DETAILED ACTION
This action is in reply to papers filed 1/8/2025. Claims 1, 9-12, 16-17, 19-22, 28, 30-33 and 44-45 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 US PGPub of this application US20210052771A1, Published 2/25/2021.
Withdrawn Rejections
The 112 (b) rejection of claims 32-33 is withdrawn in view of amendments made to each of said claim.
The 103 (a) rejection of claims 1, 9-12, 16, 19-22, 28, 30-33 and 44 as being unpatentable over Ren et al. (Biomaterials. 2016 May:89:67-78.) in view of Liu et al. (Acta Biomater. 2016 Sep 15:42:378-388), Boyle et al. (U.S. Patent 7005413B1, Published 2/28/2006) and Hofbauer et al. (Biochem Biophys Res Commun. 1998 Sep 29;250(3):776-81) is withdrawn in view of amendments made to independent claims 1, 28 and 30.
Rejections Necessitated by Amendments
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 45 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 45 is copied below.
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172
820
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For completeness, claim 1 is copied below.
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296
780
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At issue here is that claim 45 recites, inter alia, “…wherein implantation of the composition reduces..”. This recitation is not recited in an active step. That is, the recitation describes an act (i.e. implantation) that previously occurred. An active step would recite, for example, “…implanting the composition into an implantation site in a subject” or something similar to claim 19. However, there is no active step of implantation in claim 45 or in independent claim 1. Therefore, it is unclear how TRAP-positive osteoclast counts in a local implant region is reduced.
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 (i.e., changing from AIA to pre-AIA ) 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.
Claim(s) 1, 9-12, 16-17, 19-22, 28, 30-31, 33 and 44-45 are rejected under 35 U.S.C. 103 as being unpatentable over Ren et al. (Biomaterials. 2016 May:89:67-78., previously cited) in view of Liu et al. (Acta Biomater. 2016 Sep 15:42:378-388. previously cited), Nycz, J. (PgPub US20060039949A1, Published 2/23/2006) and Hofbauer et al. (Biochem Biophys Res Commun. 1998 Sep 29;250(3):776-81. previously cited).
Ren et al. teach approaches to bone tissue engineering incorporate three elements: osteogenic cells, growth factors, and scaffolding material (Abstract). Towards this end, Ren evaluated the therapeutic potential of a novel nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) scaffold (as in claim 1 (in-part), as in claim 28(in-part), and as in claim 30 (in-part)) in bone regeneration by investigating in vivo calvarial bone healing in a rabbit cranial defect model (Pg. 68, Col. 1, para. 2). Ren teaches primary BMSCs were cultured ex vivo on Col-GAG (collagen matrix- glycosaminoglycan) and (MC-GAG) with and without BMP-2. After one week of culture, the scaffolds were implanted in critical-sized rabbit calvarial defects 14 mm in diameter and bone healing was evaluated after 12 weeks (Pg. 73, Col. 1). Histologic analyses of explanted cranial defects were also performed to confirm the presence of mineralization (Fig. 5). Novel bone, as noted by a decreased thickness in comparison to native calvarium as well as a less organized appearance, was identified at the junction between the scaffold and the native bone in all specimens. In the unreconstructed and Col-GAG reconstructed defects, minimal mineralized content was found in the central portions of the defect whereas the central portions of MC-GAG scaffolds contained significantly more mineralized bone. Thus, Ren teaches the histologic and micro-CT analyses of critical-sized rabbit cranial defects suggest that MC-GAG scaffolds regenerate more bone than Col-GAG scaffolds independent of pre-culturing with BMSCs or BMSCs/BMP-2 (Pg. 74, Col. 1). At the mechanistic level, Ren demonstrated that improved osteogenesis on MC-GAG scaffolds (as in claim 19 (in-part)) corresponded to differential temporal transcription of BMPs (BMP-2 and -9 early, BMP-4 late), thereby inducing autogenous BMP receptor signaling via phosphorylation of Smad 1/5 (Pg. 76, Col. 1).
However, Ren fails to teach one or more of an osteoprotegerin (OPG) fragment (as further in claim 1).
