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
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.
Response to Amendments
Applicant’s amendments and response filed May 11, 2026 have been received and entered into the case.
Status of the Claims
Claims 1-12, 14-18, 31, 34 and 36 are currently pending.
Claims 13, 19-30, 32, 33 and 35 are cancelled.
Claim 36 is new.
Claims 1-12, 14-18, 31, 34 and 36 have been considered on the merits.
Claim Rejections - 35 USC § 112 (a) written description (new matter)
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) for written description, are withdrawn due to Applicant’s arguments being found to be persuasive. See Remarks pg. 7 last para. to pg. 8 first para.
Claim Rejections - 35 USC § 112 (a) scope of enablement
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) for scope of enablement, are withdrawn due to Applicant’s arguments being found to be persuasive. See Remarks pg. 9 last para. to pg. 13 first para.
Claim Rejections - 35 USC § 112 (d)
The claim rejections under 35 USC § 112, (d) or fourth paragraph (pre-AIA ) have been withdrawn due claim amendments.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are revised due to amendment. New claim rejections under 35 USC § 103 have been added to address new claim 36.
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 1-12, 14, 16, 18, 31, 34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Silverman et al. (US 2014/0286912 A1) (ref. of record) in view of Sakai et al. (US 2013/0078222 A1) (ref. of record), Wang et al. (Arthritis Research & Therapy, 2013) (ref. of record), Desnoyer et al. (US 7,687,460 B2) (ref. of record) and Erwin et al. (WO 2010/088775 A1) (ref. of record).
With respect to claims 1 and 34, Silverman teaches generating discogenic cell populations or intervertebral disc cells and providing the cells to restore or regenerate damaged, diseased or missing intervertebral discs of a subject (abstract and 0001). With respect to claims 1 and 34, Silverman teaches the discogenic cell populations may be from the subject or derived from an unrelated donor (abstract). With respect to claims 1, 2, 5, 10 and 34, Silverman teaches the disc tissue may include nucleus pulposus cells would include notochordal cells and small chondrocyte-like cells as defined as part of the nucleus pulposus in claim 2 and Silverman does not teach removal of any cell types (0047 and 0082). With respect to claim 34, Silverman teaches discogenic cell population includes fibroblasts (0082). In addition with respect to claims 1 and 34, Silverman teaches that the discogenic cells can be administered in conjunction with biologically active agents including cell culture media or conditioned medium derived from spinal disc, or cartilaginous tissue or discogenic cells (0086).
Silverman does not explicitly teach the nucleus pulposus cells include Tie2+ cells as recited in claims 1 and 34. However, Sakai teaches that the nucleus pulposus contains Tie2+ cells (abstract). Additionally, Sakai teaches a method of treating intervertebral disk disorders by administering intervertebral disk nucleus pulposus stem cells or progenitor cells which are positive for Tie2 (abstract, 0052 and 0061). Sakai further teaches the Tie2-positive cells are capable of differentiating into chondrocytes and possess self-renewable ability and multipotency in the intervertebral disk nucleus pulposus of mice and humans (0054 and 0137). Accordingly, at effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method taught by Silverman to include the providing of Tie2+ cells to a degenerate disc in an individual for the benefit of providing cells which are capable of differentiating into chondrocytes and possess self-renewable ability and multipotency in the intervertebral disk nucleus pulposus as taught by Sakai. Furthermore, it would have been obvious to one skilled in the art to have further modified the method taught by Silverman to include providing Tie2+ cells to the degenerated disc of an individual, since Tie2+ cells were known for such purpose and were known stem cells present in the nucleus pulposus as taught by Sakai. One of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Silverman to include the administration of Tie2+ cells, since Tie2+ are a known component of the nucleus pulposus and are known to be administered for disc repair as taught by Sakai.
By administering nucleus pulposus cells to the individual, the generation of chondrocytes or chondrocyte-like cells for an individual would inherently happen.
