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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10 Apr 2026 has been entered.
Response to Amendment
Status of the Claims
Receipt of Applicant’s response, filed 10 Apr 2026 has been entered.
Claims 1-3, 5, 10-13, 15, 16, and 19-26 remain pending in the application.
Claims 1-3, 5, 10-13, 15, 16, and 19 are amended.
Claims 4, 6-9, 14, 17, and 18 are cancelled.
Claim 26 is new.
Claims 13 and 26 are withdrawn from further consideration by the examiner, pursuant to 37 CFR 1.142(b), as being drawn to a non-elected species. Claim 26 requires administering a combination of etanercept and stem cells which is alternative to the elected administration of etanercept and claim 13 requires an alternative species to the elected target of TNF-alpha.
Claims 1-3, 5, 10-12, 15, 16, and 19-25 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Rejections Withdrawn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 § 103
The rejection of claims 1-3, 5, 6, 10, 11, 14-16, and 18-25 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), 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). is withdrawn in light of applicant’s amendment of the claims, and in favor of the new grounds of rejection set forth below.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), 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 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 Objections/Rejections
Claim Objections
Claim 15 is objected to because of the following informalities: The language of claim 15 would be improved with “the” placed before “fibroblasts.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3 depends from claim 2 and recites that the administering of step (a) occurs after the administering of (b) or at the same time as (b). Claim 2, however, requires that (a) occurs before (b). Claim 3 thus does not further limit claim 2 but instead broadens the scope by requiring that (a) is after or at the same time as (b) instead of before (b) as is required in claim 2.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 10, 11, 15, 16, and 19-25 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 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 teaches that an important process in disc degeneration is the change of differentiated chondrocyte phenotype in the nucleus pulposus into a more fibrotic phenotype ([0012], [0006]) and teaches that the injection may occur with platelet plasma and that it may be administered to the nucleus ([0049]), rendering it obvious to administer fibroblasts intradiscally to the nucleus pulposus as part of a therapy for degenerative disc disease.
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 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 teaches that the fibroblasts are anti-inflammatory and inhibition of inflammatory cytokines such as TNF and interleukins including IL-1 ([0018], [0033], [0057]), rendering obvious claims 19, 20 and 25. 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 explicitly teach administering etanercept before or after the fibroblasts (claims 2 and 3) or the processes that occur from specific inflammatory cytokines (claims 21-24). These deficiencies are made up for in the teachings of DiMauro.
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 that the antagonist may be administered with a second therapeutic simultaneously, first, or second ([0104]), rendering obvious the administration sequences as in claims 2 and 3. DiMauro teaches injection into the nucleus pulposus of a degenerating disc ([0040]), further rendering obvious injection into the nucleus pulposus. 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 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).
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 intradiscally administered modified fibroblast cells along with 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. Thus, it would have been obvious to have administered modified fibroblasts along with etanercept 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. "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 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 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 10 Apr 2026 have been fully considered but they are not persuasive. Applicant argues that the art teaches away from or is unpredictable with etanercept for disc regeneration (page 7 of remarks part A). Applicant points to alternative art of Cohen which demonstrates that etanercept administration alone fails to regenerate disc tissue and treat degenerative disc disease (page 7 of remarks). Applicant argues that applied art does not teach administering the combination of fibroblasts and etanercept (page 7 of remarks part B). Applicant argues that DiMauro does not provide guidance to select etanercept or that the combination of etanercept and fibroblasts would be expected to succeed at treating DDD (page 8 of remarks). Applicant notes that the example of DiMauro was directed to administering infliximab (page 8 of remarks). Applicant points to data in the 1.132 declaration filed (10 Apr 2026) highlighting that administration of etanercept alone did not regenerate disc tissue, administration of fibroblasts resulted in about 300% aggrecan production after 12 weeks and the combination of etanercept and fibroblasts resulted in about 900% aggrecan production after 12 weeks (page 8 of remarks, Exhibit 2 of declaration). Applicant argues that result from the combination is more than additive and would not have been expected from the prior art.
