DETAILED ACTION
This action is in reply to papers filed 8/25/2022. Claims 1-28 are pending and examined herein.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the published application, PgPub US20230031809A1, Published 2/2/2023.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 3 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites, inter alia, “…said polypeptide sequence”. There is no antecedent basis for this limitation. Specifically, no ‘sequence’ is recited in claim 1.
Clarification is requested.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Prior Art Rejection 1
Claims 1-24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Braddock et al. (PgPub US20150359858A1, Published 12/17/2015, Cited in IDS filed 12/12/2022), Braddock et al. (WO2014126965A2, Published 8/21/2014, Cited in IDS filed 12/12/2022), Rodino-Klapac (PgPub US20180340187A1, Published 11/29/2018, Cited in IDS filed 12/12/2022), Khan (PgPub US20200263153A1, Filed 9/26/2018, Cited in IDS filed 12/12/2022) and Vitalis et al. (PgPub US20170204386A1, Published 7/20/20217, Cited in IDS filed 12/12/2022).
Examiner’s Note: Braddock et al. has been cited using two identifiers. The first, a US Patent Publication (PgPub 20150359858) and the second, a WIPO document (WO2014126965A2). The WIPO document corresponds to the PgPub document. The Examiner has cited the corresponding WIPO document of Braddock only because the sequence search tool employed by the USPTO cites the WIPO document, and not the US Patent Publication.
Regarding claim 1 (in-part), claim 15 (in-part), claim 21 (in-part), and claim 24 (in-part), Braddock teaches a method of treating a disease or disorder associated with pathological calcification or pathological ossification in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising an expression vector encoding an ecto-nucleotide pyrophosphate/ phosphodiesterase-1 (NPP1) polypeptide, whereby the disease or disorder is treated in the subject (Pg. 2, para. 12; Pg. 13 , para. 118). Note that this teaching of an ‘expression vector encoding an ecto-nucleotide pyrophosphate/ phosphodiesterase-1 (NPP1) polypeptide’ embraces the inclusion of all domains of ENPP1, including the catalytic domain (as further in claim 1 and claim 15), the extracellular domain (as in claim 3) and the transmembrane domain (as in claim 4).
Regarding claim 5 and claim 16, the alignment between SEQ ID NO: 1 (Qy, query) and the ectonucleotide pyrophosphate/phosphodiesterase-1 (NPP1) polypeptide taught by Braddock et al. (Db, database) is provided below. Note that SEQ NO: 1 is 100% identical to the Human NPP1 polypeptide of Braddock.
RESULT 13
BBM35611
ID BBM35611 standard; protein; 925 AA.
XX
AC BBM35611;
XX
DT 09-OCT-2014 (first entry)
XX
DE Human NPP1 polypeptide, SEQ ID 1.
XX
KW NPP1 protein; PC-1 protein; antiarteriosclerotic; antiarthritic;
KW antiinflammatory; antilipemic; atherosclerosis; calcification;
KW ectonucleotide pyrophosphate; endocrine-gen.; metabolic-gen.;
KW nutrition-disorder-gen.; osteoarthritis; osteopathic;
KW phosphodiesterase-1; prophylactic to disease; protein therapy;
KW therapeutic; vasotropic; x linked dominant hypophosphatemic rickets.
XX
OS Homo sapiens.
XX
CC PN WO2014126965-A2.
XX
CC PD 21-AUG-2014.
XX
CC PF 12-FEB-2014; 2014WO-US015945.
XX
PR 13-FEB-2013; 2013US-0764297P.
PR 15-NOV-2013; 2013US-0904786P.
XX
CC PA (UYYA ) UNIV YALE.
XX
CC PI Braddock D, Albright R;
XX
DR WPI; 2014-P74602/59.
DR REFSEQ; NP_006199.
XX
CC PT Composition for treating e.g. calcification or ossification comprises an
CC PT agent selected from ecto-nucleotide pyrophosphate/phosphodiesterase-1 or
CC PT ecto-nucleotide pyrophosphate/phosphodiesterase-4 polypeptide and their
CC PT activator polypeptide.
XX
CC PS Claim 43; SEQ ID NO 1; 94pp; English.
XX
CC The present invention relates to a novel composition for treating or
CC preventing a disease or disorder associated with pathological
CC calcification or ossification in a subject in need thereof. The method
CC comprises administering to the subject a therapeutically effective amount
CC of a composition comprising at least one agent selected from the group
CC consisting of an ectonucleotide pyrophosphate/phosphodiesterase-1 (NPP1)
CC polypeptide and a fragment, derivative, mutant or mutant fragment thereof
CC and an activator of NPP1 polypeptide and a fragment, mutant or mutant
CC fragment thereof, whereby the disease or disorder is treated or prevented
CC in the subject. The disease or disorder is at least one selected from the
CC group consisting of idiopathic infantile arterial calcification (IIAC),
CC ossification of the posterior longitudinal ligament (OPLL),
CC hypophosphatemic rickets, osteoarthritis and calcification of
CC atherosclerotic plaques. The present sequence represents a human NPP1
CC also known as PC-1 polypeptide which is used in the preparation of a
CC composition for treating or preventing a disease or disorder of the
CC invention.
