UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Ex parte JOHN H. GRIFFIN, LAURENT 0. MOSNIER,
`AND ANDREW J. GALE
`
`Appeal 2013-000201
`Application 11/589,371
`Technology Center 1600
`
`Before ERIC B. GRIMES, ULRIKE W. JENKS, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`PERCURIAM
`
`DECISION ON APPEAL
`This is a decision on appeal 1 under 35 U.S.C. § 134 from the
`Examiner's rejection of claims 13, 16, 21, 22, 50, 51, and 53.2 We have
`jurisdiction under 35 U.S.C. § 6(b).
`
`We reverse.
`
`1 Appellants identify the Real Party in Interest as The Scripps Research
`Institute (App. Br. 2).
`2 Claims 1, 6--10, 42-44, 46-49, and 54--70 are also pending but stand
`withdrawn from consideration (App. Br 2).
`
`

`
`Appeal 2013-000201
`Application 111589,371
`
`STATEMENT OF THE CASE
`
`The Specification discloses variants or mutants "of recombinant
`
`protein C and activated protein C, an enzyme that normally has anti(cid:173)
`
`thrombotic, anti-inflammatory, and anti-apoptotic activities" (Spec. 1, ~ 3).
`
`"The recombinant activated protein C mutants ... have markedly reduced
`
`anticoagulant activity, but retain near normal anti-apoptotic ( cytoprotective)
`
`activity" (id.). "The activated protein C variants ... are useful as inhibitors
`
`of apoptosis or cell death and/or as cell survival factors, especially for cells
`
`or tissues of the nervous system and of blood vessels, which are stressed or
`
`injured" (id.). The Specification discloses that "therapeutic compositions
`
`comprising such mutant proteins ... should provide the desired
`
`cytoprotective benefits while carrying a lower risk of bleeding, a side effect
`
`of activated protein C therapy" (id.).
`
`Claim 13 is representative of the claims on appeal and reads as
`
`follows:
`
`13. A therapeutic composition comprising an effective amount of a
`variant of a wild-type recombinant activated protein C, said variant of a
`wild-type recombinant activated protein C having anticoagulant activity and
`cytoprotective activity, wherein said variant of a wild-type recombinant
`activated protein C has a mutation consisting of:
`(a) two or more than two substitutions of basic amino acid residues of
`loop 37 with alanine residues, and
`(b) one or more than one substitution of a basic amino acid residue of
`the calcium loop with an alanine residue
`relative to SEQ ID NO: 15;
`and wherein said mutation results in the reduction of the anticoagulant
`activity, but not the cytoprotective activity, relative to a wild-type
`recombinant or endogenous activated protein C.
`
`(App. Br. 23-24.)
`
`2
`
`

`
`Appeal2013-000201
`Application 11/589,371
`
`Issue
`
`The Examiner has rejected claims 13, 16, 21, 22, 50, 51, and 53 under
`35 U.S.C. § 103(a) as obvious over the combination ofGale, 3 Mosnier,4
`Riewald5 (Ans. 4---{)).
`
`The issue presented is: Is the declaration by John H. Griffin, Ph.D.,
`
`submitted pursuant to rule 37 C.F.R. § 1.132, sufficient to establish that the
`
`Mosnier is not prior art to the instant application and thereby overcome the
`
`obviousness rejection?
`
`Findings of Fact
`
`FF 1. The Examiner finds that Gale discloses mutated forms of
`
`activated protein C (APC) "that have reduced ... anti-coagulant activity"
`
`(Ans. 5 (citing Gale, 28838)).
`
`FF2. The Examiner finds that Riewald discloses that APC "has
`
`additional therapeutic activities, including anti-apoptotic activity, anti(cid:173)
`
`inflammatory activity, [and] anti-septic activity" (id. (citing Riewald, 1882,
`
`center and right co ls.)).
`
`3 Andrew J. Gale et al., Molecular Characterization of an Extended Binding Site
`for Coagulation Factor Va in the Positive Exosite of Activated Protein C*, 277
`The Journal of Biological Chemistry 28836-28840 (2002).
`4 Laurent 0. Mosnier and John H. Griffin, Inhibition of staurosporine(cid:173)
`induced apoptosis of endothelial cells by activated protein C requires
`protease-activated receptor-] and endothelial cell protein C receptor, 373 J.
`Biochem. 65-70 (2003).