Before the effective filing date of the claimed invention, Liu et al. teach gene therapy has the potential to reach long-term therapeutic effects by delivering genes of anti-resorptive proteins to patients, circumventing the need of repeated administration (Pg. 379, Col. 1, para. 1). Towards this end, Liu teaches the objectives of their study were to genetically modify rat BMSCs (as in claim 12) for OPG overexpression (as further in claim 1, as further in claim 28, as in claim 30 (in-part)) via an adenovirus (as in claim 9, as in claim 10, as in claim 11 and as further in claim 33), and investigate the anti-osteoclastogenic effect of OPG gene-modified BMSCs in vitro via bone resorption experiment and in vivo in a critical sized mandibular bone defect model in OVX induced osteoporotic rats for the first time (Pg. 379, Col. 1, para. 2) . Liu notes that the osteogenic ability of transfected cells was detected by Alizarin Red Staining (ARS) after 2 weeks of osteogenic differentiation . The cells were cultured in a 12-well plate in the osteogenic medium (DMEM containing 10% FBS, 100 mM dexamethasone, 10 nM β-glycerophosphate, and 0.25 mM l-ascorbic acids) (as in claim 31). Two weeks later, cells were fixed in 10% formaldehyde and stained with ARS for 1 h to visualize the presence of calcified deposition produced by cells (paragraph bridging Col. 1 and Col. 2 on Pg. 380).
The following hypotheses were tested: (1) rat BMSCs can be successfully modified genetically to have OPG overexpression; (2) OPG gene-modified BMSCs can inhibit osteoclastogenesis in vitro (as in claim 21); (3) OPG gene modification of BMSCs will not have adverse effects on cell attachment and proliferation on hydroxyapatite (HA) scaffolds; (4) OPG gene-modified BMSCs will exert anti-osteoclastogenic effects (as in claim 22) and promote bone regeneration (as in claim 19) in OVX rats (Pg. 379, Col. 1, para. 2). Liu observed that their in vitro bone resorption experiment demonstrated that OPG-BMSCs were capable to suppress osteoclast differentiation and subsequently inhibit osteoclast-mediated bone resorption(Pg. 387, Col. 2, para. 2) (as in claim 20). The micro-CT and histological results showed that HA-OPG-BMSC constructs boosted bone formation and reduced osteoclastogenesis in OVX rat mandibular bone defects (Abstract).
And although Liu teaches the MSC expressing exogenous osteoprotegerin was transduced with a virus comprising a nucleic acid encoding osteoprotegerin (see above), Liu fails to teach the OPG fragment is encoded by a nucleic acid, wherein the nucleic consists of a nucleic acid that is at least 90% identical to the polynucleotide of SEQ ID NO: 1 (as further in claim 1, 28 and 30).
Before the effective filing date of the claimed invention, Nycz teaches an acetabular cup having one or more osteoinductive formulations, wherein each osteoinductive formulation comprises one or more osteoinductive agent(s) (Abstract). Nycz teaches osteoinductive formulations of the invention may optionally further comprise a carrier vehicle (as in claim 17) such as water, saline, Ringer's solution, calcium phosphate based carriers, or dextrose solution (Pg. 6,para. 58). Nycz teaches isolated osteoinductive agents include osteoclastogenesis inhibitors to inhibit bone resorption of the bone tissue surrounding the site of implantation of the acetabular cup by osteoclasts. Osteoclast and osteoclastogenesis inhibitors include, but are not limited to, osteoprotegerin polynucleotides and polypeptides (Pg. 8, para. 88-89). In one embodiment, Nycz teaches the osteoinductive formulation comprises SEQ ID NO: 51, an osteoprotegerin polynucleotide. Note that the SEQ ID NO: 51 is 96% identical to SEQ ID NO: 1 (as further in claim 1, claim 28 and claim 30) of the claimed invention. See below.
RESULT 5
US-10-921-793-51
(NOTE: this sequence has 10 duplicates in the database searched.