XX
SQ Sequence 925 AA;
Query Match 100.0%; Score 5063; DB 21; Length 925;
Best Local Similarity 100.0%;
Matches 925; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MERDGCAGGGSRGGEGGRAPREGPAGNGRDRGRSHAAEAPGDPQAAASLLAPMDVGEEPL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MERDGCAGGGSRGGEGGRAPREGPAGNGRDRGRSHAAEAPGDPQAAASLLAPMDVGEEPL 60
Qy 61 EKAARARTAKDPNTYKVLSLVLSVCVLTTILGCIFGLKPSCAKEVKSCKGRCFERTFGNC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EKAARARTAKDPNTYKVLSLVLSVCVLTTILGCIFGLKPSCAKEVKSCKGRCFERTFGNC 120
Qy 121 RCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCGEKRLTRSLCACSDDCKDKGDCCINY 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCGEKRLTRSLCACSDDCKDKGDCCINY 180
Qy 181 SSVCQGEKSWVEEPCESINEPQCPAGFETPPTLLFSLDGFRAEYLHTWGGLLPVISKLKK 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SSVCQGEKSWVEEPCESINEPQCPAGFETPPTLLFSLDGFRAEYLHTWGGLLPVISKLKK 240
Qy 241 CGTYTKNMRPVYPTKTFPNHYSIVTGLYPESHGIIDNKMYDPKMNASFSLKSKEKFNPEW 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 CGTYTKNMRPVYPTKTFPNHYSIVTGLYPESHGIIDNKMYDPKMNASFSLKSKEKFNPEW 300
Qy 301 YKGEPIWVTAKYQGLKSGTFFWPGSDVEINGIFPDIYKMYNGSVPFEERILAVLQWLQLP 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 YKGEPIWVTAKYQGLKSGTFFWPGSDVEINGIFPDIYKMYNGSVPFEERILAVLQWLQLP 360
Qy 361 KDERPHFYTLYLEEPDSSGHSYGPVSSEVIKALQRVDGMVGMLMDGLKELNLHRCLNLIL 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 KDERPHFYTLYLEEPDSSGHSYGPVSSEVIKALQRVDGMVGMLMDGLKELNLHRCLNLIL 420
Qy 421 ISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYGPAARLRPSDVPDKYYSFNYEGIARNLSC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 ISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYGPAARLRPSDVPDKYYSFNYEGIARNLSC 480
Qy 481 REPNQHFKPYLKHFLPKRLHFAKSDRIEPLTFYLDPQWQLALNPSERKYCGSGFHGSDNV 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 REPNQHFKPYLKHFLPKRLHFAKSDRIEPLTFYLDPQWQLALNPSERKYCGSGFHGSDNV 540
Qy 541 FSNMQALFVGYGPGFKHGIEADTFENIEVYNLMCDLLNLTPAPNNGTHGSLNHLLKNPVY 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 FSNMQALFVGYGPGFKHGIEADTFENIEVYNLMCDLLNLTPAPNNGTHGSLNHLLKNPVY 600
Qy 601 TPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSILPIEDFQTQFNLTVAEEKIIKHETLPYG 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 TPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSILPIEDFQTQFNLTVAEEKIIKHETLPYG 660
Qy 661 RPRVLQKENTICLLSQHQFMSGYSQDILMPLWTSYTVDRNDSFSTEDFSNCLYQDFRIPL 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 RPRVLQKENTICLLSQHQFMSGYSQDILMPLWTSYTVDRNDSFSTEDFSNCLYQDFRIPL 720
Qy 721 SPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGIYSEALLTTNIVPMYQSFQVIWRYFHDTL 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 SPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGIYSEALLTTNIVPMYQSFQVIWRYFHDTL 780
Qy 781 LRKYAEERNGVNVVSGPVFDFDYDGRCDSLENLRQKRRVIRNQEILIPTHFFIVLTSCKD 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 LRKYAEERNGVNVVSGPVFDFDYDGRCDSLENLRQKRRVIRNQEILIPTHFFIVLTSCKD 840
Qy 841 TSQTPLHCENLDTLAFILPHRTDNSESCVHGKHDSSWVEELLMLHRARITDVEHITGLSF 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 TSQTPLHCENLDTLAFILPHRTDNSESCVHGKHDSSWVEELLMLHRARITDVEHITGLSF 900
Qy 901 YQQRKEPVSDILKLKTHLPTFSQED 925
|||||||||||||||||||||||||
Db 901 YQQRKEPVSDILKLKTHLPTFSQED 925
However, Braddock et al. fails to teach the expression vector is an adeno-associated viral vector (as further in claim 1 and claim 21).
Before the effective filing date of the claimed invention, Rodino-Klapac taught methods for transfecting target cells with recombinant adeno-associated viral (rAAV) vectors comprising a therapuetic polypeptide in vivo(as further in claim 1 and claim 21, in-part) (Abstract). Continuing, Rodino-Klapac teaches in vivo methods include administering an effective amount of a composition comprising rAAV to the human patient in need thereof, wherein such an amount prevents, slows, or ameliorates (eliminates or reduces) the myopathology associated with the disease being treated, wherein in one embodiment the myopathology is muscle calcification (Pg. 10, para. 76). Rodino-Klapac teaches the AAV vector is an AAV8 vector (as in claim 8, claim 15 (in-part) and claim 24, in-part) and is operably linked to a promoter (as in claim 7) (Pg. 2, para. 11; Pg. 6, para. 49).
With respect to claim 2, the recitation “…wherein administration of said viral vector to said subject increases plasma pyrophosphate (PPi) or plasma ENPP1 concentration in said subject” is not given any patentable weight. A “whereby”, or in the case claim 2, a “wherein” clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim. The courts noted (quoting Minton v. Nat'l Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.'" Accordingly, the recitation is interpreted in view of the courts’ decision.
And although Braddock teaches the NPP1 polypeptide comprises a heterologous signal peptide so that it can be expressed as a secreted protein (Pg. 3, para. 23), Braddock fails to teach the signal peptide is an Azurocidin signal peptide (as further in claim 1, claim 15, claim 21 and claim 24).