With respect to claim 3, Silverman teaches the cells can be administered in conjunction with biologically active agents (therapeutic agents) (0086). With respect to claim 4, Silverman teaches the biologically active agents may include lysates, soluble cell fractions, membrane-enriched cell fractions, proteins, growth factors (small molecules), hormones (small molecules), cell culture media or extracellular matrix (the cell lysates and cell fractions would contain nucleic acids, peptides, proteins and small molecules and cell culture media would contain peptides, proteins and small molecules) (0086). With respect to claim 5, Silverman teaches the composition contains fibroblast and nucleus pulposus cells (notochordal cells) and as explained above nucleus pulposus cells inherently contains Tie2+ cells (0082). With respect to claims 6 and 7, Silverman teaches the discogenic cells (includes fibroblast and nucleus pulposus cells (notochordal cells)) are grown and expanded ex vivo (modified ex vivo) (0075-0076). With respect to claims 8 and 9, Silverman teaches the cells (includes fibroblast and nucleus pulposus cells (notochordal cells)) may be grown under hypoxic conditions (low oxygen tension) (0060). With respect to claims 11 and 12, Silverman teaches the cell population (includes fibroblast and nucleus pulposus cells (notochordal cells)) express the gene product of Sox9 (0012). With respect to claim 14, Silverman teaches treating a damaged, diseased or missing intervertebral discs of a subject, the detection of the degenerated disc would have to have happen to be treated (abstract, 0001 and 0040-0042). Similarly, although Silverman does not explicitly teach the method where the degenerated disc is detected structurally or non-structurally as recited in claim 16, the detection of the degenerated disc would by a structurally or non-structurally method. With respect to claim 18, Silverman teaches the composition comprising fibroblasts and stem cells (0082). With respect to claim 36, Silverman teaches the composition where the discogenic cell population expresses the gene product of Sox 9 (0012)
Silverman does not teach the method further including the step of providing to a degenerated disc of an individual an effective amount of platelet-rich plasma (PRP) as recited in claim 1. However, Wang teaches treating intervertebral disc degeneration by administering PRP (abstract), reports that PRP can promote nucleus pulposus regeneration (pg. 5 last para.), and teaches PRP promotes intervertebral disc healing by releasing growth factors (abstract, pg. 1 last para., pg. 5 Col. 1 para. 3). Wang further teaches PRP contains antibacterial and bactericidal proteins that may influence the process of inflammatory response (pg. 5 Col. 1 para. 3). In further support, Silverman teaches that the discogenic cells can be administered with biologically active agents such as lysates, soluble cell fractions, membrane-enriched cell fractions, proteins, growth factors, hormones, cell culture media and extracellular matrix (0086). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would be motivated to modify the method of Silverman to include the step of further administering PRP to a subject with disc degeneration for the benefits of promoting nucleus pulposus regeneration, healing and an inflammatory response as taught by Wang. It would have been obvious to one of ordinary skill in the art to modify the method of Silverman to include an additional step of administering known beneficial compositions, such as PRP, in a method of treating a degenerated disc of individual by generating chondrocytes or chondrocyte-like cells in the disc, since Silverman teaches addition bioactive agents can be administered with the cells and Wang teaches the administration of PRP for the repair of degenerative discs. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Silverman to include the step of further administering PRP to a subject with disc degeneration, since PRP was well-known for the benefits of promoting nucleus pulposus regeneration as taught by Wang and Silverman teaches the method including the additional administration of bioactive agents.
Silverman does not teach the method further including the step of providing to a degenerated disc of an individual an effective amount of WNT1-inducible-signaling pathway protein 1 (WISP1) and/or WISP2 as recited in claim 1. However, Desnoyer teaches using WISP polypeptides in the treatment of degenerative cartilaginous disorders and various immune related conditions (Col. 1 lines 13-15). Desnoyer teaches a method of treating mammalian cartilage cells or tissue damaged from a degenerative cartilaginous disorder with an effective amount of WISP polypeptide where the WISP polypeptide is WISP-1 or WISP-2 (Col. 7 lines 50-65 and Col. 8 lines 35-56). Desnoyer further teaches that WISP-1 and WISP-2 polypeptides stimulate chondrocyte proliferation or differentiation (Col. 9 lines 2-15). In further support, Silverman teaches that the discogenic cells can be administered with biologically active agents such as lysates, soluble cell fractions, membrane-enriched cell fractions, proteins, growth factors, hormones, cell culture media and extracellular matrix (0086). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would be motivated to modify the method of Silverman to include the step of further administering WISP-1 and/or WISP-2 to a subject with disc degeneration for the benefits of promoting cartilage repair as taught by Desnoyer. It would have been obvious to one of ordinary skill in the art to modify the method of Silverman to include an additional step of administering other known beneficial agents, such as the factors WISP-1 and/or WISP-2, in a method of treating a degenerated disc of individual by generating chondrocytes or chondrocyte-like cells in the disc, since Silverman teaches additional bioactive agents can be administered with the cells and Desnoyer teaches the administration of WISP-1 and WISP-2 for the repair of degenerative cartilage and that the proteins promote chondrocyte proliferation and differentiation. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Silverman to include the step of further administering the factors WISP-1 and/or WISP-2 to a subject with disc degeneration, since WISP-1 and WISP-2 were known for their benefit of promoting cartilage regeneration as taught by Desnoyer and Silverman teaches the method including the additional administration of bioactive agents.