See complete list at the end of this report)
Sequence 51, US/10921793
Publication No. US20060039949A1
GENERAL INFORMATION
APPLICANT: Nycz, Jeffrey
TITLE OF INVENTION: Orthopaedic Device with Porous Substrate and Impregnated
TITLE OF INVENTION: Osteoinductive Material
FILE REFERENCE: 64118.000087
CURRENT APPLICATION NUMBER: US/10/921,793
CURRENT FILING DATE: 2004-08-20
NUMBER OF SEQ ID NOS: 84
SEQ ID NO 51
LENGTH: 2291
TYPE: DNA
ORGANISM: Homo sapiens
Query Match 96.0%; Score 2250.4; Length 2291;
Best Local Similarity 99.5%;
Matches 2271; Conservative 0; Mismatches 1; Indels 10; Gaps 1;
Qy 73 CTTTCCGCCCCAGCCCTGAAAGCGTTAACCCTGGAGCTTTCTGCACACCCCCCGACCGCT 132
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CTTTCCGCCCCAGCCCTGAAAGCGTTAACCCTGGAGCTTTCTGCACACCCCCCGACCGCT 60
Qy 133 CCCGCCCAAGCTTCCTAAAAAAGAAAGGTGCAAAGTTTGGTCCAGGATAGAAAAATGACT 192
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CCCGCCCAAGCTTCCTAAAAAAGAAAGGTGCAAAGTTTGGTCCAGGATAGAAAAATGACT 120
Qy 193 GATCAAAGGCAGGCGATACTTCCTGTTGCCGGGACGCTATATATAACGTGATGAGCGCAC 252
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GATCAAAGGCAGGCGATACTTCCTGTTGCCGGGACGCTATATATAACGTGATGAGCGCAC 180
Qy 253 GGGCTGCGGAGACGCACCGGAGCGCTCGCCCAGCCGCCGCCTCCAAGCCCCTGAGGTTTC 312
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GGGCTGCGGAGACGCACCGGAGCGCTCGCCCAGCCGCCGCCTCCAAGCCCCTGAGGTTTC 240
Qy 313 CGGGGACCACAATGAACAACTTGCTGTGCTGCGCGCTCGTGTTTCTGGACATCTCCATTA 372
||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||
Db 241 CGGGGACCACAATGAACAAGTTGCTGTGCTGCGCGCTCGTGTTTCTGGACATCTCCATTA 300
Qy 373 AGTGGACCACCCAGGAAACGTTTCCTCCAAAGTACCTTCATTATGACGAAGAAACCTCTC 432
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 AGTGGACCACCCAGGAAACGTTTCCTCCAAAGTACCTTCATTATGACGAAGAAACCTCTC 360
Qy 433 ATCAGCTGTTGTGTGACAAATGTCCTCCTGGTACCTACCTAAAACAACACTGTACAGCAA 492
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 ATCAGCTGTTGTGTGACAAATGTCCTCCTGGTACCTACCTAAAACAACACTGTACAGCAA 420
Qy 493 AGTGGAAGACCGTGTGCGCCCCTTGCCCTGACCACTACTACACAGACAGCTGGCACACCA 552
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 AGTGGAAGACCGTGTGCGCCCCTTGCCCTGACCACTACTACACAGACAGCTGGCACACCA 480
Qy 553 GTGACGAGTGTCTATACTGCAGCCCCGTGTGCAAGGAGCTGCAGTACGTCAAGCAGGAGT 612
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 GTGACGAGTGTCTATACTGCAGCCCCGTGTGCAAGGAGCTGCAGTACGTCAAGCAGGAGT 540
Qy 613 GCAATCGCACCCACAACCGCGTGTGCGAATGCAAGGAAGGGCGCTACCTTGAGATAGAGT 672
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 GCAATCGCACCCACAACCGCGTGTGCGAATGCAAGGAAGGGCGCTACCTTGAGATAGAGT 600
Qy 673 TCTGCTTGAAACATAGGAGCTGCCCTCCTGGATTTGGAGTGGTGCAAGCTGGAACCCCAG 732
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 TCTGCTTGAAACATAGGAGCTGCCCTCCTGGATTTGGAGTGGTGCAAGCTGGAACCCCAG 660
Qy 733 AGCGAAATACAGTTTGCAAAAGATGTCCAGATGGGTTCTTCTCAAATGAGACGTCATCTA 792
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 AGCGAAATACAGTTTGCAAAAGATGTCCAGATGGGTTCTTCTCAAATGAGACGTCATCTA 720
Qy 793 AAGCACCCTGTAGAAAACACACAAATTGCAGTGTCTTTGGTCTCCTGCTAACTCAGAAAG 852
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 AAGCACCCTGTAGAAAACACACAAATTGCAGTGTCTTTGGTCTCCTGCTAACTCAGAAAG 780
Qy 853 GAAATGCAACACACGACAACATATGTTCCGGAAACAGTGAATCAACTCAAAAATGTGGAA 912
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 GAAATGCAACACACGACAACATATGTTCCGGAAACAGTGAATCAACTCAAAAATGTGGAA 840
Qy 913 TAGATGTTACCCTGTGTGAGGAGGCATTCTTCAGGTTTGCTGTTCCTACAAAGTTTACGC 972
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 TAGATGTTACCCTGTGTGAGGAGGCATTCTTCAGGTTTGCTGTTCCTACAAAGTTTACGC 900
Qy 973 CTAACTGGCTTAGTGTCTTGGTAGACAATTTGCCTGGCACCAAAGTAAACGCAGAGAGTG 1032
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 CTAACTGGCTTAGTGTCTTGGTAGACAATTTGCCTGGCACCAAAGTAAACGCAGAGAGTG 960