Before the effective filing date of the claimed invention, Vitalis et al. taught a fusion protein comprising one or more signal peptide sequences, wherein the signal peptide sequence is an Azurocidin signal peptide (as further in claim 1, claim 15, claim 21 and claim 24) (Abstract; Pg. 13, para. 130; Pg. 13, Table 4).
However, none of Braddock et al., Rodino-Klapac or Vitalis et al. teach said polypeptide is a fusion protein comprising: (i) an ENPP1 protein and (ii) a half-life extending domain (as in claim 9, claim 18, claim 21 and claim 24).
Before the effective filing date of the claimed invention, Khan et al. taught methods of treating a cardiovascular disease by administering a fusion protein comprising a recombinant human soluble ectonucleotide pyrophosphatase phosphodiesterase (hsNPP1) (Abstract). Khan teaches the sNPP1 fusion protein comprises an NPP1 component and a peptide that increases the half-life of the fusion protein (as in claim 9, claim 18 and as further in claim 21 and claim 24), most preferably the Fc of an immunoglobulin (e.g., Fc or human IgG1) (as in claim 10, claim 19 and claim 22) of an albumin domain (as in claim 11) (Pg. 8-9, para. 81). Khan adds that preferred NPP1 fusion proteins comprise from N-terminus to C-terminus an NPP1 component, optionally a linker (as in claim 13), an Fc region of an immunoglobulin (e.g., human IgG1 Fc optionally including hinge or a portion thereof) (as in claim 12), optionally a second linker, and optionally a targeting moiety. Khan adds that the moiety increases protein targeting to calcification sites (Pg. 9, para. 86-87)
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A, B and G are applicable. At the time of invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Braddock et al., wherein Braddock teaches a method of treating or preventing a disease or disorder associated with pathological calcification or pathological ossification in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising an expression vector encoding an ecto-nucleotide pyrophosphate/ phosphodiesterase-1 (NPP1) polypeptide, with the teachings of Rodino-Klapac, wherein Rodino-Klapac taught methods of transfecting target cells with a recombinant AAV vector in vivo for the purposes of treating muscle calcification, with a reasonable expectation of success. That is, one of ordinary skill in the art would have found it prima facie obvious to substitute the generic expression vector of Braddock for the AAV vector of Rodino-Klapac because Rodino-Klapac teaches treatment of a myopathology using an AAV vector in vivo.
Furthermore, the skilled artisan would have found it prima facie obvious to substitute the generic signal peptide of Braddock for the Azurocidin signal peptide of Vitalis for the purposes of expressing the NPP1 polypeptide as a secreted protein. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)." "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.)." It is further noted that when substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297,213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. Thus, the substitution would have been prima facie obvious.
Finally, the skilled artisan would have found it prima facie obvious to fuse the ENPP1 polypeptide to a half-life extending domain, as taught in Khan, because Khan observed success when treating a cardiovascular disease, defined by calcification, by administering a fusion protein comprising a recombinant human soluble ectonucleotide pyrophosphatase phosphodiesterase (hsNPP1) and a peptide that increases the half-life of the fusion protein.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Prior Art Rejection 2
Claims 6, 14, 17, 20, 23, 25 and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Braddock et al. (PgPub US20150359858A1, Published 12/17/2015; Cited in IDS filed 12/12/2022) Braddock et al. (WO2014126965A2, Published 8/21/2014, Cited in IDS filed 12/12/2022), Rodino-Klapac (PgPub US20180340187A1, Published 11/29/2018; Cited in IDS filed 12/12/2022), Khan (PgPub US20200263153A1, Filed 9/26/201; Cited in IDS filed 12/12/20228) and Vitalis (PgPub US20170204386A1, Published 7/20/20217; Cited in IDS filed 12/12/2022) as applied to claims 1-24 and 26 above, and further in view of Albright et al. (WO2016187408-A1, Published 11/24/2016; Cited in IDS filed 12/12/2022 as ‘Univ Yale’).
The teachings of Braddock et al., Rodino-Klapac et al., Khan et al. and Vitalis et al. are relied upon as detailed above. However, none of the aforementioned references teach SEQ ID NO: 82 or 84 (as in claim 6 or claim 17) SEQ ID NO: 82 (as in claim 25), SEQ ID NO: 84 (as in claim 26), SEQ ID NO: 82, 84, 85 or 86 (as in claim 14 or claim 20), SEQ ID NO: 85 (as in claim 27) or SEQ ID NO: 86 (as in claim 28).
Regarding claim 6 (in the alternative), claim 14(in the alternative), claim 17(in the alternative), claim 20 (in the alternative), claim 23 (in the alternative) and claim 25, the alignment between SEQ ID NO: 82 (Qy, query) and the ectonucleotide pyrophosphate/phosphodiesterase-1 (NPP1) polypeptide taught by Albright (Db, database) is provided below.
RESULT 2
BDJ72659
ID BDJ72659 standard; protein; 1155 AA.
XX
AC BDJ72659;
XX
DT 12-JAN-2017 (first entry)
XX
DE NPP121-human immunoglobulin G Fc domain fusion protein, SEQ 16.
XX
KW Immunoglobulin G; NPP1 protein; NPP2 protein; aging;
KW ankylosing spondylitis; antiarteriosclerotic; antiarthritic;
KW antiinflammatory; antilipemic; atherosclerosis; bone repair;
KW calcification; calciphylaxis; cardiant; ecto-nucleotide pyrophosphate;
KW endocrine-gen.; fusion protein; heart disease; metabolic-gen.;
KW musculoskeletal-gen.; nutrition-disorder-gen.; ossification;
KW osteoarthritis; osteopathic; phosphodiesterase-1; phosphodiesterase-2;
KW prophylactic to disease; protein therapy; pseudoxanthoma elasticum;
KW recombinant protein; therapeutic; vasotropic;
KW x linked dominant hypophosphatemic rickets.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Region 1..925
FT /label= NPP121
FT Region 80..95
FT /label= Swapped_NPP2_protein_fragment
FT Region 926..928
FT /note= "Linker"
FT Domain 929..1155
FT /label= IgG_Fc_domain
XX
CC PN WO2016187408-A1.