`5 Matthias Riewald et al., Activation of Endothelial Cell Protease Activated
`Receptor 1 by the Protein C Pathway, 296 Science 1880--1882 (2002).
`
`3
`
`

`
`Appeal2013-000201
`Application 11/589,371
`
`FF3. The Examiner finds that Mosnier discloses that "different
`
`regions of APC are responsible for its different activities. The anti-apoptotic
`
`activity is independent of the anti-coagulant activity, and certain mutants
`
`may lack anti-coagulant activity but retain anti-apoptotic activity" (id.
`
`(citing Mosnier, 65, 66, 68, and Fig. 4)). "Such mutants would be
`
`therapeutically useful because APC has a neuroprotective effect and an anti(cid:173)
`
`inflammatory effect, as well as anti-apoptotic effect, and these mutant
`
`proteins would not increase the risk of bleeding" (id.).
`FF4. The authors ofMosnier are Laurent 0. Mosnier and John H.
`
`Griffin (Mosnier 65), a subset of the inventors on the instant application,
`
`which are John H. Griffin, Laurent 0. Mosnier, and Andrew J. Gale.
`
`FF5. Mosnier discloses that "[i]n a model of staurosporine-induced
`
`apoptosis ... inhibition of apoptosis by activated protein C ... required the
`
`enzyme's active site, implicating activated protein C-mediated proteolysis"
`
`(Mosnier, Abstract). "Consistent with this implication, both protease(cid:173)
`
`activated receptor- I (P AR-1) and endothelial cell protein C receptor (EPCR)
`
`were required for the anti-apoptotic effects of activated protein C" (id.).
`
`FF6. Mosnier discloses that APC "inhibition of staurosporine(cid:173)
`
`induced apoptosis required APC's active site, since ... an inactive APC
`
`mutant, in which the active-site Ser was replaced by Ala, S360A-APC ... ,
`
`were devoid of anti-apoptotic activity ... This implied that the anti(cid:173)
`
`apoptotic activity of APC was mediated by proteolysis" (id. at 66, right col.
`
`(citations omitted)).
`
`FF7. Mosnier discloses that "[b]ecause binding of APC to EPCR is
`
`essential for APC's anti-apoptotic activity, we conclude that the anti-
`
`4
`
`

`
`Appeal2013-000201
`Application 11/589,371
`
`apoptotic activity of APC is independent of its anti-coagulant activity" (id. at
`
`68, left col.). "This suggests that certain APC mutants may lack anti(cid:173)
`
`coagulant activity but retain anti-apoptotic activity; such mutants could be
`
`therapeutically useful if they provided patients with direct cell-survival
`
`activity without increased risks of bleeding" (id.).
`
`FF8. Mosnier states the following: "[ w ]e thank Dr Andy Gale
`
`(Scripps Research Institute) for providing S360A-APC ... Stimulating
`
`discussions with Dr Andy Gale and Dr Berislav Zlokovic are gratefully
`
`acknowledged" (id. at 69, left col.).
`
`FF9. Appellants have provided a declaration under 37 C.F.R. § 1.132
`
`(Declaration of John H. Griffin, Ph.D., filed Nov. I, 2010, App. Br. 9).
`
`FFlO. Dr. Griffin declares that he is a named co-inventor on the
`
`instant application, along with Laurent 0. Mosnier and Andrew J. Gale
`(Griffin Declaration ii 4).
`FF 11. Dr. Griffin declares that he is one of two co-authors of the
`cited Mosnier reference, along with Laurent 0. Mosnier (id., ii 6).
`FF12. Dr. Griffin declares that Mosnier "describes Applicants' own
`
`work, i.e., prepared from the research of the co-inventors of the '371
`
`application, a portion of which pertains to the claimed invention of the
`pending claims" (id. ii 9). "It is directed to our research efforts in defining
`the molecular mechanisms responsible for Activated Protein C's (APC's)
`
`direct anti-inflammatory and anti-apoptotic effects on cells by evaluating the
`
`effects of a modified model of staurosporine-induced apoptosis with
`endothelial cells" (id. ii 9).
`
`5
`
`

`
`Appeal2013-000201
`Application 11/589,371
`
`FF 13. Dr. Griffin declares that Mosnier was cited in the instant
`
`application, but that "the cited publication disclosure is in fact derived from
`
`the Applicants and co-inventors of the '371 application" (id.~ 10).