Qy 1033 TAGAGAGGATAAAACGGCAACACAGCTCACAAGAACAGACTTTCCAGCTGCTGAAGTTAT 1092
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 TAGAGAGGATAAAACGGCAACACAGCTCACAAGAACAGACTTTCCAGCTGCTGAAGTTAT 1020
Qy 1093 GGAAACATCAAAACAAAGACCAAGATATAGTCAAGAAGATCATCCAAGATATTGACCTCT 1152
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 GGAAACATCAAAACAAAGACCAAGATATAGTCAAGAAGATCATCCAAGATATTGACCTCT 1080
Qy 1153 GTGAAAACAGCGTGCAGCGGCACATTGGACATGCTAACCTCACCTTCGAGCAGCTTCGTA 1212
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 GTGAAAACAGCGTGCAGCGGCACATTGGACATGCTAACCTCACCTTCGAGCAGCTTCGTA 1140
Qy 1213 GCTTGATGGAAAGCTTACCGGGAAAGAAAGTGGGAGCAGAAGACATTGAAAAAACAATAA 1272
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 GCTTGATGGAAAGCTTACCGGGAAAGAAAGTGGGAGCAGAAGACATTGAAAAAACAATAA 1200
Qy 1273 AGGCATGCAAACCCAGTGACCAGATCCTGAAGCTGCTCAGTTTGTGGC----------TG 1322
|||||||||||||||||||||||||||||||||||||||||||||||| ||
Db 1201 AGGCATGCAAACCCAGTGACCAGATCCTGAAGCTGCTCAGTTTGTGGCGAATAAAAAATG 1260
Qy 1323 GCGACCAAGACACCTTGAAGGGCCTAATGCACGCACTAAAGCACTCAAAGACGTACCACT 1382
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1261 GCGACCAAGACACCTTGAAGGGCCTAATGCACGCACTAAAGCACTCAAAGACGTACCACT 1320
Qy 1383 TTCCCAAAACTGTCACTCAGAGTCTAAAGAAGACCATCAGGTTCCTTCACAGCTTCACAA 1442
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1321 TTCCCAAAACTGTCACTCAGAGTCTAAAGAAGACCATCAGGTTCCTTCACAGCTTCACAA 1380
Qy 1443 TGTACAAATTGTATCAGAAGTTATTTTTAGAAATGATAGGTAACCAGGTCCAATCAGTAA 1502
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1381 TGTACAAATTGTATCAGAAGTTATTTTTAGAAATGATAGGTAACCAGGTCCAATCAGTAA 1440
Qy 1503 AAATAAGCTGCTTATAACTGGAAATGGCCATTGAGCTGTTTCCTCACAATTGGCGAGATC 1562
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1441 AAATAAGCTGCTTATAACTGGAAATGGCCATTGAGCTGTTTCCTCACAATTGGCGAGATC 1500
Qy 1563 CCATGGATGAGTAAACTGTTTCTCAGGCACTTGAGGCTTTCAGTGATATCTTTCTCATTA 1622
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1501 CCATGGATGAGTAAACTGTTTCTCAGGCACTTGAGGCTTTCAGTGATATCTTTCTCATTA 1560
Qy 1623 CCAGTGACTAATTTTGCCACAGGGTACTAAAAGAAACTATGATGTGGAGAAAGGACTAAC 1682
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1561 CCAGTGACTAATTTTGCCACAGGGTACTAAAAGAAACTATGATGTGGAGAAAGGACTAAC 1620
Qy 1683 ATCTCCTCCAATAAACCCCAAATGGTTAATCCAACTGTCAGATCTGGATCGTTATCTACT 1742
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1621 ATCTCCTCCAATAAACCCCAAATGGTTAATCCAACTGTCAGATCTGGATCGTTATCTACT 1680
Qy 1743 GACTATATTTTCCCTTATTACTGCTTGCAGTAATTCAACTGGAAATTAAAAAAAAAAAAC 1802
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1681 GACTATATTTTCCCTTATTACTGCTTGCAGTAATTCAACTGGAAATTAAAAAAAAAAAAC 1740
Qy 1803 TAGACTCCATTGTGCCTTACTAAATATGGGAATGTCTAACTTAAATAGCTTTGAGATTTC 1862
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1741 TAGACTCCATTGTGCCTTACTAAATATGGGAATGTCTAACTTAAATAGCTTTGAGATTTC 1800
Qy 1863 AGCTATGCTAGAGGCTTTTATTAGAAAGCCATATTTTTTTCTGTAAAAGTTACTAATATA 1922
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1801 AGCTATGCTAGAGGCTTTTATTAGAAAGCCATATTTTTTTCTGTAAAAGTTACTAATATA 1860
Qy 1923 TCTGTAACACTATTACAGTATTGCTATTTATATTCATTCAGATATAAGATTTGTACATAT 1982
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1861 TCTGTAACACTATTACAGTATTGCTATTTATATTCATTCAGATATAAGATTTGTACATAT 1920
Qy 1983 TATCATCCTATAAAGAAACGGTATGACTTAATTTTAGAAAGAAAATTATATTCTGTTTAT 2042
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1921 TATCATCCTATAAAGAAACGGTATGACTTAATTTTAGAAAGAAAATTATATTCTGTTTAT 1980
Qy 2043 TATGACAAATGAAAGAGAAAATATATATTTTTAATGGAAAGTTTGTAGCATTTTTCTAAT 2102
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1981 TATGACAAATGAAAGAGAAAATATATATTTTTAATGGAAAGTTTGTAGCATTTTTCTAAT 2040
Qy 2103 AGGTACTGCCATATTTTTCTGTGTGGAGTATTTTTATAATTTTATCTGTATAAGCTGTAA 2162