Silverman does not explicitly teach that the conditioned medium is from nucleus pulposus cells as recited in claims 1 and 34, or where the nucleus pulposus conditioned media is generated by exposing the nucleus pulposus cells to hypoxia as recited in claims 1 and 34. Additionally, Silverman does not teach explicitly teach administering a mixture generated in vitro comprising fibroblasts and nucleus pulposus conditioned media as recited in claim 34. However, Erwin teaches a similar method of inhibiting nucleus pulposus degeneration in a subject by administering to the subject or contacting nucleus pulposus (NP) cells of the subject with NP conditioned medium and an isolated cell population (0015-0018). Erwin further teaches producing a nucleus pulposus conditioned medium (NPCM) and teaches that the conditioned media is prepared by exposing the cells to an oxygen concentration between 1.5-10% (hypoxia) (0014 and 0031). Erwin teaches that nucleus pulposus and notochordal cells produce soluble factors that are useful for inhibiting inflammatory cytokine and death receptor signaling of NP cells (00120-00121). Erwin teaches that nucleus pulposus and notochordal cells produce soluble factors that are useful for inhibiting inflammatory cytokine and death receptor signaling of NP cells and is useful for inhibiting cell death and treating degenerative diseases (00120-00121 and 00127). In further support, Silverman teaches discogenic cell population includes fibroblasts (0082). In addition with respect to claims 1 and 34, Silverman teaches that the discogenic cells can be administered in conjunction with biologically active agents including cell culture media or conditioned medium derived from spinal disc, or cartilaginous tissue or discogenic cells (0086). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Silverman to
include the step of further administering nucleus pulposus conditioned media prepared by exposing nucleus pulpous cells and fibroblast cells to a subject with disc degeneration for the benefits of inhibiting inflammatory cytokine and death receptor signaling of NP cells, inhibiting cell death and treating degenerative discs as taught by Erwin. It would have been obvious to one of ordinary skill in the art to modify the method of Silverman to include an additional step of administering known beneficial compositions, such as nucleus pulposus conditioned media, in a method of treating a degenerated disc of individual by generating chondrocytes or chondrocyte-like cells in the disc, since Silverman teaches conditioned medium and fibroblasts can be administered and Erwin teaches the administration of nucleus pulposus conditioned media for the repair of degenerative discs. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Silverman to include the step of further administering nucleus pulposus conditioned media prepared by exposing nucleus pulpous cells and fibroblast cells to a subject with disc degeneration, since both were well-known for the benefits of promoting nucleus pulposus regeneration as taught by Erwin and Silverman teaches the method including the additional administration of fibroblasts. Additionally, it would have been obvious to one of ordinary skill in the art to mix the fibroblasts with the conditioned media and other components of the composition being administered to the subject. For instance, Silverman teaches that the discogenic cells can be administered in conjunction with biologically active agents including cell culture media or conditioned medium derived from spinal disc, or cartilaginous tissue or discogenic cells (0086).
Silverman does not teach the method comprising the step of providing to the disc one or more composition comprising an effective amount of transforming growth factor beta-1 (TGFB1) and connective tissue growth factor (CTGF) as recited in claim 31. However, Wang teaches treating intervertebral disc degeneration by administering growth factors and by administering PRP which contains the growth factors, TGFB1 and CTGF (abstract, pg. 1 last para. and Tables 1 and 2 and pg. 5 Col. 1 para. 3). Additionally, Wang teaches that many growth factors have been proven to be effective in reversing the degeneration of discs (abstract). In further support, Silverman teaches that the discogenic cells can be administered with biologically active agents such as lysates, soluble cell fractions, membrane-enriched cell fractions, proteins, growth factors, hormones, cell culture media and extracellular matrix (0086). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would be motivated to modify the method of Silverman to include the step of further administering TGFB1 and CTGF to a subject with disc degeneration for the benefits of promoting disc regeneration as taught by Wang. It would have been obvious to one of ordinary skill in the art to modify the method of Silverman to include an additional step of administering known beneficial agent, such as the growth factors TGFB1 and CTGF, in a method of treating a degenerated disc of individual by generating chondrocytes or chondrocyte-like cells in the disc, since Silverman teaches additional bioactive agents can be administered with the cells and Wang teaches the administration of growth factors and growth factor TGFB1 and CTGF-containing PRP for the repair of degenerative discs. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Silverman to include the step of further administering the growth factors TGFB1 and CTGF to a subject with disc degeneration, since the growth factors were known for their benefit of promoting nucleus pulposus regeneration as taught by Wang and Silverman teaches the method including the additional administration of bioactive agents.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 15 and 17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Silverman in view of Sakai, Wang, Desnoyer and Erwin (as applied to claims 1-12, 14, 16, 18, 31, 34 and 36 above), and further in view of Brayda-Bruno et al. (European Spine Journal, 2014) (ref. of record) and Omlor et al. (Spine, 2009)(ref. of record).
The teachings of Silverman, Sakai, Wang, Desnoyer and Erwin can be found in the previous rejection above.