`
`Analysis
`
`Appellants argue that Mosnier should be disqualified as prior art
`
`because the publication is not by another, as required by 35 U.S.C. § 102(a)
`
`(App. Br. 7-9). Appellants argue that the Griffin Declaration provides
`
`evidence "that the portion of the presently claimed invention disclosed in
`
`Mosnier is NOT a publication by another ... because the cited disclosure
`
`was derived from the joint inventors" (id. at 9 (citing the Griffin Declaration
`iii! 6-10)).
`The Examiner responds that the authors of Mosnier "are a different
`
`entity than the instant inventors, and Examiner does not have the authority or
`
`the prerogative to disregard this fact. Thus, this article is prior art" (Ans. 7).
`
`The Examiner responds that "the subject matter of the article and the subject
`
`matter of the claims are different, although some aspects of the two are
`
`similar ... [and therefore] the subject matter of the article cannot be
`
`considered automatically to be the work of the instant inventors" (id.).
`
`The Examiner asserts that "the article may ... be disqualified as prior
`
`art in one of three ways. Inventorship may be amended to match the
`
`authorship of the article ... [T]he article may be antedated by evidence ...
`
`filed with a declaration under 37 CFR § 1.131. Or, Appellant[s] may
`
`provide evidence that Inventor Gale should or could have been an author"
`
`(id.). With respect to the latter, the Examiner states that "[t]his evidence is
`
`documentation that at least some of the key intellectual ideas in the article
`
`6
`
`

`
`Appeal2013-000201
`Application 111589,371
`
`were those of Inventor Gale and that he explained these ideas to the other
`
`authors, along with an explanation as to how to carry out the necessary
`
`experiments to prove these ideas" (id.). The Examiner further states that
`
`"[t]his evidence may be in the form of signed and witnessed notebook pages
`
`from Inventor Gale, notes from meetings of the three Inventors or a printed
`
`fonn of presentations by Inventor Gale at meetings of the three Inventors"
`
`(id.).
`
`We are not persuaded by the Examiner's reasoning. That is, we find
`
`that Appellants' 3 7 CPR § 1.13 2 Declaration provides a sufficient showing
`
`that the Mosnier reference was derived from the work of all of the inventors
`
`of the instant application. "An uncontradicted 'unequivocal statement' from
`
`the applicant regarding the subject matter disclosed in an article, patent, or
`
`published application will be accepted as establishing inventorship." MPEP
`
`§ 716.10, see also§ 2136.05.
`
`The standard set forth by the court in DeBaun was that "it was
`
`incumbent on appellant to provide satisfactory evidence, in light of the total
`
`circumstances of the case, that the reference reflected his own work." In re
`
`DeBaun, 687 F.2d 459, 463 (1982) (citing In re Facius, 408 F.2d 1396, 1406
`
`(CCP A 1969)). Although a statement by Appellants may not be sufficient
`
`where there is evidence to the contrary, in the instant situation, the Examiner
`
`does not provide any evidence to the contrary. Cf Ex parte Kroger, 219
`
`USPQ 370 (BPAI 1982) (a rejection under 35 U.S.C. § 102(f) was affirmed
`
`notwithstanding declarations by the alleged actual inventors as to their
`
`inventorship in view of a nonapplicant author submitting a letter declaring
`
`the author's inventorship ).
`
`7
`
`

`
`Appeal2013-000201
`Application 11/589,371
`
`Appellants have proffered the Griffin Declaration as evidence to
`
`establish that the portions of the Mosnier reference relied on in the
`
`obviousness rejection are derived from the work of all three present
`
`inventors (FFs 12 and 13), and this evidence is supported by the Mosnier
`
`reference itself, wherein Dr. Andy Gale, of Scripps Research Institute, is
`
`acknowledged for providing experimental materials, i.e. the S360A-APC
`
`mutant, and for providing stimulating discussions (FF 8).
`
`The Examiner has not provided any evidence to contradict
`
`Appellants' assertions and evidence that the Mosnier publication was
`
`derived from the work of all three of the instant inventors. Therefore, by a
`
`preponderance of evidence, we find that Mosnier is not available as prior art
`
`because Appellants have shown that the Mosnier disclosure was derived
`
`from Appellants' own work. Thus, the Mosnier reference is not prior art
`
`under 35 USC§ 102(a), as asserted by the Examiner, and we reverse the
`
`obviousness rejection because the rejection is based on the combination of
`
`Gale, Riewald, and Mosnier.
