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 .
DETAILED ACTION
Response to Amendment
Status of the Claims
Receipt of Applicant’s response, filed 01 March 2023 has been entered.
Claims 1-16, and 18-25 remain pending in the application.
Claims 1-3, 5, 6, 18, and 19 are amended.
Claim 17 is cancelled.
Claims 4, 7-9 and 13 are withdrawn from further consideration by the examiner, pursuant to 37 CFR 1.142(b), as being drawn to a non-elected species. Claims 4 and 7 require species alternative to etanercept, claims 8 and 9 require stem cells instead of the elected anti-inflammatory composition and claim 13 requires an alternative species to the elected TNF-alpha of target.
Claims 1-3, 5, 6, 10-12, 14-16, and 18-25 are under consideration to the extent of the elected species, i.e., an anti-inflammatory composition comprising etanercept as the administered composition, TNF-alpha as the modified fibroblast target, skin and adipose fibroblast as the fibroblast source and inflammatory cytokines as the association of disc inflammation.
Rejections Withdrawn
Rejections Pursuant to 35 USC § 112
The rejections of claims 2, 3, 5 and 6 pursuant to 35 U.S.C. 112(b) set forth in the Non-Final Office Action mailed 09 May 2025 are hereby withdrawn in light of applicants amendment of the claims.
Rejections Pursuant to 35 USC § 101
The rejection of claims 1-3, 5, 6, and 16 under 35 U.S.C. 101 is withdrawn in light of applicant’s amendment of the claims.
Rejections Pursuant to 35 USC § 103
The rejection of claims 1-3, 5, 6, 10, 11 and 14-25 under 35 U.S.C. 103 as being unpatentable over O’Heeron et al. (US 2018/0195044, published 12 Jul 2018, listed in IDS filed 14 June 2022) in view of DiMauro et al. (US 2007/0237777, published 11 Oct 2007) is withdrawn in light of applicant’s amendment of the claims, and in favor of the new grounds of rejection set forth below.
The rejection of claim 12 under 35 U.S.C. 103 as being unpatentable over O’Heeron et al. (US 2018/0195044, published 12 Jul 2018, listed in IDS filed 14 June 2022) in view of DiMauro et al. (US 2007/0237777, published 11 Oct 2007) as applied to claims 1-3, 5, 6, 10, 11, 14-25 and further in view of Chen et. al. (Laryngoscope. 2010 September ; 120(9): 1819–1825) is withdrawn in light of applicant’s amendment of the claims, and in favor of the new grounds of rejection set forth below.
New Grounds of Rejections
Claim Rejections - 35 USC § 103
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.
Claims 1-3, 5, 6, 10, 11, 14-16, and 18-25 are rejected under 35 U.S.C. 103 as being unpatentable over O’Heeron et al. (US 2018/0195044, published 12 Jul 2018, listed in IDS filed 14 June 2022) in view of DiMauro et al. (US 2007/0237777, published 11 Oct 2007), O’Heeron et al. (WO 2018/195308, published 25 Oct 2018, referred to as O’Heeron308) and Weber et al. (WO 2011/064354, published 03 Jun 2011).
O’Heeron teaches methods with modified fibroblast cells for therapy in discs ([0018]). O’Heeron teaches that the methods result in an increased disc matrix, including by increasing synthesis in the disc, by decreasing degradation and/or by preventing matrix loss by inhibiting degradative enzymes ([0019]). O’Heeron teaches augmenting the efficacy of the fibroblasts for regeneration of cells and/or tissues to enhance the efficacy of the fibroblasts for regeneration of the cells and/or tissues ([0020]) O’Heeron teaches that the fibroblasts are for use in individuals with degenerative disc disease ([0036], [0032]) and that the methods are for degenerative disc repair ([0017]). O’Heeron teaches the use of fibroblasts for local delivery (such as by intra-disc injections) in individuals with degenerative disc disease ([0036]) and thus, it is obvious to administer fibroblasts as part of a therapy for degenerative disc disease and that the administration is in a disc.