None of Silverman, Sakai, Wang, Desnoyer or Erwin teach the method where the degenerated disc is detected by measuring the level of notochord cells in the nucleus pulposus of a disc in the individual suspected of being degenerated as recited in claim 15. Similarly, none of Silverman, Sakai, Wang, Desnoyer or Erwin teach the method where the degenerated disc is detected by non-structurally by biochemical or molecular means as recited in claim 17. However, Omlor teaches that disc degeneration is associated with changes in NP cell phenotype (pg. 2731 Col. 1 last para.). In addition, Omlor teaches that there is a decrease in notochordal cells in an animal model of disc degeneration and that the loss of NCs can serve as a marker for disc degeneration (abstract and pg. 2735 Col. 1 para. 1, and pg. 2738 para. 1). In further support, Brayda-Bruno teaches methods of detecting degenerated disc structurally by MRI (abstract) and by determining intradiscal pressure and chemical quantities (structural and non-structural detection) (pg. S318-S319 bridging para.). In addition, Brayda-Bruno teaches methods of detecting degenerated disc by measuring chemical quantities such as PG (proteoglycan) content (a biochemical and molecular means) (pg. S318-S319 bridging para.) and by measuring aggrecan concentration. Accordingly, at effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Silverman, Sakai, Wang, Desnoyer and Erwin to include additional methods of detecting degenerated discs in an individual. Furthermore, it would have been obvious to one skilled in the art to have further modified the method taught by the combined teachings of Silverman, Sakai, Wang, Desnoyer and Erwin to include such that method of detecting the degenerated disc included measuring the level of notochordal cells or using a non-structurally by biochemical or molecular means, since methods detecting degenerated discs were known to use such methods as taught by Omlor and Brayda-Bruno. Such a modification merely involves the substitution of one known method of detecting degenerated discs for another.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1-12, 14, 16, 18, 31, 34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Sakai et al. (US 2013/0078222 A1) (ref. of record) in view of Wang et al. (Arthritis Research & Therapy, 2013) (ref. of record), Desnoyer et al. (US 7,687,460 B2) (ref. of record), Erwin et al. (WO 2010/088775 A1) (ref. of record) and Silverman et al. (US 2014/0286912 A1) (ref. of record).
With respect to claims 1 and 34, Sakai teaches a method of treating intervertebral disk disorders by administering intervertebral disk nucleus pulposus stem cells or progenitor cells which are positive for Tie2 (abstract, 0052 and 0061). Sakai teaches the Tie2-positive cells are capable of differentiating into chondrocytes (0054). With respect to claims 1 and 34, Sakai teaches the human nucleus pulposus cells may be from a different species (0071). With respect to claims 1, 2, 5, 10, 18 and 34, Sakai teaches intervertebral disk nucleus pulposus stem cells or progenitor cells which are nucleus pulposus cells would be considered notochordal cells and the cells express Tie2 (abstract). By administering the Tie2-positive nucleus pulposus cells to the individual, the generation of chondrocytes or chondrocyte-like cells for an individual would inherently happen.
With respect to claims 3 and 4, Sakai teaches the cells can be administered in conjunction with angiopoietin (a therapeutic agent, a protein and a growth factor) (0098). With respect to claims 6, 7 and 8, Sakai teaches the intervertebral disk nucleus pulposus stem cell/progenitor cell population (Tie2 positive cells) may be separated from the nucleus pulposus by digesting, dispersing (mechanical strain) and washing the cells and then cultured (modified ex vivo) (0084). (0060). With respect to claims 11 and 12, Sakai teaches the nucleus pulposus cells (notochordal cells) express the gene product of Sox9 (0072). With respect to claim 14, Sakai teaches treating a damaged, diseased or missing intervertebral discs of a subject, the detection of the degenerated disc would have to have happen to be treated (abstract and 0141). Similarly, although Sakai does not explicitly teach the method where the degenerated disc is detected structurally or non-structurally as recited in claim 16, the detection of the degenerated disc would by a structurally or non-structurally method. With respect to claim 36, Sakai teaches the composition where the nucleus pulpous cell population expresses the gene product of Sox 9 (0072, 0121 and Table 1)
Sakai does not teach the method further including the step of providing to a degenerated disc of an individual an effective amount of platelet-rich plasma (PRP) as recited in claims 1 and 34. However, Wang teaches treating intervertebral disc degeneration by administering PRP (abstract), reports that PRP can promote nucleus pulposus regeneration (pg. 5 last para.), and teaches PRP promotes intervertebral disc healing by releasing growth factors (abstract, pg. 1 last para., pg. 5 Col. 1 para. 3). Wang further teaches PRP contains antibacterial and bactericidal proteins that may influence the process of inflammatory response (pg. 5 Col. 1 para. 3). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would be motivated to modify the method of Sakai to include the step of further administering PRP to a subject with disc degeneration for the benefits of promoting nucleus pulposus regeneration, healing and an inflammatory response as taught by Wang. It would have been obvious to one of ordinary skill in the art to modify the method of Sakai to include an additional step of administering known beneficial compositions, such as PRP, in a method of treating a degenerated disc of individual by generating chondrocytes or chondrocyte-like cells in the disc, since Wang teaches the administration of PRP for the repair of degenerative discs. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Sakai to include the step of further administering PRP to a subject with disc degeneration, since PRP was well-known for the benefits of promoting nucleus pulposus regeneration as taught by Wang.