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2041 AGGTACTGCCATATTTTTCTGTGTGGAGTATTTTTATAATTTTATCTGTATAAGCTGTAA 2100
Qy 2163 TATCATTTTATAGAAAATGCATTATTTAGTCAATTGTTTAATGTTGGAAAACATATGAAA 2222
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2101 TATCATTTTATAGAAAATGCATTATTTAGTCAATTGTTTAATGTTGGAAAACATATGAAA 2160
Qy 2223 TATAAATTATCTGAATATTAGATGCTCTGAGAAATTGAATGTACCTTATTTAAAAGATTT 2282
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2161 TATAAATTATCTGAATATTAGATGCTCTGAGAAATTGAATGTACCTTATTTAAAAGATTT 2220
Qy 2283 TATGGTTTTATAACTATATAAATGACATTATTAAAGTTTTCAAATTATTTTTTAAAAAAA 2342
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2221 TATGGTTTTATAACTATATAAATGACATTATTAAAGTTTTCAAATTATTTTTTAAAAAAA 2280
Qy 2343 AA 2344
||
Db 2281 AA 2282
The teachings of Ren et al. and Liu et al. are relied upon as detailed above. However, neither Ren et al., Liu et al. nor Nycz et al. teach the cell is an osteoblast or an osteocyte (as in claim 16).
Before the effective filing date of the claimed invention, Hofbauer et al. assessed OPG mRNA expression and protein secretion in human osteoblastic lineage cells. Hofbauer teaches 1,25-Dihydroxyvitamin D3(10-7M) increased OPG mRNA levels by 90 and 50% in a fetal osteoblastic cell line (hFOB) and normal trabecular osteoblastic cells (hOB) cells (as in claim 16), respectively, but did not affect OPG mRNA levels in a marrow stromal preosteoblastic (hMS) cell line. Interleukin (IL)-1β (5 x 10-9M), tumor necrosis factor (TNF)-α (9 x 10-9M), and bone morphogenetic protein (BMP)-2 (100 ng/ml) also increased OPG mRNA levels in hFOB cells by 4-, 6-, and 4-fold, respectively. Treatment with 1,25-dihydroxyvitamin D3, IL-1β, TNF-α, and BMP-2 increased OPG protein production by hFOB cells by 60, 390, 300, and 80%, respectively (P< 0.001). Because it is expressed in various types of human osteoblastic cells, and is stimulated by vitamin D, BMP-2 and cytokines, OPG may be an important paracrine modulator of bone remodeling (Abstract; paragraph bridging Col. 1 and Col. 2 of Pg. 780).
Given the teachings of each of these references, a kit (as in claim 44) comprising instructions of using the claimed composition would have been prima facie obvious.
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. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Ren et al., wherein Ren teaches bone healing in a rabbit cranial defect model, one of ordinary skill in the art would have found it prima facie obvious to include the teachings of Liu et al. who teach therapeutic use of OPG gene-modified BMSCs in a critical sized mandibular bone defect model. That is, one of ordinary skill in the art would have found it prima facie obvious to seed the OPG gene-modified BMSCs of Liu et al. on the mineralized collagen glycosaminoglycan (MC-GAG) scaffold of Ren et al. for the purposes of treating a bone defect model.
Further, one of ordinary skill in the art would have found it prima facie obvious to substitute the BMSCs for the osteoblasts of Hofbauer in order to determine the therapeutic ability of the osteoblasts to treat the bone defect. The skilled artisan would have found it prima facie obvious to do so because Hofbauer teaches normal trabecular osteoblastic cells can be stimulated to produce OPG. Thus, the skilled artisan would have found it obvious to compare the therapeutic ability of the OPG gene-modified BMSCs and OPG gene-modified hOBs in the bone defect model.
In addition, one of ordinary skill in the art would have found it prima facie obvious to substitute the OPG gene of Liu et al. with the OPG gene of Nycz et al. in order to compare the therapeutic ability of the OPG of Liu and the OPG of Nycz in treating the bone defect.