The examiner does not find these arguments persuasive as the administration of etanercept and fibroblasts intradiscally is obvious form the prior art as described in the rejection above. The examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the administration of 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. As administering etanercept and fibroblasts are both known for treatment of degenerative disc disease it would have been obvious to one of ordinary skill in the art to administer a composition of etanercept and fibroblasts. The art does not criticize, discredit or discourage the administration of either compound and thus is not understood to teach away or lead to a lack of a reasonable expectation of success. Regarding the teaching of the alternative art of Cohen, while Cohen does suggest that a single low dose of intradiscal etanercept is not effective for treatment for chronic radicular or discogenic low back pain (conclusion of abstract), Cohen does not in any way rule out the whole concept of administering etanercept for disc degeneration. Cohen even describes their finding as not uniformly negative (page 103 right column) and as neutral (page 105) and notes that the administration of etanercept did not have any adverse effects (page 104 right column). Cohen further suggests the idea that alternative dosages and multiple injections may have led to pain relief or functional benefit (page 104 left column). Thus, the teachings of Cohen are not sufficient to lead one away from administration of etanercept.
While the art may not explicitly teach the combination of etanercept and fibroblasts, the administration of such a combination is obvious from the art. The examiner notes that the rejection was made under 35 U.S.C. 103 which requires that “a patent for a claimed invention may not be obtained… if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been prima facie 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.” “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR, 550 U.S. at ___, 82 USPQ2d at 1397. “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At, 82 USPQ2d at 1396. While the art may not provide a specific embodiment of the instantly claimed invention, the examiner maintains that the invention as claimed is nonetheless made obvious for the reasons described above. Further, the exemplification of infliximab by DiMauro instead of etanercept does not render the administration of etanercept as any less obvious as DiMauro clearly teaches etanercept as suitable for the invention (e.g. [0050]).
Regarding the data presented in Exhibit 2 of the declaration, the examiner does not find this sufficient to overcome the prima facie case of obviousness as the data is not commensurate in scope with the claims. The claims are currently broad in their scope as they are merely directed to a method of administering etanercept and fibroblasts intradiscally to the nucleus pulposus. The claims are not directed to any particular treatment, or subject group, or the enhancement of a fibroblast therapy. The data appears to be directed to a form of disc regeneration observed in rats but the claims are much broader in their application. Additionally, the data presented are much narrower in scope that what is covered by the currently claims. For instance, the data used a specific foreskin fibroblast whereas the claims are open to any fibroblast material. The data utilized 500,000 foreskin fibroblast administration and 2 mg/kg of etanercept twice a week but the claims do not require any limitations regarding dosing. As noted by the applicant and discussed above, the teachings of Cohen suggest a single low dose of etanercept as ineffective for treatment and thus there is an general understanding that the dosing would be an important variable as part of the administration. There is nothing currently provided that would lead to the expectation that the enhanced results for disc regeneration would be expected across any dosing regimen. Thus, the data is insufficient to overcome the prima facie case of obviousness presented in the rejection.
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), as applied to claims 1-3, 10, 11, 15, 16 and 19-25 above and further in view of Chen et. al. (Laryngoscope. 2010 September ; 120(9): 1819–1825).
The teachings of O’Heeron and DiMauro 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 and DiMauro 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.
Claim 5 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), as applied to claims 1-3, 10, 11, 15, 16 and 19-25 above and further in view of Olmarker et. al. (US 2008/0019964, published 24 Jan 2008).
The teachings of O’Heeron and DiMauro are described supra.
O’Heeron and DiMauro do not teach intravenous administration of etanercept. This deficiency is made up for in the teachings of Olmarker.
Olmarker teaches inhibiting the action of TNF-alpha for treating disorders in a subject by administering a TNF-alpha inhibitor such as etanercept ([0034], [0037]). Olmarker teaches various administration routes including intravenous administration ([0077], claims 35/38). Olmarker teaches administering etanercept intravenously as part of a method of treating a spinal disorder (claim 112) and for reducing the inflammation of neuronal tissue (claim 188).
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 the etanercept intravenously. It is obvious from O’Heeron and DiMauro to administer etanercept and fibroblasts as part of spinal related conditions and it is known from Olmarker that etanercept may be administered intravenously as part of methods of treating spinal disorders and reducing inflammation in neuronal tissue. Thus, it would have been obvious to one of ordinary skill in the art to administer etanercept intravenously as this is a known method of administering etanercept for spinal related conditions and merely represents using a method of administration known for use with etanercept.
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 claim is allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EDWIN C MITCHELL whose telephone number is (571)272-7007. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/EDWIN COLEMAN MITCHELL/Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600
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