XX
CC PD 24-NOV-2016.
XX
CC PF 19-MAY-2016; 2016WO-US033236.
XX
PR 19-MAY-2015; 2015US-0163500P.
XX
CC PA (UYYA ) UNIV YALE.
XX
CC PI Braddock D, Albright R;
XX
DR WPI; 2016-72744M/01.
DR REFSEQ; NP_006199, NP_001124335.
XX
CC PT New protein-Z-domain-X-Y compound useful for preventing or treating
CC PT disease or disorder associated with pathological calcification or
CC PT ossification e.g. idiopathic infantile arterial calcification, and
CC PT osteoarthritis in mammal.
XX
CC PS Example; SEQ ID NO 16; 108pp; English.
XX
CC The present invention relates to a novel compound (PROTEIN-Z-DOMAIN-X-Y)
CC useful for preventing or treating disease or disorder associated with
CC pathological calcification or ossification in mammal. The compound
CC comprises a protein, a domain (human IgG Fc domain (Fc), human serum
CC albumin protein (ALB) and fragment thereof), a peptide comprising 1-20
CC amino acids; and a peptide of SEQ ID NO:4-14 (see BDJ72647-BDJ72657). The
CC invention also provides: a method for reducing or preventing cardiac
CC calcifications, arterial calcifications and/or elastic fiber
CC mineralization in infant afflicted with a disease or disorder
CC (generalized arterial calcification of infancy (GACI), idiopathic
CC infantile arterial calcification (IIAC), ossification of the posterior
CC longitudinal ligament (OPLL), hypophosphatemic rickets, osteoarthritis,
CC calcification of atherosclerotic plaques, pseudoxanthoma elasticum (PXE),
CC hereditary and non-hereditary forms of osteoarthritis, ankylosing
CC spondylitis, hardening of the arteries occurring with aging, and
CC calciphylaxis resulting from end stage renal disease and progeria, by
CC administering the compound; and a method for reducing or preventing
CC cardiac calcifications, arterial calcifications and/or elastic fiber
CC mineralizations in an infant afflicted with a disease (GACI and PXE). The
CC present sequence represents a human modified ecto-nucleotide
CC pyrophosphate/phosphodiesterase-1 (NPP1) protein (NPP121) comprising a
CC fragment swapped with NPP2 protein (1-27 residues)/immunoglobulin G Fc
CC domain fusion protein, which can be useful for preparing the compound of
CC the invention.
XX
SQ Sequence 1155 AA;
Query Match 100.0%; Score 5830; DB 23; Length 1155;
Best Local Similarity 100.0%;
Matches 1063; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 FTAGLKPSCAKEVKSCKGRCFERTFGNCRCDAACVELGNCCLDYQETCIEPEHIWTCNKF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 93 FTAGLKPSCAKEVKSCKGRCFERTFGNCRCDAACVELGNCCLDYQETCIEPEHIWTCNKF 152
Qy 61 RCGEKRLTRSLCACSDDCKDKGDCCINYSSVCQGEKSWVEEPCESINEPQCPAGFETPPT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 153 RCGEKRLTRSLCACSDDCKDKGDCCINYSSVCQGEKSWVEEPCESINEPQCPAGFETPPT 212
Qy 121 LLFSLDGFRAEYLHTWGGLLPVISKLKKCGTYTKNMRPVYPTKTFPNHYSIVTGLYPESH 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 213 LLFSLDGFRAEYLHTWGGLLPVISKLKKCGTYTKNMRPVYPTKTFPNHYSIVTGLYPESH 272
Qy 181 GIIDNKMYDPKMNASFSLKSKEKFNPEWYKGEPIWVTAKYQGLKSGTFFWPGSDVEINGI 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 273 GIIDNKMYDPKMNASFSLKSKEKFNPEWYKGEPIWVTAKYQGLKSGTFFWPGSDVEINGI 332
Qy 241 FPDIYKMYNGSVPFEERILAVLQWLQLPKDERPHFYTLYLEEPDSSGHSYGPVSSEVIKA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 333 FPDIYKMYNGSVPFEERILAVLQWLQLPKDERPHFYTLYLEEPDSSGHSYGPVSSEVIKA 392
Qy 301 LQRVDGMVGMLMDGLKELNLHRCLNLILISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 393 LQRVDGMVGMLMDGLKELNLHRCLNLILISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYG 452
Qy 361 PAARLRPSDVPDKYYSFNYEGIARNLSCREPNQHFKPYLKHFLPKRLHFAKSDRIEPLTF 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 453 PAARLRPSDVPDKYYSFNYEGIARNLSCREPNQHFKPYLKHFLPKRLHFAKSDRIEPLTF 512
Qy 421 YLDPQWQLALNPSERKYCGSGFHGSDNVFSNMQALFVGYGPGFKHGIEADTFENIEVYNL 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 513 YLDPQWQLALNPSERKYCGSGFHGSDNVFSNMQALFVGYGPGFKHGIEADTFENIEVYNL 572
Qy 481 MCDLLNLTPAPNNGTHGSLNHLLKNPVYTPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSI 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 573 MCDLLNLTPAPNNGTHGSLNHLLKNPVYTPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSI 632
Qy 541 LPIEDFQTQFNLTVAEEKIIKHETLPYGRPRVLQKENTICLLSQHQFMSGYSQDILMPLW 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 633 LPIEDFQTQFNLTVAEEKIIKHETLPYGRPRVLQKENTICLLSQHQFMSGYSQDILMPLW 692
Qy 601 TSYTVDRNDSFSTEDFSNCLYQDFRIPLSPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGI 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 693 TSYTVDRNDSFSTEDFSNCLYQDFRIPLSPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGI 752