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,
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Ren et al. (Biomaterials. 2016 May:89:67-78., previously cited) in view of Liu et al. (Acta Biomater. 2016 Sep 15:42:378-388. previously cited), Nycz, J. (PgPub US20060039949A1, Published 2/23/2006) and Hofbauer et al. (Biochem Biophys Res Commun. 1998 Sep 29;250(3):776-81. previously cited) as applied to claims 1, 9-12, 16-17, 19-22, 28, 30-31, 33 and 44-45 and further in view of Haaing et al. (WO200264782A2, Published 8/22/2002).
The teachings of Ren et al., Liu et al., Nycz, J. and Hofbauer et al. are relied upon as detailed above. However, none of these references teach the OPG fragment is encoded by a nucleic acid consisting of a sequence at least 95% identical to the polynucleotide encoding SEQ ID NO: 2 over the length of the fragment.
However, before the effective filing date of the claimed invention, Haaing et al. taught a Macaca fascicularis OPG encoded by SEQ ID NO: 2. Note that SEQ ID NO: 2 of Haaing is 98.8% identical to the polynucleotide encoding SEQ ID NO: 2 over the length of the fragment (as in claim 32).
RESULT 3
BFM82118
ID BFM82118 standard; protein; 428 AA.
XX
AC BFM82118;
XX
DT 20-SEP-2018 (first entry)
XX
DE Macaca fascicularis OPG, SEQ 2.
XX
KW OPG protein; Osteoclast differentiation factor ligand;
KW alphavirus infection; analgesic; anti-hiv; antiarteriosclerotic;
KW antiarthritic; antibody therapy; antidiabetic; antiinflammatory;
KW antilipemic; antimicrobial-gen.; antiparasitic; apoptosis stimulation;
KW arthralgia; arthritis; atherosclerosis; autoimmune disease; bone disease;
KW bone resorption; breast tumor; calcification; cancer; cardiant;
KW cardiovascular disease; cardiovascular-gen.; cerebroprotective;
KW cerebrovascular disease; chronic obstructive pulmonary disease;
KW connective tissue disease; coronary artery disease; cytostatic;
KW diabetes mellitus; endocrine-gen.; fibrosis; gastrointestinal-gen.;
KW hiv infection; hypertension; hypotensive;
KW idiopathic pulmonary arterial hypertension; immune modulation;
KW immunosuppressive; infectious disease; metabolic syndrome x;
KW metabolic-gen.; multiple myeloma; musculoskeletal-gen.; oral-dental-gen.;
KW osteopathic; osteoporosis; pagets bone disease; periodontal disease;
KW peripheral vascular disease; plasmodium falciparum infection;
KW postmenopausal osteoporosis; prophylactic to disease; prostate tumor;
KW protein inhibition; protein interaction; pulmonary artery hypertension;
KW pulmonary fibrosis; pulmonary hypertension; renal fibrosis;
KW resistant hypertension; respiratory-gen.; rheumatoid arthritis;
KW therapeutic; vasotropic; virucide; vulnerary.
XX
OS Macaca fascicularis.
XX
CC PN WO2018138297-A1.
XX
CC PD 02-AUG-2018.
XX
CC PF 26-JAN-2018; 2018WO-EP052017.
XX
PR 27-JAN-2017; 2017GB-00001416.
PR 16-OCT-2017; 2017GB-00017006.
XX
CC PA (KYMA-) KYMAB LTD.
XX
CC PI De Abreu Carvalho J, Holmes S, Lawrie A;
XX
DR WPI; 2018-60409J/55.
DR GENBANK; EHH64388.1.
XX
CC PT Antibody or fragment specifically binds to human osteoprotegerin (hOPG)
CC PT comprises certain amino acid sequences, and inhibits such as neutralizes
CC PT interaction of hOPG with human RANKL (hRANKL) and/or human TRAIL
CC PT (hTRAIL).
XX
CC PS Claim 14; SEQ ID NO 2; 191pp; English.