Sakai does not teach the method further including the step of providing to a degenerated disc of an individual an effective amount of WNT1-inducible-signaling pathway protein 1 (WISP1) and/or WISP2 as recited in claims 1 and 34. However, Desnoyer teaches using WISP polypeptides in the treatment of degenerative cartilaginous disorders and various immune related conditions (Col. 1 lines 13-15). Desnoyer teaches a method of treating mammalian cartilage cells or tissue damaged from a degenerative cartilaginous disorder with an effective amount of WISP polypeptide where the WISP polypeptide is WISP-1 or WISP-2 (Col. 7 lines 50-65 and Col. 8 lines 35-56). Desnoyer further teaches that WISP-1 and WISP-2 polypeptides stimulate chondrocyte proliferation or differentiation (Col. 9 lines 2-15). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would be motivated to modify the method of Sakai to include the step of further administering WISP-1 and/or WISP-2 to a subject with disc degeneration for the benefits of promoting cartilage repair as taught by Desnoyer. It would have been obvious to one of ordinary skill in the art to modify the method of Sakai to include an additional step of administering other known beneficial agents, such as the factors WISP-1 and/or WISP-2, in a method of treating a degenerated disc of individual by generating chondrocytes or chondrocyte-like cells in the disc, since Desnoyer teaches the administration of WISP-1 and WISP-2 for the repair of degenerative cartilage and that the proteins promote chondrocyte proliferation and differentiation. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Sakai to include the step of further administering the factors WISP-1 and/or WISP-2 to a subject with disc degeneration, since WISP-1 and WISP-2 were known for their benefit of promoting cartilage regeneration as taught by Desnoyer.
Sakai does not teach the method further including the step of providing to a degenerated disc of an individual a conditioned medium is from nucleus pulposus cells as recited in claims 1 and 34, or where the nucleus pulposus conditioned media is generated by exposing the nucleus pulposus cells to hypoxia as recited in claims 1, 34 and 35. Additionally, Sakai does not teach the method further including the step of providing a mixture generated in vitro comprising fibroblasts and nucleus pulposus conditioned media as recited in claim 34. However, Erwin teaches a similar method of inhibiting nucleus pulposus degeneration in a subject by administering to the subject or contacting nucleus pulposus (NP) cells of the subject with NP conditioned medium and an isolated cell population (0015-0018). Erwin further teaches producing a nucleus pulposus conditioned medium (NPCM) and teaches that the conditioned media is prepared by exposing the cells to an oxygen concentration between 1.5-10% (hypoxia) (0014 and 0031). Erwin teaches that nucleus pulposus and notochordal cells produce soluble factors that are useful for inhibiting inflammatory cytokine and death receptor signaling of NP cells (00120-00121). Erwin teaches that nucleus pulposus and notochordal cells produce soluble factors that are useful for inhibiting inflammatory cytokine and death receptor signaling of NP cells and is useful for inhibiting cell death and treating degenerative diseases (00120-00121 and 00127). In further support, Silverman teaches discogenic cell population includes fibroblasts (0082). In addition Silverman teaches that the discogenic cells can be administered in conjunction with biologically active agents including cell culture media or conditioned medium derived from spinal disc, or cartilaginous tissue or discogenic cells (0086). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Sakai to include the step of further administering nucleus pulposus conditioned media prepared by exposing nucleus pulpous cells and fibroblast cells to a subject with disc degeneration for the benefits of inhibiting inflammatory cytokine and death receptor signaling of NP cells, inhibiting cell death and treating degenerative discs as taught by Erwin and Silverman. It would have been obvious to one of ordinary skill in the art to modify the method of Sakai to include an additional step of administering known beneficial compositions, such as nucleus pulposus conditioned media, in a method of treating a degenerated disc of individual by generating chondrocytes or chondrocyte-like cells in the disc, since Silverman teaches conditioned medium and fibroblasts can be administered and Erwin teaches the administration of nucleus pulposus conditioned media for the repair of degenerative discs. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Sakai to include the step of further administering nucleus pulposus conditioned media prepared by exposing nucleus pulpous cells and fibroblast cells to a subject with disc degeneration, since both were well-known for the benefits of promoting nucleus pulposus regeneration as taught by Erwin and Silverman teaches the method including the additional administration of fibroblasts. Additionally, it would have been obvious to one of ordinary skill in the art to mix the fibroblasts with the conditioned media and other components of the composition being administered to the subject. For instance, Silverman teaches that the discogenic cells can be administered in conjunction with biologically active agents including cell culture media or conditioned medium derived from spinal disc, or cartilaginous tissue or discogenic cells (0086).
None of Sakai, Wang, Desnoyer, or Erwin teach the method where the cells are exposed to a mechanical strain that is intermittent hydrostatic pressure, fluid shear stress, low oxygen tension, direct compression or a combination thereof as recited in claim 9. However, Silverman teaches a similar method of generating discogenic cell populations or intervertebral disc cells and providing the cells to restore or regenerate damaged, diseased or missing intervertebral discs of a subject (abstract and 0001). Silverman teaches the disc tissue may include nucleus pulposus cells would include notochordal cells and teaches the cells (includes fibroblast and nucleus pulposus cells (notochordal cells)) may be grown under hypoxic conditions (low oxygen tension) (0047, 0060 and 0082). Accordingly, at effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Sakai, and Wang to exposing the cells to low oxygen tension for culturing of the cells as taught by Wilson. Furthermore, it would have been obvious to one skilled in the art to have further modified the method taught by the combined teachings of Sakai and Wang to include such a method of culturing the nucleus pulposus cells, since methods of culturing such cells were known to use low oxygen tension as taught by Wilson. For these same reasons, one skilled in the art would have had a reasonable expectation of success in modifying the method taught by the combined teachings of Sakai and Wang to include the culturing the nucleus pulposus cells under low oxygen tension.
