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, IDS, and response filed Dec. 5, 2025 have been received and entered into the case.
Status of the Claims
Claims 1-12, 14-18, 31, 34 and 35 are currently pending.
Claims 1, 5, and 34 are amended.
Claims 13, 19-30, 32 and 33 are cancelled.
Claims 1-12, 14-18, 31, 34 and 35 have been considered on the merits.
Claim Rejections - 35 USC § 112 (a)
New claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) have been added after further consideration.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-12, 14-18, 31, 34 and 35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor, at the time the application was filed, had possession of the claimed invention. Claims 1, 34 and 35 recite a limitation of “wherein the nucleus pulposus conditioned media is generated by exposing nucleus pulposus cells to hypoxia” or “wherein the nucleus pulposus conditioned media is generated by culturing nucleus pulposus cells to hypoxia”. The specification describes exposing the cells which are administered to hypoxia (0023 and 0042 of the published application), but there is no description of exposing nucleus pulposus cells to hypoxia to generate conditioned medium.
This is a new matter rejection.
Claims 1-12, 14-18, 31, 34 and 35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification describes in general the delivery or providing of compositions containing allogeneic, xenogeneic or autologous nucleus pulposus cells, conditioned medium generated from the nucleus pulposus cells, PRP, Tie2+ cells and other components to an individual (0023-0030, 0040-0044 and 0049 of the published application), does not reasonably provide enablement for a method of generating chondrocytes or chondrocyte-like cells in the degenerative disc of any individual with any type of disc degeneration by providing to the degenerative disc an effective amount of the components listed in claim 1 using any amount of the composition and any mode of administration. The components being one or more components from the nucleus pulposus (NP) of the same individual or another individual from the same or different species and comprising Tie2+ cells; (b) platelet-rich plasma (PRP); (c) WNT1-inducible-signaling pathway protein 1 (WISPl) and/or WISP2; and (d) nucleus pulposus conditioned media generated by culturing nucleus pulposus cells under hypoxic conditions.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, the enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of generating chondrocytes or chondrocyte-like cells in the degenerative disc of an individual by providing to the degenerative disc an effective amount of one or more components from the nucleus pulposus (NP) of the same individual or another individual from the same or different species and comprising Tie2+ cells; (b) platelet-rich plasma (PRP); (c) WNT1-inducible-signaling pathway protein 1 (WISPl) and/or WISP2; and (d) nucleus pulposus conditioned media generated by culturing nucleus pulposus cells under hypoxic conditions. Thus, the claims taken together with the specification imply that chondrocytes or chondrocyte-like cells can be generated in any type of degenerative disc of any type of animal, by providing the claimed composition using any mode of administration.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The prior art in general teaches there are still many challenges in treating degenerated discs with cell therapy. For instance, Tang et al. (Advanced Healthcare Materials, 2025) states “challenges remain in ensuring the survival, proliferation, and functional differentiation of transplanted cells within the harsh microenvironment of degenerated discs—characterized by low oxygen levels, nutrient deprivation, acidic pH, and inflammatory cytokines” (pg. 1 para. 3). Tang further teaches that recent research has focuses on hydrogels for cell delivery vehicles (pg. 1-2 bridging para.). Tang teaches that intervertebral disc degeneration or “IDD is a multifaceted condition driven by aging, trauma, overloading, and poor nutrition” (pg. 2 Col. 1 para. 4). Tang teaches mode of cell transplantation is a crucial step in cell therapy and that direct injection into the disc rather than intravenous delivery of cells has a better outcome (pg. 15 Col. 2 last para.). Tang further teaches that the dosing of stem cells into the IVD (intervertebral disc) lacks standardized guidelines (pg. 16 Col. 1 para. 3). Thus, as the state of the art stands, the method would be unpredictable depending on the specific type of degeneration of the disc, the subject and the mode and amount of administration.