`
`We reverse the rejection of claims 13, 16, 21, 22, 50, 51, and 53 under
`
`SUMMARY
`
`35 U.S.C. § 103(a).
`
`llw
`
`REVERSED
`
`8
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www .uspto.gov
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONFIRMATION NO.
`
`111589,371
`
`10/30/2006
`
`John H. Griffin
`
`TSRI 991.2
`
`4347
`
`09128/2015
`7590
`26621
`THE SCRIPPS RESEARCH INSTITUTE
`OFFICE OF PATENT COUNSEL, TPC-8
`10550 NORTH TORREY PINES ROAD
`LA JOLLA, CA 92037
`
`EXAMINER
`
`KOSSON, ROSANNE
`
`ART UNIT
`
`PAPER NUMBER
`
`1657
`
`MAIL DATE
`
`DELIVERY MODE
`
`09/28/2015
`
`PAPER
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`PTOL-90A (Rev. 04/07)
`
`

`
`69139/88670
`
`CUSTOMER NUMBER
`
`Docket No. 214 190-30003
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant(s): JOHN H. GRIFFIN
`
`Confirmation No.: 4347
`
`Serial No.:
`
`11/589,371
`
`Group Art Unit:
`
`1652
`
`Filed:
`
`For:
`
`October 30, 2006
`
`Examiner:
`
`Rosanne KOSSON
`
`ACTIVATED PROTEIN C VARIANTS WITH NORMAL CYTOPROTECTIVE
`ACTIVITY BUT REDUCED ANTICOAGULANT ACTIVITY
`
`DECLARATION OF JOHN H. GRIFFIN UNDER 37 C.F.R. § 1.132
`
`Mail Stop RCE
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`I, JOHN H. GRIFFIN, Ph.D., hereby declare that
`
`1)
`
`I am a Professor in the Department of Molecular and Experimental
`
`Medicine at The Scripps Research Institute (TSRI), a non-profit biomedical research
`
`institute located at 10550 North Torrey Pines Road, MEM-180, La Jolla, California
`
`92037. I am also an Adjunct Professor of Medicine at the University of California at San
`Diego located at 9500 Gillman Drive,# 0912, La Jolla, California 92093-0912. I recently
`
`chaired in 2008-2009 the Hemostasis and Thrombosis Study Section that is part of the
`
`Hematology Integrated Review Group of the Center for Scientific Review at the National
`Institutes of Health.
`
`2)
`
`I received a Bachelor of Science in Physics from Santa Clara
`
`University and a Doctor of Philosophy in Biophysics from the University of California,
`
`Davis in 1969. I performed four years of post-doctoral training in spectroscopic studies
`
`of protein structure and function with Dr. Elkan R. Blout at Harvard Medical School and
`
`with Dr. Christian B. Anfinsen at the NIH in Bethesda who were awarded the
`
`Presidential Medal of Science and the Nobel Prize, respectively. I continued NMR
`
`studies of peptide and protein structure at the French Atomic Energy Commission
`
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`Serial No. 11/589.371
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`Laboratory (C.E.A.) in Saclay, France. In 1974, I was appointed to the staff as
`equivalent to Assistant Professor in the Department of Experimental Pathology at TSRI.
`
`3)
`
`Over the past 30 years while at TSRI, my research has been
`
`focused on thrombosis, blood coagulation, and the Protein C pathway that provides
`
`anti-thrombotic, anti-inflammatory, and anti-apoptotic activities.
`
`4)
`
`I am a named co-inventor on the above-captioned application to
`
`John H. Griffin, Laurent 0. Mosnier, and Andrew J. Gale under U.S. Serial No.
`11/589,371 (the "'371 application"). A copy of my curriculum vitae is attached hereto as
`
`Exhibit 1.