Qy 661 YSEALLTTNIVPMYQSFQVIWRYFHDTLLRKYAEERNGVNVVSGPVFDFDYDGRCDSLEN 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 753 YSEALLTTNIVPMYQSFQVIWRYFHDTLLRKYAEERNGVNVVSGPVFDFDYDGRCDSLEN 812
Qy 721 LRQKRRVIRNQEILIPTHFFIVLTSCKDTSQTPLHCENLDTLAFILPHRTDNSESCVHGK 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 813 LRQKRRVIRNQEILIPTHFFIVLTSCKDTSQTPLHCENLDTLAFILPHRTDNSESCVHGK 872
Qy 781 HDSSWVEELLMLHRARITDVEHITGLSFYQQRKEPVSDILKLKTHLPTFSQEDLINDKTH 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 873 HDSSWVEELLMLHRARITDVEHITGLSFYQQRKEPVSDILKLKTHLPTFSQEDLINDKTH 932
Qy 841 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 933 TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 992
Qy 901 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 993 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 1052
Qy 961 EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1053 EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 1112
Qy 1021 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 1063
|||||||||||||||||||||||||||||||||||||||||||
Db 1113 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 1155
Regarding claim 6 (in the alternative), claim 14 (in the alternative), claim 17 (in the alternative), claim 20 (in the alternative), claim 23 (in the alternative), and claim 26, the alignment between SEQ ID NO: 84 (Qy, query) and the ectonucleotide pyrophosphate/phosphodiesterase-1 (NPP1) polypeptide taught by Albright (Db, database) is provided below.
RESULT 3
BDJ72661
ID BDJ72661 standard; protein; 1082 AA.
XX
AC BDJ72661;
XX
DT 12-JAN-2017 (first entry)
XX
DE NPP71-human immunoglobulin G Fc domain fusion protein, SEQ 18.
XX
KW Immunoglobulin G; NPP1 protein; NPP7 protein; aging;
KW ankylosing spondylitis; antiarteriosclerotic; antiarthritic;
KW antiinflammatory; antilipemic; atherosclerosis; bone repair;
KW calcification; calciphylaxis; cardiant; ecto-nucleotide pyrophosphate;
KW endocrine-gen.; fusion protein; heart disease; metabolic-gen.;
KW musculoskeletal-gen.; nutrition-disorder-gen.; ossification;
KW osteoarthritis; osteopathic; phosphodiesterase-1; phosphodiesterase-7;
KW prophylactic to disease; protein therapy; pseudoxanthoma elasticum;
KW recombinant protein; therapeutic; vasotropic;
KW x linked dominant hypophosphatemic rickets.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Region 1..22
FT /label= NPP7_protein_fragment
FT Region 23..852
FT /label= NPP1_protein_fragment
FT Region 853..855
FT /label= Linker
FT Domain 856..1082
FT /label= Immunoglobulin_G_Fc_domain
XX
CC PN WO2016187408-A1.
XX
CC PD 24-NOV-2016.
XX
CC PF 19-MAY-2016; 2016WO-US033236.
XX
PR 19-MAY-2015; 2015US-0163500P.
XX
CC PA (UYYA ) UNIV YALE.
XX
CC PI Braddock D, Albright R;
XX
DR WPI; 2016-72744M/01.
DR REFSEQ; NP_006199.
XX
CC PT New protein-Z-domain-X-Y compound useful for preventing or treating
CC PT disease or disorder associated with pathological calcification or
CC PT ossification e.g. idiopathic infantile arterial calcification, and
CC PT osteoarthritis in mammal.
XX
CC PS Example; SEQ ID NO 18; 108pp; English.
XX
CC The present invention relates to a novel compound (PROTEIN-Z-DOMAIN-X-Y)
CC useful for preventing or treating disease or disorder associated with
CC pathological calcification or ossification in mammal. The compound
CC comprises a protein, a domain (human IgG Fc domain (Fc), human serum
CC albumin protein (ALB) and fragment thereof), a peptide comprising 1-20
CC amino acids; and a peptide of SEQ ID NO:4-14 (see BDJ72647-BDJ72657). The
CC invention also provides: a method for reducing or preventing cardiac
CC calcifications, arterial calcifications and/or elastic fiber
CC mineralization in infant afflicted with a disease or disorder
CC (generalized arterial calcification of infancy (GACI), idiopathic
CC infantile arterial calcification (IIAC), ossification of the posterior
CC longitudinal ligament (OPLL), hypophosphatemic rickets, osteoarthritis,
CC calcification of atherosclerotic plaques, pseudoxanthoma elasticum (PXE),
CC hereditary and non-hereditary forms of osteoarthritis, ankylosing
CC spondylitis, hardening of the arteries occurring with aging, and
CC calciphylaxis resulting from end stage renal disease and progeria, by
CC administering the compound; and a method for reducing or preventing
CC cardiac calcifications, arterial calcifications and/or elastic fiber
CC mineralizations in an infant afflicted with a disease (GACI and PXE). The
CC present sequence represents a human modified ecto-nucleotide
CC pyrophosphate/phosphodiesterase-1 (NPP1) protein/NPP7 fusion (NPP71)-
CC immunoglobulin G Fc domain fusion protein, which can be useful for
CC preparing the compound of the invention.