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The instant specification provides does not provide any working examples and specific guidance for the use of the instantly claimed method for generating chondrocytes or chondrocyte-like cells in the degenerative disc of any individual with any type of disc degeneration by providing to the degenerative disc an effective amount of the components listed in claim 1. The applicants have not provided data demonstrating that the claimed method with an animal model. Therefore, there is no conclusive evidence in the instant disclosure to indicate that the instantly claimed method can be used to generating chondrocytes or chondrocyte-like cells in the degenerative disc of any individual with any type of disc degeneration by simply providing to the degenerative disc an effective amount of the components listed in claim 1.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to use the claimed invention within the broad scope as instantly claimed.
Claim Rejections - 35 USC § 112 (d)
New claim rejections under 35 USC § 112, (d) or fourth paragraph (pre-AIA ) have been added to address the claim amendments.
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 35 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. In this case, claim 35 recites exposing the nucleus pulposus cells to hypoxia and claim 34 from which is depends from requires that the nucleus pulposus cells be cultured under hypoxic conditions. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
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 35 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).
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, 34, and 35. 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 35 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 35 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.
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 35 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 Dec. 5, 2025 have been fully considered but they are not persuasive.
Applicant argues that the data from the Declaration under 37 CFR §1.132 of Dr. Thomas Ichim filed no Nov. 15, 2024 is now commensurate in scope with the present claims and states that the data does not need to show unexpected results over the entire range properties possessed by the composition (Remarks pg. 8 para. 3-4 and pg. 10 para. 2). Additionally, Applicant argues that the results in the Declaration demonstrates reasonable correlation to the claimed invention (Remarks pg. 9 para. 2).
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 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 evidence that PRP or WISP proteins would inhibit the claimed methods and has instead argued that Wang teaches PRP promotes nucleus pulposus regeneration and Desnoyer teaches using WISP polypeptides in the treatment of degenerative cartilaginous disorders (Remarks pg. 9 para. 1). However, this argument was not found to be persuasive, since the Office did not state that PRP or WISP proteins would inhibit the claimed methods but that these components of the composition which are required by the claims are not included in the composition used in the Declaration. Therefore, it is difficult to compare the results of the Declaration with the claimed method.
Applicant argues that the results in the Declaration demonstrates reasonable correlation to the claimed invention and argues that chondrocytes are therapeutically desired in the disc since they provide extra cellular matrix proteins (Remarks pg. 9 para. 2). Applicant argues that this is supported by the teaching in Sakai that maintaining notochord-derived nucleus pulposus cells is the ultimate goal when treating and preventing intervertebral disk degeneration. In addition, Applicant argues this is support by the teachings in Silverman that the treatment of degenerative disc disorders requires restoring the structure of the disc, regenerating the cells or expanding the cartilaginous tissue of the disc, treatment can include providing chondrocytes which produce aggrecan and collagen 2, and the retention of extracellular matrix proteins is desired during treatment. Applicant argues this is further supported by the teaching in Wang that chondrogenesis is a therapeutic goal for degenerative disc disorders (Remarks pg. 9 para. 2). However, these arguments were not found to be persuasive for the reasons given above. Specifically, no evidence has been present 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.
Applicant argues that Exhibit 2 of the Declaration under 37 CFR §1.132 of Dr. Thomas Ichim filed on Nov. 15, 2024, demonstrates synergism from the combination of NP CM with Tie2+ cells to stimulate chondrogenesis (Remarks pg. 10 para. 3). Applicant further argues that the sum of the effects of the separate NP CM and Tie2+ cell groups is less than the effect of the combined NP CM and Tie2+ cell group which is an unexpected or unpredictable result (Remarks pg. 10 para. 3). Applicant argues that the Office has not provided any evidence that these results would be predictable (Remarks pg. 10 para. 3). However, these arguments were not found to be persuasive for the reasons given above. Specifically, no evidence has been present 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.
Conclusion
No claims are allowed.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632