`
`5)
`
`I have read the pending Final Office Action dated July 30, 2010 that
`
`rejects claims 13, 16, 21, 22, 50, 51, and 53 under§ 103(a) as being unpatentable over
`
`Gale, et al. ("Molecular Characterization Of An Extended Binding Site For Coagulation
`Factor Va In The Positive Exosite Of Activated Protein C," JBC, 277(32):28836-28840,
`
`June 12, 2002; the "Gale publication") in view of Mosnier, et al. ("Initiation Of
`
`Staurosporine-lnduced Apoptosis Of Endothelial Cells By Activated Protein C
`
`Receptor," Biochem J. 373:65-70, 2003), and Riewald, et al. ("Activation Of Endothelial
`
`Cell Protease Activated Receptor 1 By The Protein C Pathway," Science, 296:1880-
`
`1882, 2002; the "Riewald publication"). Claims 1, 6-10, 13, 16, 21-22, 42-44, 46-51,
`
`and 53-70 are pending in the subject '371 application, of which claims 13, 16, 21-22,
`
`50-51, and 53 are being examined.
`
`6)
`
`I am one of two co-authors of the publication to Laurent 0. Mosnier
`
`and John H. Griffin, "Inhibition of Staurosporine-lnduced Apoptosis of Endothelial Cells
`
`By Activated Protein C Requires Protease-Activated Receptor-1 and Endothelial Cell
`Protein C Receptor," Biochem J., 373:65-70, 2003; published April 8, 2003 (the
`
`"Mosnier publication").
`
`7)
`
`Laurent 0. Mosnier and I are co-authors of the cited Mosnier
`
`publication who are also identified as co-inventors of the '371 application.
`
`The third co-inventor of the subject matter in the '371 application,
`8)
`Andrew J. Gale, and Laurent 0. Mosnier and I, all of whom are employed by The
`
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`Scripps Research Institute, mutually participated in the conception, research, and
`reduction to practice of the claimed invention of the subject application.
`
`9)
`
`The Mosnier publication describes Applicants' own work, i.e.,
`
`prepared from the research of the co-inventors of the '371 application, a portion of
`
`which pertains to the claimed invention of the pending claims. It is directed to our
`
`research efforts in defining the molecular mechanisms responsible for Activated Protein
`
`C's (APC's) direct anti-inflammatory and anti-apoptotic effects on cells by evaluating the
`
`effects of a modified model of staurosporine-induced apoptosis with endothelial cells.
`
`Nothing in Mosnier discloses the claimed quintuple APC mutant having point mutations
`
`of KKK 191-193AAA and RR229-230AA.
`
`10)
`
`The above-captioned Mosnier publication has been cited in the
`
`'371 application for allegedly attributing the disclosed invention to someone other than
`
`the Applicants, i.e., the three co-inventors to the '371 application; however, the cited
`
`publication disclosure is in fact derived from the Applicants and co-inventors of the '371
`
`application.
`
`11)
`
`Laurent Mosnier, co-inventor of the subject '371 application,
`
`performed a PubMed search of the literature regarding protein C and mutagenesis
`
`studies prior to May 2002. His search identified 160 different mutations of protein C,
`
`none of which were the quintuple KKK191-193AAA and RR229-230AA APC mutant.
`
`12) One search result by Friedrich, et al. (JBC, 276:24122-24128,
`2001) discloses a quintuple mutation of K37S/K38Q/K39Q/K62N/K63D (Our numbering:
`K191S/K192Q/K193Q/K217N/K218D); however, this publication does not disclose the
`
`claimed quintuple mutation. In fact, on page 24124 (last sentence of paragraph bridging
`
`cols. 1-2), Friedrich, et al. suggests that "clustering of three to five alanine residues
`
`could create a destabilizing solvent-exposed hydrophobic patch no longer able to form
`
`hydrogen bonds with water molecules or could induce misfolding due to the high helical
`
`propensity of this amino acid." A person of ordinary skill in the art, having read and
`
`understood the Friedrich teaching in the art of protein C, would not have prepared such
`
`an activated protein C mutant having clusters of three to five alanines.
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`13)
`
`I am also one of the three co-authors of the above-mentioned Gale
`
`publication to Andrew J. Gale, Alexander Tsavaler, and John H. Griffin that was cited
`
`against the pending claims in the '371 patent application.
`
`14)
`
`The cited Gale publication is directed to our research efforts in
`
`defining the FVa binding site in the positive exosite of Activated Protein C (APC) by
`
`evaluating the effects of APC mutations and their functional activities such as for
`
`example, rate of inactivation of APC in plasma and anticoagulant activity.