XX
CC The present invention relates to a novel antibody or its fragment, useful
CC for treating or preventing human osteoprotegerin (hOPG)-mediated disease
CC or condition in a subject. The antibody or its fragment specifically
CC binds to a hOPG of SEQ ID NO: 1 (see BFM82117) and inhibits or
CC neutralizes the interaction of the hOPG with human receptor activator of
CC nuclear factor kappa B (NFkB) ligand (hRANKL) and/or human tumor necrosis
CC factor (TNF) related apoptosis inducing-ligand (hTRAIL). The antibody
CC comprises a heavy chain variable region (VH) and light chain variable
CC region (VL) with their corresponding complementarity determining regions
CC (CDRs). The invention further claims: (1) a multispecific (bispecific)
CC antibody or fusion protein comprising the antibody or its fragment; (2) a
CC method for treating or preventing hOPG-mediated disease or condition by
CC administering the antibody or its fragment to the subject; (3) a
CC pharmaceutical composition or a kit comprising the antibody or its
CC fragment; (4) a method for modulating TRAIL/OPG and/or RANKL/OPG
CC interaction in a patient by adminitering an efective amount of the
CC antibody or its fragment; (5) a method for inhibiting OPG activity in a
CC patient; (6) a nucleic acid encoding VH, VL, heavy chain, light chain,
CC and/or CDRH3 of the antibody or its fragment; (7) a vector comprising the
CC nucleic acid; and (8) a host comprising the nucleic acid. The antibody is
CC useful for treating or preventing hOPG-mediated disease or condition such
CC as hypertension, cancer, bone-related disorders, fibrotic diseases and
CC disorders, chronic obstructive pulmonary disease (COPD), infectious
CC diseases and autoimmune disorders; such as systemic hypertension,
CC resistant hypertension, pulmonary hypertension (PH), pulmonary arterial
CC hypertension (PAH) (idiopathic pulmonary arterial hypertension (IPAH),
CC hereditary pulmonary arterial hypertension (hPAH) and/or associative
CC pulmonary arterial hypertension (APAH)), prostate cancer, breast cancer,
CC multiple myeloma, tumor-induced bone disease, kidney fibrosis, lung
CC fibrosis and connective tissue fibrosis and diseases, COPD, malaria, HIV-
CC associated cardiovascular disease, HIV-associated bone loss, persistent
CC arthralgia following alphavirus infection, Paget's disease, osteoporosis
CC (postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and
CC senile osteoporosis), arthritis, rheumatoid arthritis, metabolic
CC syndrome, atherosclerosis, diabetes, vascular calcification, metastatic
CC bone disease, periodontal disease, cardiovascular disease, coronary
CC artery disease, cerebrovascular disease, and peripheral vascular disease,
CC where hypertension is pulmonary hypertension. The antibody or its
CC fragment can enhance TRAIL-mediated apoptosis. The present sequence is a
CC Macaca fascicularis OPG, where the OPG activity is inhibited by the
CC antibody or its fragment for treating or preventing hOPG-mediated disease
CC or condition in a subject. Note: SEQ ID NO: 17, SEQ ID NO: 37, SEQ ID NO:
CC 57, SEQ ID NO: 77, and SEQ ID NO: 97 shown in sequence listing is not
CC included as a part of Geneseq Indexing, as the sequence does not fit the
CC Geneseq selection criteria.
XX
SQ Sequence 428 AA;
Query Match 98.5%; Score 2300; Length 428;
Best Local Similarity 98.8%;
Matches 423; Conservative 2; Mismatches 3; Indels 0; Gaps 0;
Qy 1 MSARAAETHRSARPAAASKPLRFPGTTMNKLLCCALVFLDISIKWTTQETFPPKYLHYDE 60
||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||:
Db 1 MSARAAETHRSARPAAASKRLRFPGTTMNKLLCCALVFLDISIKWTTQETFPPKYLHYDQ 60
Qy 61 ETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHTSDECLYCSPVCKELQYV 120
|||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||
Db 61 ETSHQLLCDKCPPGTYLKQHCTAKRKTVCAPCPDHYYTDSWHTSDECLYCSPVCKELQYV 120
Qy 121 KQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTVCKRCPDGFFSNE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTVCKRCPDGFFSNE 180
Qy 181 TSSKAPCRKHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTLCEEAFFRFAVPT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TSSKAPCRKHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTLCEEAFFRFAVPT 240
Qy 241 KFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQLLKLWKHQNKDQDIVKKIIQD 300
|||||||||||||||||||||||||||||:||||||||||||||||||||||||||||||
Db 241 KFTPNWLSVLVDNLPGTKVNAESVERIKRRHSSQEQTFQLLKLWKHQNKDQDIVKKIIQD 300
Qy 301 IDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKPSDQILKLLSLWR 360
|||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||
Db 301 IDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTTKACKPSDQILKLLSLWR 360
Qy 361 IKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLYQKLFLEMIGNQV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 IKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLYQKLFLEMIGNQV 420
Qy 421 QSVKISCL 428
||||||||
Db 421 QSVKISCL 428
When taken with the teachings of Ren et al., Liu et al., Nycz, J. and Hofbauer et al., one of ordinary skill in the art would have found it prima facie obvious to substitute the human OPG fragment of Nycz for the macaca fascicularis OPG fragment of Haaing. A reasonable expectation is present here as both Ren’s and Nycz’s are drawn to primate OPGs. Insofar as humans share approximately 95%+ DNA with monkeys, a reasonable expectation in success is present. Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Applicant’s Arguments/Response to Arguments
In the interest of compact prosecution, and to the extent that they are relevant to the prior art rejection above, Applicant’s arguments are addressed below.