XX
SQ Sequence 1082 AA;
Query Match 100.0%; Score 5815; DB 23; Length 1082;
Best Local Similarity 100.0%;
Matches 1060; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GLKPSCAKEVKSCKGRCFERTFGNCRCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 23 GLKPSCAKEVKSCKGRCFERTFGNCRCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCG 82
Qy 61 EKRLTRSLCACSDDCKDKGDCCINYSSVCQGEKSWVEEPCESINEPQCPAGFETPPTLLF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 83 EKRLTRSLCACSDDCKDKGDCCINYSSVCQGEKSWVEEPCESINEPQCPAGFETPPTLLF 142
Qy 121 SLDGFRAEYLHTWGGLLPVISKLKKCGTYTKNMRPVYPTKTFPNHYSIVTGLYPESHGII 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 143 SLDGFRAEYLHTWGGLLPVISKLKKCGTYTKNMRPVYPTKTFPNHYSIVTGLYPESHGII 202
Qy 181 DNKMYDPKMNASFSLKSKEKFNPEWYKGEPIWVTAKYQGLKSGTFFWPGSDVEINGIFPD 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 203 DNKMYDPKMNASFSLKSKEKFNPEWYKGEPIWVTAKYQGLKSGTFFWPGSDVEINGIFPD 262
Qy 241 IYKMYNGSVPFEERILAVLQWLQLPKDERPHFYTLYLEEPDSSGHSYGPVSSEVIKALQR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 263 IYKMYNGSVPFEERILAVLQWLQLPKDERPHFYTLYLEEPDSSGHSYGPVSSEVIKALQR 322
Qy 301 VDGMVGMLMDGLKELNLHRCLNLILISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYGPAA 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 323 VDGMVGMLMDGLKELNLHRCLNLILISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYGPAA 382
Qy 361 RLRPSDVPDKYYSFNYEGIARNLSCREPNQHFKPYLKHFLPKRLHFAKSDRIEPLTFYLD 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 383 RLRPSDVPDKYYSFNYEGIARNLSCREPNQHFKPYLKHFLPKRLHFAKSDRIEPLTFYLD 442
Qy 421 PQWQLALNPSERKYCGSGFHGSDNVFSNMQALFVGYGPGFKHGIEADTFENIEVYNLMCD 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 443 PQWQLALNPSERKYCGSGFHGSDNVFSNMQALFVGYGPGFKHGIEADTFENIEVYNLMCD 502
Qy 481 LLNLTPAPNNGTHGSLNHLLKNPVYTPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSILPI 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 503 LLNLTPAPNNGTHGSLNHLLKNPVYTPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSILPI 562
Qy 541 EDFQTQFNLTVAEEKIIKHETLPYGRPRVLQKENTICLLSQHQFMSGYSQDILMPLWTSY 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 563 EDFQTQFNLTVAEEKIIKHETLPYGRPRVLQKENTICLLSQHQFMSGYSQDILMPLWTSY 622
Qy 601 TVDRNDSFSTEDFSNCLYQDFRIPLSPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGIYSE 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 623 TVDRNDSFSTEDFSNCLYQDFRIPLSPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGIYSE 682
Qy 661 ALLTTNIVPMYQSFQVIWRYFHDTLLRKYAEERNGVNVVSGPVFDFDYDGRCDSLENLRQ 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 683 ALLTTNIVPMYQSFQVIWRYFHDTLLRKYAEERNGVNVVSGPVFDFDYDGRCDSLENLRQ 742
Qy 721 KRRVIRNQEILIPTHFFIVLTSCKDTSQTPLHCENLDTLAFILPHRTDNSESCVHGKHDS 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 743 KRRVIRNQEILIPTHFFIVLTSCKDTSQTPLHCENLDTLAFILPHRTDNSESCVHGKHDS 802
Qy 781 SWVEELLMLHRARITDVEHITGLSFYQQRKEPVSDILKLKTHLPTFSQEDLINDKTHTCP 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 803 SWVEELLMLHRARITDVEHITGLSFYQQRKEPVSDILKLKTHLPTFSQEDLINDKTHTCP 862
Qy 841 PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 863 PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA 922
Qy 901 KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 923 KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 982
Qy 961 VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 983 VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY 1042
Qy 1021 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 1060
||||||||||||||||||||||||||||||||||||||||
Db 1043 SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 1082
Regarding claim 27, the alignment between SEQ ID NO: 85 (Qy, query) and the ectonucleotide pyrophosphate/phosphodiesterase-1 (NPP1) polypeptide taught by Albright (Db, database) is provided below.
RESULT 6
BDJ72663
ID BDJ72663 standard; protein; 1079 AA.
XX
AC BDJ72663;
XX
DT 12-JAN-2017 (first entry)
XX
DE NPP71 (lacking N-terminal GLK)-IgG Fc domain fusion protein, SEQ 20.
XX
KW Immunoglobulin G; NPP1 protein; NPP7 protein; aging;
KW ankylosing spondylitis; antiarteriosclerotic; antiarthritic;
KW antiinflammatory; antilipemic; atherosclerosis; bone repair;
KW calcification; calciphylaxis; cardiant; ecto-nucleotide pyrophosphate;
KW endocrine-gen.; fusion protein; heart disease; metabolic-gen.;
KW musculoskeletal-gen.; nutrition-disorder-gen.; ossification;
KW osteoarthritis; osteopathic; phosphodiesterase-1; phosphodiesterase-7;
KW prophylactic to disease; protein therapy; pseudoxanthoma elasticum;
KW recombinant protein; therapeutic; vasotropic;
KW x linked dominant hypophosphatemic rickets.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Region 1..22
FT /label= NPP7_protein_fragment
FT Region 23..849
FT /label= NPP1_protein_fragment
FT Region 850..852
FT /label= Linker
FT Domain 853..1079
FT /label= Immunoglobulin_G_Fc_domain
XX
CC PN WO2016187408-A1.