`
`15)
`
`The Gale publication discloses 15 APC mutants including single,
`
`double, and triple point mutations, including an APC KKK191-193AAA mutant and an
`
`APC RR229-230AA mutant. Until the co-authors measured the kinetic parameters of
`
`the APC mutants for cleavage, we could not conclude whether or not the mutations
`
`altered protein folding or maintained their effects at a distance from the interaction site
`
`rather than modify a specific protein-protein interaction.
`
`16)
`
`I attest to the fact that it is very complicated to predict protein
`
`structure, let alone function, based solely on visualizing an amino acid sequence or
`
`primary structure. Any time a mutation is made, a protein's structure and/or stability
`
`may be altered. As a result of these mutations, the tertiary structure of the protein may
`
`be modified such that the mutated protein aggregates and becomes insoluble deposits,
`
`and therefore loses the ability to function as originally intended. Moreover, the general
`
`destabilizations of the altered protein structure are only tolerable to some degree that is
`
`unknown until tested.
`
`17)
`
`The Gale publication describes Applicants' own work, i.e., prepared
`
`from the research of the co-inventors of the '371 application, a portion of which pertains
`
`to the claimed invention of the pending claims. Gale does not disclose a quintuple APC
`
`mutant having point mutations of KKK191-193AAA and RR229-230AA.
`
`18)
`
`The third co-author of the cited Gale publication, Alexander
`
`Tsavaler, was a laboratory technician working under the direction of the co-inventors of
`
`the pending application. Alexander Tsavaler did not contribute to the conception of the
`pending claimed invention, and is thus, not a co-inventor. The inventorship of the
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`Serial No. 11/589.371
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`Docket No. 214190-30003
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`subject application is correctly recorded with John H. Griffin, Laurent 0. Mosnier, and
`Andrew J. Gale.
`
`19)
`
`I have read the Riewald publication that has been cited against the
`
`claims in the '371 patent application. The Riewald publication discloses the role of
`
`Protease Activated Receptor (PAR) in the protective protein C signaling pathway. More
`
`specifically, Riewald discloses that PAR 1 can be cleaved and activated by APC in an
`
`endothelial cell protein C receptor (EPCR)-dependent fashion.
`
`20) Riewald discloses that cells pretreated with a 10 fold concentration
`
`of APC results in inhibition of inflammation signals, thereby inducing cell survival in
`
`endothelial and monocyte cells (p1882, col 2, ~1 ). Riewald continues to state that the
`
`"concordant up-regulation of protective genes by PAR1 agonist and APC suggests that
`
`all anti-inflammatory and anti-apoptotic effects of APC signaling are PAR-mediated in
`
`endothelial cells." Data demonstrated that cell activation by APC is dependent on
`EPCR and PAR expression. However, nothing in Riewald discloses the quintuple APC
`
`mutant having point mutations of KKK191-193AM and RR229-230AA. Nor does
`
`Riewald disclose either the three or two mutations alone. In fact, Riewald does not
`
`disclose any APC mutants.
`
`The activated Protein C was found to inhibit inflammation signaling
`21)
`and induce cell survival in endothelial cells. However, Riewald does not disclose the
`
`effects of a mutated APC. One skilled in the art would not expect a mutated APC to
`
`function similarly to the wild type. Even if a mutated APC were found to have reduced
`anti-coagulant activity, the skilled artisan could not draw any conclusions with respect to
`
`the anti-apoptotic effect until further experiments were performed.
`
`22)
`
`Therefore, based on my extensive research and knowledge in
`
`diseases or conditions associated with thrombosis, I believe that one of ordinary skill in
`
`the art would not have prepared a quintuple APC mutant having mutations of KKK191-
`
`193AM and RR229-230M based on the disclosures of Gale and Riewald.
`
`23)
`
`I am making this declaration in support of the allowance of the above-
`
`referenced patent application.
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`NY862809.1
`214190-30003
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`- 5 -
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`

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`Serial No. 11/589,371
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`Docket No. 214190-30003
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`I further declare that all statements made herein of my own knowledge are
`
`true and that all statements made on information and belief are believed to be true; and
`
`further that these statements were made with the knowledge that willful false statements
`and the like so made are punishable by fine or Imprisonment, or both, under Section
`
`1001 of Title 18 of the United States Code and that such willful false statements may
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`jeopardize the validity of the application or any patent issued thereon.
