction and sural nerve structure in the
`spontaneously diabetic blo-brocding mt. J. Clin. Invest. 85: 141 0·1420, 1990.
`
`Kim J, Kyriazi H, Greene DA: Normalization of (Nn,K)-ATPasc activity in an isolated
`membmnc rraclion from scinlic nerves of strcptozotocin-diabctic rats by dicl4ry myo·inositol
`supplementation in vivo or protein kinnsc C agonists in vitro. Dittbetea 40:558-567, 1991.
`Stevens MJ, Lattimcl' SA, Kumijo M, Van Huysen c. Sima AAF, Greene DA: Osmoticully
`induced nerve taurine depletion in experimental diabetes: An hypothetical medilttor of painful
`neuropathy. D/Qbatologia 36:608-614, 1993.
`
`Henry ON, Del Monte M, Greene J)A, Killen PD: Altered uldosc reductase gene regulation in
`cultured humun retinol pigment epithelial cells. J. Clin. lnve.vt. 92:617-623, 1993.
`
`The DCCT Research Group: The effect of intensive treatment of diabetes on the development
`and progression of long-tenn complicntions in insulin-dependent diubetes mellitu.-.. N. Eng. J.
`Med. 329:977·986, 1993.
`
`Thomas TP, Feldman BL, Nakamum J, Knto K, Lien M, Stevens MJ, Greene DA: Ambient
`glucose and aldose reductase-induced myo-inositol depletion modulate basal and carbachol(cid:173)
`stimulated inositol phospholipid metabolism and diacylglyccrolaecumulation in human retinal
`pigment epithelial cells in culture. Proc. NatL A cad. Sci. USA 90:9712-9716, I 993.
`
`ThomnsTP, Porcellnti F. Knto K, Steven.~ M1, Sherman WR, Greene DA: Effects of glucose on
`sorbitol pathway activation. cellular redox, and metabolism of myo-inositol, phosphoino.~itide and
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`11pdated OS/28110
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`diacylglycerol in cultured human retinal pigment epithelial cells. J. Clin. Invest. 93:2718-2724,
`1994.
`
`Stevens MJ, Dananberg J, Feldmun BL, Lattimer SA, Kamijo M, Thomas TP, Shindo H, Sima
`AAF, Oreenc, DA: The linkcd.roles of nitric oxide, aldose reductase and (NA •,K,·ATPasc in
`the slowing of nerve conduction in the streptozotocin diabetic rat. J. Clin. Invest. 94:853-859,
`1994.
`
`feldman BL, Stevens MJ, Thomas PK, Brown MD, Canal N, Greene DA: A practical two-step
`quantitative clinicalnnd clcctrophyslologicnlnssc.l!sment for the diagnosis and staging of diabetic
`neuropathy. Diabetes Care 17:1281-1289, 1994.
`
`The DCCT Research Group: The effect of intensive treatment of diabetes on nerve conduction
`measures in the DCCT. Atmal.v ofNeuro. 38:869-880, 1995.
`
`Stevens MJ, Feldman BL, Greene DA: The aetiology of diabetic neuropathy: The combined roles
`of metabolic and vascular defects. DiaiJellc Medicine I 2:566-579, 1995.
`
`Shindo H, Thomas TP, Larkin DO, Knrlhaloo AK, Inadn H, Onaya T, Stevens MJ, Greene DA:
`Modulation or basal nitric oxide-dependent cyclic-OMP production by ambient glucose, myo(cid:173)
`inositol, and protein kinase C in SH-SYSY human neuroblastoma cells. J Clln Invest 97:736· 745,
`1996.
`
`Sima AAF, Rislic H, Merry A, Kamijo M, Lattimer SA, Stevens MJ, Greene DA: Primary
`preventive and secondary lnlerventionary effects of acetyl-L-camitine on diabetic neuropathy in
`the bio-breeding Worchester rat. J Clin Invest 97:1900-1907, 1996.
`
`Karihaloo A, Kato K, Greene DA, Thomas TP: Protein kinase and cystololic calcium modulation
`of n•yo-inosito1 transport in cultured retinal pigment epithelial cells. Am J Physioi213:C611·618,
`1997.
`
`The DCCT Research Group: Bffect of intensive thcmpy on rc.41idual B-cell function in patients
`with Type I diabetes in the DCCT: A mndomizcd, controlled trinl. Ann Tnt Med 128:517-523,
`1998.
`
`The DCCT Research Group: The effect of intensive diabetes therapy on measures of autonomic
`nervous system function in the DCCl'. Dicrbetologia 41 :4 I 6-423, 1998.
`
`Porccllati P, HlaingT, Togawa M, Stevens MJ, Larkin DD, Hosalw Y, OloverTW, Henry DN,
`Greene DA, Killen PO: Human Nn • -myo-inositol cotmnsportcr gene: alternate splicing generales
`diversetransaipts.AmJ Physio. 274: CI215-CI225, 1998.
`
`Porcellati P,llosaka Y Hlaing T, Tognwa M, Larkin DO, Karihaloo A, Stevens MJ, Killen PD,
`Greene DA: alternate splicing in human Nn•·MI cotransportcr gene yields differentially
`regulated transport isoforms. Am J Physio1216:132S-1331, 1999.
`
`Greene DA, Stevens MJ, Obrosova I, Feldman BL. Olucosc-induccd oxidative stress and
`programmed cell death in diabetic neuropathy. European Journal of Pharmacology 375:217·223,
`1999.
`
`Greene DA, A1"C'1.1.o JC. Brown MB: Effect of aldose reductase inhibition on nerve conduction
`and morphometry in diabetic neuropathy. Neurology 53:580-591, 1999.
`
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`Douglns A. Greene, M.D.
`updated OS/28110
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`Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and
`Complications Research Group: Retinopathy and nephropathy in patients with type I diabetes
`