O’Heeron teaches various therapeutic activities of the fibroblasts that may be enhanced including anti-inflammatory activity and angiogenic properties ([0018]) and that fibroblast cells may be genetically modified to upregulate expression of angiogenic stimuli or anti-inflammatory activities ([0054]). O’Heeron specifically teaches that gene inhibitory technologies may be used with cells that are used for treatment of lower back pain by blocking the ability of cells to express inflammatory proteins such as TNF-alpha ([0054]), rendering obvious instant claims 10 and 11. O’Heeron teaches that the regeneration of cells or tissue by the fibroblasts comprises angiogenesis ([0020]). Regarding claim 14, as it is taught that the fibroblasts may be delivered intradiscally, as described above, it is thus obvious that the fibroblast would need to be suitable for intradiscal environment, rendering obvious the “cultured in a manner to adapt the fibroblasts to the intradiscal environment.” Regarding claim 18, O’Heeron teaches that an important process in disc degermation is the change of differentiated chondrocyte phenotype in the nucleus pulposus into a more fibrotic phenotype ([0012]), rendering it obvious that the disc comprises nucleus pulposus. O’Heeron further teaches that the injection may occur with platelet plasma and that it may be administered to the nucleus ([0049]), rendering it obvious to administer to the nucleus pulposus. Regarding claim 15, O’Heeron teaches that the fibroblasts may be exposed to hypoxia ([0055]). Regarding claim 16, O’Heeron teaches that the fibroblasts may be derived from tissues comprising skin and adipose ([0059]). O’Heeron further teaches that the fibroblasts may be co-administered with one or more agents for enhancing the fibroblast activities ([0033]).
O’Heeron does not teach administering an additional anti-inflammatory composition comprising etanercept (the elected species) or the administration of exosomes and apoptotic bodies (claim 1) or the processes that occur from the administration of the anti-inflammatory (claim 19-25). These deficiencies are made up for in the teachings of DiMauro, O’Heeron308.
DiMauro teaches treating degenerative disc disease ([0026]) by a method of treating an intervertebral disc in which a high specificity inhibitor of a pro-inflammatory cytokine is administered transdiscally ([0028]). DiMauro teaches that many cytokines such as TNF-alpha play a role in mediating the degradation of the extracellular matrix (ECM) of the nucleus pulposus and thus injecting an antagonist or inhibitor of these proteins directly into the disc prevents the target cytokine from inducing any further ECM degradation and thus the transdiscal administration of the cytokine antagonist arrests the aging process of the degenerating disc ([0030]). DiMauro teaches that the high specificity cytokine antagonist may be administered with other therapeutic agents ([0033]) and specifically with agents that may at least partially repair the disc ([0102]) DiMauro teaches injection into the nucleus pulposus of a degenerating disc ([0040]). DiMauro teaches that the antagonist is capable of inhibiting a pro-inflammatory cytokine such as TNF-alpha ([0047]) and that etanercept is a TNF antagonist that inhibits the TNF by binding to solubilized TNF ([0049]-[0051]). DiMauro further teaches inhibiting cytokines by binding to a natural receptor of the target cytokine ([0048]). Thus, DiMauro renders obvious suppressing activation of TNF-alpha receptors and inhibiting activity of TNF-alpha as in instant claims 2, 5 and 6. As TNF is a pro-inflammatory cytokine and etanercept is a TNF antagonist, the administration of the etanercept would necessarily reduce inflammation as recited in claim 19 and the inflammation is thus from an inflammatory cytokine (claim 20) such as TNF-alpha (claim 25).
O’Heeron308 teaches the stimulation of angiogenesis by administering fibroblast derived exosomes (title, [0007]) and that the exosomes are utilized to augment endogenous regenerative processes such as angiogenesis (abstract, [0006]). O’Heeron308 teaches therapy with exosomes for a medical condition in which stimulation of angiogenesis would be therapeutic ([0020]). O’Heeron308 teaches that the fibroblast exosomes stimulate VEGF production (Example 1 [0045]).
Weber teaches that apoptotic bodies induce proliferation and differentiation of endothelial progenitor cells, indicating a connection with angiogenesis, and can also be engulfed by phagocytes, triggering secretion of cytokines of growth factors such as VEGF (page 2 lines 27-30). Weber teaches that apoptotic bodies and the components such as miR-126 present in apoptotic bodies are able to promote postnatal tissue repair and are a treatment for tissue damage (page 3 line 32 – page 4 line 3, lines 21-30) and that miR-126 is known for modulating angiogenesis (page 3 lines 25-27).