`
`By:
`
`John H. Griffin
`
`Dated:
`
`October 27. 2010
`
`NY862809.1
`214190-30003
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`- 6 -
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`

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`CURRICULUM VITAE - John H. Griffin, Ph.D.
`
`PERSONAL STATISTICS
`
`Date of Birth: June 26, 1943
`
`Place of Birth: Seattle, WA
`
`Address:
`
`The Scripps Research Institute
`Department of Molecular & Experimental Medicine
`10550 North Torrey Pines Road - MEM180
`La Jolla, CA 92037
`Phone (858) 784-8220; Fax (858) 784-2243; email <jgriffin@scripps.edu>
`
`EDUCATION
`
`1965
`1969
`1969-1971
`
`1971-1973
`
`Santa Clara University, California, B.S., Physics
`University of California at Davis, Ph.D., Biophysics
`Harvard Medical School, Department of Biological Chemistry,
`postdoctoral training with Professor Elkan R. Blout
`National Institutes of Health, Lab Chemical Biology, NIAMDD
`postdoctoral training with Dr. Christian B. Anfinsen Jr.(Nobel Laureate)
`
`PROFESSIONAL POSITIONS
`
`1967-1969
`1969-1971
`1971-1973
`1973-1974
`1974-present
`
`2008-present
`
`Teaching Asst., Advanced Biochemistry Lab Course, Univ. of California
`Research Fellow in Biological Chemistry, Harvard Medical School
`Senior Postdoctoral Research Fellow, National Institutes of Health
`Staff, Service Biochimie, Centre D'Etudes Nucleaires, Saclay, France
`The Scripps Research Institute, Assistant, Associate, Associate Member
`(tenured), Professor in Department of Molecular & Experimental Medicine
`Adjunct Professor of Medicine, University of California at San Diego
`
`FELLOWSHIPS AND RESEARCH AWARDS
`
`1961-1964
`1961-1965
`1966-1969
`1969-1972
`1972-1973
`1976-1981
`1977-present
`1979-1989
`1982-1989
`1989-1994
`1994-present
`1994-1999
`1999-present
`2004-2005
`2005-present
`
`RCA Physics Scholarship, undergraduate
`Santa Clara Jesuit Scholarship, undergraduate
`NIH Predoctoral Fellowship, graduate
`Helen Hay Whitney Foundation Postdoctoral Fellow
`NIH Special Fellowship
`NIH Research Career Development Award (HL00192)
`NIH Award (R01 HL21544, Principal Investigator)
`NIH Award (P01 HL 16411, Project Leader)
`NIH Award (R01 HL24891, Principal Investigator)
`NIH Award (P01 HL31950, Program Director)
`NIH MERIT Award (R37 HL52246, Principal Investigator)
`NIH Award (P01 NS31945, Project Co-Investigator)
`NIH Award (R01 HL63290, Co-Principal Investigator)
`NIH Award (R01 HL78684, Principal Investigator)
`NIH Award (P01 HL31950, Project Leader)
`
`Page 1
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`

`
`-American Society Hematology, Atlanta, 2007.
`- Hemophilia Workshop, London, UK, 2008.
`- European Respiratory Society Science Symposium, Estoril, Portugal, 2008.
`
`U.S. PATENTS
`
`US Patent # 5,084,27 4
`Griffin, Gruber, Hanson and Harker
`Inhibition of arterial thrombotic occlusion or thromboembolism.
`
`US Patent# 5,279,956
`Griffin and Masters
`Activated protein C polypeptides and anti-peptide antibodies. Diagnostic methods and systems
`for inhibiting activated protein C.
`
`US Patent # 5,288,612
`Griffin and Gruber
`Assay methods for detecting serum proteases, particularly activated protein C.
`
`US Patent# 5,321, 123
`Griffin and Fernandez
`Protein S polypeptides and anti-peptide antibodies that inhibit protein S binding to C4B binding
`protein. Diagnostic systems and therapeutic methods.
`
`US Patent# 5,350,578
`Griffin, Gruber, Hanson and Harker
`Inhibition of arterial thrombotic occlusion or thromboembolism.
`
`US Patent# 5,405,946
`Griffin, Bouma and Bertina
`Recombinant protein S variants deficient in C4BP binding activity, compositions and therapeutic
`methods.
`
`US Patent #5, 705,395
`Griffin, Rapaport, and Le
`Method for diagnosis of thrombotic disorders.