XX
CC PD 24-NOV-2016.
XX
CC PF 19-MAY-2016; 2016WO-US033236.
XX
PR 19-MAY-2015; 2015US-0163500P.
XX
CC PA (UYYA ) UNIV YALE.
XX
CC PI Braddock D, Albright R;
XX
DR WPI; 2016-72744M/01.
DR REFSEQ; NP_006199.
XX
CC PT New protein-Z-domain-X-Y compound useful for preventing or treating
CC PT disease or disorder associated with pathological calcification or
CC PT ossification e.g. idiopathic infantile arterial calcification, and
CC PT osteoarthritis in mammal.
XX
CC PS Example; SEQ ID NO 20; 108pp; English.
XX
CC The present invention relates to a novel compound (PROTEIN-Z-DOMAIN-X-Y)
CC useful for preventing or treating disease or disorder associated with
CC pathological calcification or ossification in mammal. The compound
CC comprises a protein, a domain (human IgG Fc domain (Fc), human serum
CC albumin protein (ALB) and fragment thereof), a peptide comprising 1-20
CC amino acids; and a peptide of SEQ ID NO:4-14 (see BDJ72647-BDJ72657). The
CC invention also provides: a method for reducing or preventing cardiac
CC calcifications, arterial calcifications and/or elastic fiber
CC mineralization in infant afflicted with a disease or disorder
CC (generalized arterial calcification of infancy (GACI), idiopathic
CC infantile arterial calcification (IIAC), ossification of the posterior
CC longitudinal ligament (OPLL), hypophosphatemic rickets, osteoarthritis,
CC calcification of atherosclerotic plaques, pseudoxanthoma elasticum (PXE),
CC hereditary and non-hereditary forms of osteoarthritis, ankylosing
CC spondylitis, hardening of the arteries occurring with aging, and
CC calciphylaxis resulting from end stage renal disease and progeria, by
CC administering the compound; and a method for reducing or preventing
CC cardiac calcifications, arterial calcifications and/or elastic fiber
CC mineralizations in an infant afflicted with a disease (GACI and PXE). The
CC present sequence represents a human modified ecto-nucleotide
CC pyrophosphate/phosphodiesterase-1 (NPP1) protein/NPP7 fusion (NPP71,
CC lacking N-terminal GLK)-immunoglobulin G Fc domain fusion protein, which
CC can be useful for preparing the compound of the invention.
XX
SQ Sequence 1079 AA;
Query Match 100.0%; Score 5800; DB 23; Length 1079;
Best Local Similarity 100.0%;
Matches 1057; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 PSCAKEVKSCKGRCFERTFGNCRCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCGEKR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 23 PSCAKEVKSCKGRCFERTFGNCRCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCGEKR 82
Qy 61 LTRSLCACSDDCKDKGDCCINYSSVCQGEKSWVEEPCESINEPQCPAGFETPPTLLFSLD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 83 LTRSLCACSDDCKDKGDCCINYSSVCQGEKSWVEEPCESINEPQCPAGFETPPTLLFSLD 142
Qy 121 GFRAEYLHTWGGLLPVISKLKKCGTYTKNMRPVYPTKTFPNHYSIVTGLYPESHGIIDNK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 143 GFRAEYLHTWGGLLPVISKLKKCGTYTKNMRPVYPTKTFPNHYSIVTGLYPESHGIIDNK 202
Qy 181 MYDPKMNASFSLKSKEKFNPEWYKGEPIWVTAKYQGLKSGTFFWPGSDVEINGIFPDIYK 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 203 MYDPKMNASFSLKSKEKFNPEWYKGEPIWVTAKYQGLKSGTFFWPGSDVEINGIFPDIYK 262
Qy 241 MYNGSVPFEERILAVLQWLQLPKDERPHFYTLYLEEPDSSGHSYGPVSSEVIKALQRVDG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 263 MYNGSVPFEERILAVLQWLQLPKDERPHFYTLYLEEPDSSGHSYGPVSSEVIKALQRVDG 322
Qy 301 MVGMLMDGLKELNLHRCLNLILISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYGPAARLR 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 323 MVGMLMDGLKELNLHRCLNLILISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYGPAARLR 382
Qy 361 PSDVPDKYYSFNYEGIARNLSCREPNQHFKPYLKHFLPKRLHFAKSDRIEPLTFYLDPQW 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 383 PSDVPDKYYSFNYEGIARNLSCREPNQHFKPYLKHFLPKRLHFAKSDRIEPLTFYLDPQW 442
Qy 421 QLALNPSERKYCGSGFHGSDNVFSNMQALFVGYGPGFKHGIEADTFENIEVYNLMCDLLN 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 443 QLALNPSERKYCGSGFHGSDNVFSNMQALFVGYGPGFKHGIEADTFENIEVYNLMCDLLN 502
Qy 481 LTPAPNNGTHGSLNHLLKNPVYTPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSILPIEDF 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 503 LTPAPNNGTHGSLNHLLKNPVYTPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSILPIEDF 562
Qy 541 QTQFNLTVAEEKIIKHETLPYGRPRVLQKENTICLLSQHQFMSGYSQDILMPLWTSYTVD 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 563 QTQFNLTVAEEKIIKHETLPYGRPRVLQKENTICLLSQHQFMSGYSQDILMPLWTSYTVD 622
Qy 601 RNDSFSTEDFSNCLYQDFRIPLSPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGIYSEALL 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 623 RNDSFSTEDFSNCLYQDFRIPLSPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGIYSEALL 682
Qy 661 TTNIVPMYQSFQVIWRYFHDTLLRKYAEERNGVNVVSGPVFDFDYDGRCDSLENLRQKRR 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 683 TTNIVPMYQSFQVIWRYFHDTLLRKYAEERNGVNVVSGPVFDFDYDGRCDSLENLRQKRR 742
Qy 721 VIRNQEILIPTHFFIVLTSCKDTSQTPLHCENLDTLAFILPHRTDNSESCVHGKHDSSWV 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 743 VIRNQEILIPTHFFIVLTSCKDTSQTPLHCENLDTLAFILPHRTDNSESCVHGKHDSSWV 802
Qy 781 EELLMLHRARITDVEHITGLSFYQQRKEPVSDILKLKTHLPTFSQEDLINDKTHTCPPCP 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 803 EELLMLHRARITDVEHITGLSFYQQRKEPVSDILKLKTHLPTFSQEDLINDKTHTCPPCP 862
Qy 841 APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 863 APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 922
Qy 901 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 923 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 982
Qy 961 LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 983 LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 1042
Qy 1021 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 1057
|||||||||||||||||||||||||||||||||||||
Db 1043 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 1079
Regarding claim 28, the alignment between SEQ ID NO: 86(Qy, query) and the ectonucleotide pyrophosphate/phosphodiesterase-1 (NPP1) polypeptide taught by Albright (Db, database) is provided below.