Therefore, it would have been prima facie obvious to one of ordinary skill in the
art, before the effective filing date of the claimed invention to have administered modified fibroblast cells along with exosomes, apoptotic bodies and the TNF antagonist etanercept as part of a method of treating degenerative disc disease. Administering modified fibroblasts for disc repair in degenerative discs, is known from the teachings of O’Heeron and inhibiting pro-inflammatory cytokines such as TNF-alpha with the antagonist etanercept as part of treating degenerative disc disease is known from the teachings of DiMauro. The fibroblast therapy of O’Heeron is used to promote angiogenesis, and fibroblast derived exosomes are known to stimulate angiogenesis and be used in therapies needing stimulation of angiogenesis, as taught by O’Heeron308 and apoptotic bodies are also known to carry components such as miR-126 which modulates angiogenesis, as taught by Weber. Thus, it would have been obvious to have administered modified fibroblasts along with etanercept, exosomes and apoptotic bodies as part of a method of treating degenerative disc disease and one would have a reasonable expectation of success as etanercept and fibroblast administration are both known for the same purpose of treating degenerative disc disease and the fibroblast disc therapy works to promote angiogenesis, which exosomes and apoptotic bodies are also both known to be associated with angiogenesis modulation. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Regarding the preamble of the claim that the method is for “increasing the efficacy of a fibroblast cell therapy,” the examiner notes that while the art does not explicitly teach etanercept, exosomes or apoptotic bodies as increasing the efficacy of a fibroblast cell therapy, this increase in efficacy would be a natural result of administering etanercept, exosomes, and apoptotic bodies and fibroblast therapy as described above. The preamble of “increasing the efficacy” does not distinguish the instant method from the method steps rendered obvious from the prior art, namely administering both etanercept and modified fibroblasts for treating degenerative disc disease.
Regarding claims 21-24, it is noted that the limitations of these claims describe natural processes that occur from the inflammatory cytokine and do not limit the active administration steps of the claim. Inducing STAT3 activation in monocytes, activating at least one inhibitor of kappa B kinase and activating NF-kappa B describe functional parameters that the inflammatory cytokine may engage in but these do not limit the administration steps of the instant method. It is obvious to administer exosomes, apoptotic bodies, etanercept and modified fibroblasts and it is known that etanercept is an antagonist to the inflammatory cytokine TNF-alpha, as described above, and the activation processes that the cytokine engages in does not change the obvious method steps.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references.
Response to Arguments
Applicant's arguments filed 01 March 2023 have been fully considered but they are not persuasive. Applicant states that the applied references do not disclose exosomes and apoptotic bodies (page 7 of remarks). The examiner notes that the rejection has been updated to account for the additional administration of exosomes and apoptotic bodies.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over O’Heeron et al. (US 2018/0195044, published 12 Jul 2018, listed in IDS filed 14 June 2022) in view of DiMauro et al. (US 2007/0237777, published 11 Oct 2007), O’Heeron et al. (WO 2018/195308, published 25 Oct 2018, referred to as O’Heeron308) and Weber et al. (WO 2011/064354, published 03 Jun 2011) as applied to claims 1-3, 5, 6, 10, 11, 14-16 and 18-25 above and further in view of Chen et. al. (Laryngoscope. 2010 September ; 120(9): 1819–1825).
The teachings of O’Heeron, DiMauro, O’Heeron308 and Weber are described supra.
O’Heeron further teaches that the enhancement of fibroblasts may come from contacting the fibroblasts with one or more biologically active substances and or culturing fibroblasts under conditions to enhance efficacy of the fibroblasts for regeneration of the cells and/or tissues ([0020]). O’Heeron teaches that the fibroblasts may be cultured with cytokines and growth factors ([0033]) and that the growth factor may include tumor necrosis factor (TNF) ([0030]).
O’Heeron, DiMauro, O’Heeron308 and Weber do not teach contacting with the specific tumor necrosis factor of TNF-alpha as in claim 12. This deficiency is made up for in the teachings of Chen.
Chen teaches that TNF-alpha is known to stimulate fibroblast proliferation and release growth factors (page 2 first paragraph).
Therefore, it would have been prima facie obvious to one of ordinary skill in the
art, before the effective filing date of the claimed invention to have contacted the fibroblasts with TNF-alpha to stimulate fibroblast proliferation and enhance the efficacy of the fibroblasts for regeneration of cells and or tissues. Contacting and culturing fibroblasts with active substances such as cytokine growth factors such as tumor necrosis factor is known from the teachings of O’Heeron. TNF-alpha is not specifically taught as the TNF for contacting the fibroblasts by O’Heeron, but TNF-alpha is known to stimulate fibroblast proliferation and release growth factors from the teachings of Chen, thereby rendering it obvious to use the alpha TNF in the contacting method. One would have a reasonable expectation of success as TNF is already taught as a possible agent for contacting the fibroblasts and TNF-alpha is specifically known for fibroblast proliferation. Regarding the limitation of the claim that contacting the TNF-alpha is “to prevent or reduce expression or secretion of one or more inflammatory cytokines,” this limitation does not alter the active step of the claim which is to contact the fibroblast cell therapy with TNF-alpha. It is obvious to contact the fibroblasts of the therapy with TNF-alpha to enhance efficacy of the fibroblasts for regeneration of the cells and/or tissue, rendering obvious the contacting step of the claim.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references.
Conclusion
No claims are 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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/E.C.M./Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner., Art Unit 1600