`
`US Patent #5,834,223
`Griffin, Rapaport, and Le
`Method for diagnosis of thrombotic disorders.
`
`US Patent #5,968, 751
`Griffin and Mesters
`Method for detecting the presence of protein C antibody in a fluid sample
`
`US Patent #6,083, 757
`Griffin, Rapaport, and Le
`Method for diagnosis of thrombotic disorders.
`
`US Patent #6,867,045
`Griffin, Rapaport, and Le
`Method for diagnosis of thrombotic disorders.
`
`Page 32
`
`

`
`US Patent #6, 756,205
`Griffin, Deguchi, and Fernandez
`Plasma glucosylceramide deficiency as thrombosis risk factor and modulator of anticoagulant
`protein C
`
`US Patent, pending
`Griffin, Zlokovic
`Neuroprotective, Antithrombotic and Anti-inflammatory Uses of Activated Protein (APC)
`
`US Patent, pending
`Griffin, Gale, Getzoff, and Pellequer
`Stabilitized proteins with engineered disulfide bonds
`
`US Patent, pending
`Zlokovic and Griffin
`Protein S protects the nervous system from injury
`
`US Patent, pending
`Zlokovic, Griffin
`Neuroprotective activity of activated protein C is independent of its anticoagulant activity
`
`US Patent, pending
`Griffin, Mosnier, and Gale
`Activated protein C variants with normal cytoprotective activity but reduced anticoagulant activity
`
`US Patent, pending
`Griffin, Deguchi, Elias, and Pecheniuk
`Dyslipoproteinemia associated with venous thrombosis
`
`Page 33
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`

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`XP-002532146
`
`Biocimn J. (2003) 373, 6!HO (Printed in Gr!al Britain}
`
`65
`
`Inhibition of staurosporine-induced apoptosis of endothelial cells by
`activated protein C requires protease-activated receptor-1 a~d endothelial
`cell prot~in C receptor
`Laurent 0. MOSNIER and John H. GRIFFIN1
`Department ot Molecular and Experimenlal Medicine. The Sctiops Research lnstitµte. 10550 North Torrey Pines Road, La Jolla, CA 92037. U.S.A.·
`
`In a model of staurosporine-induced apoptosis using EAhy926
`endothelial cells, inhibition of apoptosis by activated protei!l C
`was dose-dependent and required the enzyme's active site,
`implicating activated protein C-mediatcd proteolysis. Consistent
`with this implication, both protease-activated receptor-I (PAR-I)
`
`and endothelial cell protein C rec.cptor (EPCR) were required for
`the anti-apoptotic effects of activated protein c:
`
`Key words: activated protein C, apoptosis, endothelial cell protein
`C receptor (EPCR), protease;activated receptor (PAR).
`
`INTRODUCTION
`The protein C pathway provides a natural anti-coagulant feedback
`mechanism [I). Activation of protein C is mediated by thrombin
`which binds to thrombomodulin on the endothelial surface such
`that the procoagulant activity of thrombin involving its exosite
`I is blocked while its anti-coagulant properties, i.e. activation
`of protein C, are enhanced [2). Activation of protein C by the
`thrombin-thrombomodulin complex is facilitated by localization
`of protein C on the endothelial surface by binding to the
`endothelial cell protein C receptor (EPCR). Activated protein
`C (APC), aided by its cofactor protein S, degrades the activated
`cofactors factor Villa and factor Va that are required to sustain
`thrombin formation through the intrinsic coagulation pathway [I].
`Components of the protein C pathway contribute not only anti(cid:173)
`coagulant activity but also anti-inflammatory functions, as shown
`in various animal models or ccll-cuhure studies [3]. J'he anti(cid:173)
`inflammatory effects of thrombomodulin, recently attributed to its
`lectin-like domain, can protect mice against neutrophil-mediated
`tissue damage [4]. The murine centrosomal protein CCD41,
`or centrocyclin, ·involved in cell-cycle regulation is identica_J
`to murine EPCR lacking the N-terminal 31 amino acids [5,6).
`Structural similarity of EPCR to the MHC class I/CD! ·family of
`proteins, most of which are involved in inflammatory processes,
`suggests that the function ofEPCR may not be limited m its ability
`to localize APC or protein C on the endoiheliat membrane [7].
`APC can down-regulate pro-inflammatory cytokine production
`and favourably alter tissue factor expression or blood pressure
`in vario