RESULT 3
BDJ72663
ID BDJ72663 standard; protein; 1079 AA.
XX
AC BDJ72663;
XX
DT 12-JAN-2017 (first entry)
XX
DE NPP71 (lacking N-terminal GLK)-IgG Fc domain fusion protein, SEQ 20.
XX
KW Immunoglobulin G; NPP1 protein; NPP7 protein; aging;
KW ankylosing spondylitis; antiarteriosclerotic; antiarthritic;
KW antiinflammatory; antilipemic; atherosclerosis; bone repair;
KW calcification; calciphylaxis; cardiant; ecto-nucleotide pyrophosphate;
KW endocrine-gen.; fusion protein; heart disease; metabolic-gen.;
KW musculoskeletal-gen.; nutrition-disorder-gen.; ossification;
KW osteoarthritis; osteopathic; phosphodiesterase-1; phosphodiesterase-7;
KW prophylactic to disease; protein therapy; pseudoxanthoma elasticum;
KW recombinant protein; therapeutic; vasotropic;
KW x linked dominant hypophosphatemic rickets.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Region 1..22
FT /label= NPP7_protein_fragment
FT Region 23..849
FT /label= NPP1_protein_fragment
FT Region 850..852
FT /label= Linker
FT Domain 853..1079
FT /label= Immunoglobulin_G_Fc_domain
XX
CC PN WO2016187408-A1.
XX
CC PD 24-NOV-2016.
XX
CC PF 19-MAY-2016; 2016WO-US033236.
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PR 19-MAY-2015; 2015US-0163500P.
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CC PA (UYYA ) UNIV YALE.
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CC PI Braddock D, Albright R;
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DR WPI; 2016-72744M/01.
DR REFSEQ; NP_006199.
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CC PT New protein-Z-domain-X-Y compound useful for preventing or treating
CC PT disease or disorder associated with pathological calcification or
CC PT ossification e.g. idiopathic infantile arterial calcification, and
CC PT osteoarthritis in mammal.
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CC PS Example; SEQ ID NO 20; 108pp; English.
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CC The present invention relates to a novel compound (PROTEIN-Z-DOMAIN-X-Y)
CC useful for preventing or treating disease or disorder associated with
CC pathological calcification or ossification in mammal. The compound
CC comprises a protein, a domain (human IgG Fc domain (Fc), human serum
CC albumin protein (ALB) and fragment thereof), a peptide comprising 1-20
CC amino acids; and a peptide of SEQ ID NO:4-14 (see BDJ72647-BDJ72657). The
CC invention also provides: a method for reducing or preventing cardiac
CC calcifications, arterial calcifications and/or elastic fiber
CC mineralization in infant afflicted with a disease or disorder
CC (generalized arterial calcification of infancy (GACI), idiopathic
CC infantile arterial calcification (IIAC), ossification of the posterior
CC longitudinal ligament (OPLL), hypophosphatemic rickets, osteoarthritis,
CC calcification of atherosclerotic plaques, pseudoxanthoma elasticum (PXE),
CC hereditary and non-hereditary forms of osteoarthritis, ankylosing
CC spondylitis, hardening of the arteries occurring with aging, and
CC calciphylaxis resulting from end stage renal disease and progeria, by
CC administering the compound; and a method for reducing or preventing
CC cardiac calcifications, arterial calcifications and/or elastic fiber
CC mineralizations in an infant afflicted with a disease (GACI and PXE). The
CC present sequence represents a human modified ecto-nucleotide
CC pyrophosphate/phosphodiesterase-1 (NPP1) protein/NPP7 fusion (NPP71,
CC lacking N-terminal GLK)-immunoglobulin G Fc domain fusion protein, which
CC can be useful for preparing the compound of the invention.
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SQ Sequence 1079 AA;
Query Match 100.0%; Score 5804; DB 23; Length 1079;
Best Local Similarity 100.0%;
Matches 1058; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APSCAKEVKSCKGRCFERTFGNCRCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCGEK 60
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Db 22 APSCAKEVKSCKGRCFERTFGNCRCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCGEK 81
Qy 61 RLTRSLCACSDDCKDKGDCCINYSSVCQGEKSWVEEPCESINEPQC