Sakai does not teach the method comprising the step of providing to the disc one or more composition comprising an effective amount of transforming growth factor beta-1 (TGFB1) and connective tissue growth factor (CTGF) as recited in claim 31. However, Wang teaches treating intervertebral disc degeneration by administering growth factors and by administering PRP which contains the growth factors, TGFB1 and CTGF (abstract, pg. 1 last para. and Tables 1 and 2 and pg. 5 Col. 1 para. 3). Additionally, Wang teaches that many growth factors have been proven to be effective in reversing the degeneration of discs (abstract). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would be motivated to modify the method of Sakai to include the step of further administering TGFB1 and CTGF to a subject with disc degeneration for the benefits of promoting disc regeneration as taught by Wang. It would have been obvious to one of ordinary skill in the art to modify the method of Sakai to include an additional step of administering known beneficial agent, such as the growth factors TGFB1 and CTGF, in a method of treating a degenerated disc of individual by generating chondrocytes or chondrocyte-like cells in the disc, since Wang teaches the administration of growth factors and growth factor TGFB1 and CTGF-containing PRP for the repair of degenerative discs. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Sakai to include the step of further administering the growth factors TGFB1 and CTGF to a subject with disc degeneration, since the growth factors were known for their benefit of promoting nucleus pulposus regeneration as taught by Wang.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 15 and 17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Sakai in view of Wang, Desnoyer, Erwin and Silverman (as applied to claims 1-12, 14, 16, 18, 31, 34 and 36 above), and further in view of Brayda-Bruno et al. (European Spine Journal, 2014) (ref. of record) and Omlor et al. (Spine, 2009) (ref. of record).
The teachings of Sakai, Wang, Desnoyer and Erwin can be found in the previous rejection above.
None of Sakai, Wang, Desnoyer, or Erwin teach the method where the degenerated disc is detected by measuring the level of notochord cells in the nucleus pulposus of a disc in the individual suspected of being degenerated as recited in claim 15. Similarly, none of Sakai, Wang, Desnoyer, or Erwin teach the method where the degenerated disc is detected by non-structurally by biochemical or molecular means as recited in claim 17. However, Omlor teaches that disc degeneration is associated with changes in NP cell phenotype (pg. 2731 Col. 1 last para.). In addition, Omlor teaches that there is a decrease in notochordal cells in an animal model of disc degeneration and that the loss of NCs can serve as a marker for disc degeneration (abstract and pg. 2735 Col. 1 para. 1, and pg. 2738 para. 1). In further support, Brayda-Bruno teaches methods of detecting degenerated disc structurally by MRI (abstract) and by determining intradiscal pressure and chemical quantities (structural and non-structural detection) (pg. S318-S319 bridging para.). In addition, Brayda-Bruno teaches methods of detecting degenerated disc by measuring chemical quantities such as PG (proteoglycan) content (a biochemical and molecular means) (pg. S318-S319 bridging para.) and by measuring aggrecan concentration. Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Sakai, Wang, Desnoyer, and Erwin to include additional methods of detecting degenerated discs in an individual. Furthermore, it would have been obvious to one skilled in the art to have further modified the method taught by the combined teachings of Sakai, Wang, Desnoyer, and Erwin to include such that method of detecting the degenerated disc included measuring the level of notochordal cells or using a non-structurally by biochemical or molecular means, since methods detecting degenerated discs were known to use such methods as taught by Omlor and Brayda-Bruno. Such a modification merely involves the substitution of one known method of detecting degenerated discs for another.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed May 11, 2026 have been fully considered but they are not persuasive.
In summary with respect to the rejections under 35 U.S.C. §103, Applicant argues that the rejection is deficient since the inherency assertions are unsupported and contrary to the teachings of the art, the Office fails to articulate the specific motivation to combine the references into the particular four component method claimed and relies on the generalized desire to improve disc therapy which amounts to impermissible hindsight given the vast combination of potential disc therapies and the Office’s own enablement analysis acknowledges the unpredictability in the field (Remarks pg. 14 para. 2).
With respect to the insufficient showing of inherency, Applicant argues that no evidence was provided showing that administering nucleus pulposus cells to an individual would generate chondrocytes or chondrocyte-like cells for an individual and is not an inevitable consequence of doing what is allegedly taught in the art (Remarks pg. 14 para. 3). However, this argument was not found to be persuasive, since the art in combination teach administering the same composition, therefore, it should have the same effect. In particular, it appears that components from nucleus pulposus provide this effect. The specification supports this and states “embodiments of the disclosure include methods of generating chondrocytes or chondrocyte-like cells for an individual, comprising the step of providing to a degenerated disc of an individual an effective amount of components from the nucleus pulposus (NP) of the same individual or another individual from the same or different species (0022 of published application). In further support, claim 1 from the Aug. 3, 2021 claim set only required one or more components from the nucleus pulposus and PRP to achieve the generation of chondrocytes or chondrocyte-like cells in the degenerated disc. Both Silverman and Sakai teach administering components from nucleus pulposus to a degenerative disc and therefore should have this same effect. Furthermore, step (d) of claim 1 defines the outcomes of the treatment and does not define the technical features necessary for achieving this result.