Applicant argues: Applicant respectfully submits that Boyle does not teach or disclose a OPG fragment consisting of a polypeptide at least 95% identical to SEQ ID NO: 2 over the length of the fragment, or a OPG fragment that is encoded by a nucleic acid that is at least 95% identical to a polynucleotide that encodes SEQ ID NO: 2.
In Response: Examiner agrees that the cited art did not teach disclose a OPG fragment consisting of a polypeptide at least 95% identical to SEQ ID NO: 2 over the length of the fragment, or a OPG fragment that is encoded by a nucleic acid that is at least 95% identical to a polynucleotide that encodes SEQ ID NO: 2. Accordingly, the rejection was withdrawn. However, note that Nycz has been cited for teaching a OPG fragment is encoded by a nucleic acid, wherein the nucleic acid consists of a nucleic acid that is at least 90% identical to the polynucleotide of SEQ ID NO: 1.
Applicant argues: The distinct biological responses of MC-GAG and HA scaffolds are attributable to their physicochemical differences. MC-GAG, as demonstrated in Ren, is characterized by a calcium: phosphate ratio of 1: 1, corresponding to a brushite mineral phase. See Specification para. [0215]. This is distinct from a HA scaffold, which has a calcium: phosphate ratio of 5 :3 .1 Additionally, the porosity and stiffness of MC-GAG significantly differ from HA scaffolds. The HA scaffolds of Liu have a porosity of 60% and> 2 MPa. See Liu p. 381 right column. In contrast, the MC-GAG scaffolds of Ren have a porosity of 85±3% and compressive modulus< 0.5 MPa. See Ren p. 68 left column. Ren also discloses that MC-GAG is a biodegradable, ion releasing matrix that up-regulates endogenous BMP signaling. See Ren at p. 68. In contrast, a person of ordinary skill in the art would understand HA scaffold has low biodegradability and does not up-regulate BMP signaling.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. In Applicant’s previous arguments, Applicant argued that one of ordinary skill in the art would not assume with any reasonable expectation of success that the HA scaffold of Liu would be interchangeable with or predictive of success of a MC-GAG scaffold in the composition, as HA and MC-GAG have different properties. Examiner maintains that this an opinion of counsel. Nevertheless, Examiner notes that the claims are drawn to a composition or a method of preparing the composition. There are no method claims that require an effect. For example, there are no claimed methods of treating with the composition. Thus, it is unclear how Applicant’s argument regarding interchangeability is relevant. Moreover, the intent of the comparison between the scaffolds of Ren and Liu are unclear as these scaffolds were made by different processes. Therefore, it is reasonable to conclude that the characteristics would be different.
With respect to Applicant’s argument regarding the HA scaffold not upregulating BMP signaling, Examiner cites Suto et al. (Arch Oral Biol. 2013 Aug;58(8):1021-8.;see attached). Suto investigated the effect of nano-HA on BMP-2 expression in human PDL cells. Real time PCR analysis revealed that the expression of BMP-2 increased upon stimulation with nano-HA in dose- and time-dependent manners. An immunofluorescence assay demonstrated the synthesis of BMP-2 proteins. Concentrations of Ca(2+) as well as phosphate (Pi) in culture supernatants were unchanged, suggesting that nano-HA functioned as a nanoparticle rather than as a possible source for releasing Ca(2+) and/or Pi extracellularly (Abstract).
Applicant argues: Applicant respectfully submits that the unexpected synergistic effects of MC-GAG and the OPG fragment provided in the present application inherently flow from the claimed composition. Example 1 and FIG. 7B in the present application demonstrates that the combination of MC-GAG and OPG-expressing MSCs yield above 2-fold increase in mineralized volume compared to the combination of MC-GAG and unmodified MSCs.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. MPEP 716.02 (a) teaches a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). In this regard, Applicant has not shown that the results were greater than those which would have been expected from the prior art to an unobvious extent. Grundt et al. (attached herewith) measured in vitro mineralization in response to OPG treatment. Grundt teaches as expected (Examiner’s emphasis) from the OPG-dependent increase in osteoblastic ALP activity we found that OPG also increased matrix mineralization by HOC. Therefore, Grundt notes that OPG may shift the balance of bone resorption and bone formation towards bone formation not only by inhibiting bone resorption but also by enhancing osteoid mineralization (Pg. 554, Col. 1, para. 2).
As such, Examiner does not agree that the 2-fold increase found in the present application was unexpected.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632