In support that it is not an inherent outcome, Applicant argues that Sakai demonstrates that not all nucleus pulposus cells survive when administered to an individual (Remarks pg. 15 para. 2). However, this argument was not found to be persuasive, since this not a measurement of the generating of chondrocytes of chondrocyte-like cells or at least does not demonstrate that the cells which do not survive also do not help generate chondrocyte or chondrocyte-like cells in the degenerated disc. Furthermore, as stated above, step (d) of claim 1 defines the outcomes of the treatment and does not define the technical features necessary for achieving this result. Both Silverman and Sakai teach administering components from nucleus pulposus to a degenerative disc and therefore should have this same effect.
Applicant argues that Sakai teaches that not all individuals have Tie2+ cells and shows that NP cells from 70 year old individuals do not contain any Tie2+ cells (Remarks pg. 15 last para.). However, this argument was not found to be persuasive, since the rejection is not relying on inherency to show that the NP cells of Silverman possess Tie2+ cells.
With respect to the lack of motivation to combine the references and the use of hindsight reasoning, Applicant argues that since each component is known individually in the art for its beneficial effect on disc or cartilage tissue is insufficient in establishing motivation to combine which requires some rational reasoning (Remarks pg. 16). However, this argument was not found to be persuasive, since the references independently address the identical medical problem, therefore one of ordinary skill in the art would have been motivated to combine them. Functionally equivalents can provide motivation to combine the claimed components.
Applicant further argues that the number potential combinations from which the four-component combination is selected from in the cited references does not support the Office’s reasons to combine and the references collectively disclose more than 170 distinct candidate therapeutic components including various cell types, growth factors, cytokines, conditioned media, scaffolds, biomaterials and gene products (Remarks pg. 17 para. 2 to pg. 19 para. 1). However, this argument was not found to be persuasive, since the cited references focus on each of the claim component for healing degenerative discs or degenerative cartilage tissue and do not list the claimed components in a laundry list. Specifically, Silverman is directed to NP cells to heal discs, Wang is directed to administering PRP to heal IDD (intervertebral disc degeneration), Desnoyer is focused on WISP polypeptide in the treatment of degenerative cartilaginous disorders (degenerative disc is a type of degenerative cartilaginous disorder), and Erwin is focused on CM for inhibiting nucleus pulposus inflammation (0016).
Applicant argues that none of the references suggest the co-administration of all four components (Remarks pg. 19 last para.). Applicant further argues that Desnoyer is related to articular cartilage and arthritis which is biochemically and mechanically distinct from the avascular, hypoxic, high-pressure IVD and only teaches administering WISP polypeptide alone. Applicant argues that Wang discloses PRP administration alone, Erin discloses NP conditioned medium alone, and none teach by combining the four ingredients there would be a synergistic or additive benefit over any of them alone (Remarks pg. 19-20 bridging para.). However, these arguments were not found to be persuasive, since the motivation to combine is that each component has a known benefit in treating degenerative discs or degenerative cartilage tissue.
With respect to the lack of reasonable expectation of success, Applicant argues that the Office has relied on Tang to provide support for the unpredictability of the field in the enablement rejection, therefore, a POSITA would not combine the five references to arrive at the claimed invention with a reasonable expectation of success. The arguments that the art is predictable were found to be persuasive with respect to the rejection under 35 U.S.C. §112(a) scope of enablement (see Remarks pg. 9 last para. to pg. 13 first para).
Applicant argues that Bruno and Omlor fail to remedy the deficiencies of Silverman, Sakai, Wang, Desnoyer, Erwin, and Brayda-Bruno (Remarks pg. 21-22 bridging para.). However, this argument was not found to be persuasive, since the arguments with respect to the rejections over Silverman, Sakai, Wang, Desnoyer, Erwin, and Brayda-Bruno were not found to be persuasive as explained above.
Applicant argues that Sakai teaches that Tie2+ cells are capable of differentiating into chondrocytes but does not provide evidence that this feature is necessarily present in every situation and instead shows that some cells from the NP when injected into the disc of animals failed to survive (Remarks pg. 22 last para.). Applicant further argues that the inherency assertion by the Office is deficient, since Sakai teaches that not every Tie2+ cell has the same differentiation abilities (Remarks pg. 22-23 bridging para.). However, these arguments were not found to be persuasive, since this not a measurement of the generating of chondrocytes of chondrocyte-like cells or at least does not demonstrate that the cells which do not survive also do not help generate chondrocyte or chondrocyte-like cells in the degenerated disc. Furthermore, as stated above, step (d) of claim 1 defines the outcomes of the treatment and does not define the technical features necessary for achieving this result. Both Silverman and Sakai teach administering components from nucleus pulposus to a degenerative disc and therefore should have this same effect.
Applicant argues that no rationale was provided to select Tie2+ cells in combination with PRP, WISP1/2 and NP conditioned media to induce chondrocyte or chondrocyte-cell generation in the degenerated disc of an individual without the use of hindsight reasoning given the potential over 33 million possible combinations (Remarks pg. 22 last para. to pg. 23 para. 2). However, this argument was not found to be persuasive, since the references independently address the identical medical problem, therefore one of ordinary skill in the art would have been motivated to combine them.
Each of cited references teaches a claimed component for healing degenerative discs or degenerative cartilage tissue. Silverman is directed to NP cells to heal discs, Wang is directed to administering PRP to heal IDD (intervertebral disc degeneration), Desnoyer is focused on WISP polypeptide in the treatment of degenerative cartilaginous disorders (degenerative disc is a type of degenerative cartilaginous disorder), and Erwin is focused on CM for inhibiting nucleus pulposus inflammation (0016).
Applicant argues that Bruno and Omlor fail to remedy the deficiencies of Sakai, Wang, Desnoyer, Erwin, Brayda-Bruno and Silverman (Remarks pg. 23-24 bridging para.). However, this argument was not found to be persuasive, since the arguments with respect to the rejections over Sakai, Wang, Desnoyer, Erwin, Brayda-Bruno and Silverman were not found to be persuasive as explained above.
Applicant argues that new claim 36 is independently patentable, since the Office has not provide a reason or motivation to further include a Sox9 gene product (Remarks pg. 24 para. 3). The Applicant’s amendments for include Sox9 gene product necessitated a new rejection. Applicant’s arguments are drawn to the cited references failing to teach this new limitation. However, this new limitation is addressed in the new rejection.
In response to the Office’s previous arguments, Applicant argues that there is no general rule that a skilled artisan cannot reasonably extrapolate in vivo success from in vivo effects (Remarks pg. 24 para. 4). However, this argument was not found to be persuasive, since no evidence has been provided demonstrating that the
in vivo models used in the Declarations are considered equivalent to in vivo models.
Applicant further argues that the in vitro methods utilized by the Applicant can be reasonably correlated to in vivo effects and in support Applicant notes that Sakai tested the differentiation potential of cells in vitro and confirmed this potential in vivo (Remarks pg. 24 last para.). However, these arguments were not found to be persuasive, since no evidence has been presented that the results for the neonatal human dermal fibroblast cell culture which show an increase in sulfated GAG expression when treated with both NP CM and Tie2+ cells would correlate to the in vivo generation of chondrocytes or chondrocyte-like cells in a degenerated disc of an individual when provided in composition including NP CM, Tie2+ cells, platelet-rich plasma and a WISP1 or WISP2. Additionally, it is unclear whether the data is statistically significant.
Applicant argues that the in vitro data presented in the Declarations demonstrate that fibroblasts cultured with the claimed elements undergo differentiation into chondrocytes which are found in intervertebral discs. Applicant argues that a POSITA would have reasonably extrapolated from the in vitro data in the Applicant’s specification that the method could successfully be utilized in vivo for the generation of chondrocytes, since it known in the art that chondrocytes contribute to disc integrity and hydration and aid in the treatment of degenerate discs (Remarks pg. 25 para. 1). Applicant further argues that their unexpected in vitro results should therefore be given full weight and consideration (Remarks pg. 25 para. 1).
However, these arguments were not found to be persuasive, since data presented in the Declaration is not commensurate in scope with the claims and are not easily correlated with the claimed method. The data appears to show when both nucleus pulposus conditioned media (NP CM) and Tie2+ cells are present in neonatal human dermal fibroblast cultures there is an increase differentiation of the fibroblasts into chondrocytes. However, there is no evidence for the in vivo effects of both NP CM and Tie2+ cells and the claims are directed to generating chondrocytes or chondrocyte-like cells in a degenerated disc of an individual. It is unclear how a fibroblast culture containing only two of the claimed components can be correlated to an in vivo treatment method with additional components in the therapeutic composition. It is maintained that the claimed composition used in the method of generating chondrocytes or chondrocyte-like cells for an individual is different than the compositions for generating the data in the Declaration. Specifically, the composition in the Declaration which exhibits increased chondrocyte generation contains NP CM generated by culturing nucleus pulposus cells under hypoxic conditions for three days with FBS-deficient ADMEM/F-12 medium and Tie-2+ cells at a concentration of 1 million/ml. It is unclear if the same effects would be achieved under different conditions or with the additional components of claim 1 including platelet-rich plasma and a WISP1 or WISP2.
Applicant argues that the Office failed to provide any evidence that the in vitro method disclosed would not reasonably correlated to in vivo results and no references have been provide to factual support the position by the Office (Remarks pg. 25-26 bridging para.). However, this argument was not found to be persuasive, since the data in the Declaration, even if it can be extrapolated to in vivo data is not commensurate in scope with the claimed method as explained previously. The claims are not to the differentiation of neonatal dermal fibroblasts isolated from human foreskin into chondrocytes in cell culture, but instead to administering a composition to a degenerative disc of an individual to generated chondrocyte or chondrocyte cells in the degenerative disc. The environment of a degenerated disc is highly acidic, hypoxic and nutrient-deprived, and has dynamic mechanical loading which is different from the cell culture of neonatal dermal fibroblasts.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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