DETAILED ACTION
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 .
Status of clams
Claims 1-10 as amended on 6/10/2026 are currently pending.
Claims 8-10 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/20/2026.
Claims 1-7 as amended on 6/10/2026 are under examination in the instant office action.
Claim Rejections - 35 USC § 112
Claims 1-7 as amended are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 as amended is indefinite because it is unclear what is “a control nucleus pulposus cell population” (last 2 lines) as claimed and as intended.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3 and 6 as presently amended are rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0078222 (Sakai et al).
The cited US 2013/0078222 (Sakai et al) is relied upon for the disclosure of a method for isolating (par. 0104) and characterizing a population of nucleus pulposus progenitor cells as based on expression of embryonic stem cell genes including Nanog, Oct3/4 (same as Oct-4) and SOX2 (par. 0134, par. 0072), for expression of mesenchymal stem cell genes using markers CD44, CD73, CD90 and CD105 (par. 0078) and for capabilities of NP cell populations for differentiation to osteocytes, adipocytes and chondrocytes (par. 0122). The cited US 2013/0078222 (Sakai et al) teaches the use of NP progenitor cells for tissue regeneration in treating intervertebral disk (IVD) disorders (abstract).
In particular and with regard to claim 1 as amended: US 2013/0078222 (Sakai et al) discloses a method for isolating and characterizing nucleus pulposus progenitor or stem cells, wherein the method comprises steps of:
a) providing a nucleus pulposus (NP) tissue, and cutting the nucleus pulposus tissue into a plurality of small pieces or blocks (par. 0104; lines 1-2);
b) hydrolyzing the tissue pieces or blocks with an enzyme including trypsin product “TrypLE” and collagenase for a total time of about 3 hours (par. 0104, lines 3-5);
c) removing the enzyme by washing and culturing the enzyme-treated pieces or cells in a culture dish in a culture medium to obtain cultured NP stem cell populations (par. 104); and
d) screening the cultured NP stem cell populations for expression of embryonic stem cell genes including Nanog, Oct3/4 (same as Oct-4) and SOX2 (par. 0134, par. 0072).
The cited document US 2013/0078222 (Sakai et al) does not expressively teach a specific quantitative threshold for expression of Nanog, Oct-4 and SOX2 by a population of nucleus pulposus progenitor cells being greater than 1.5 relative to the other nucleus pulposus cells. However, the cited document US 2013/0078222 (Sakai et al) clearly teaches that stem cell markers such as Nanog, Oct-4 and SOX2 are “highly expressed” by a population of nucleus pulposus progenitor cells “compared to the other cell populations” (par. 0135) and the cited document clearly recognizes a clinical significance of this population of nucleus pulposus progenitor cells (abstract; par. 0135-00136).
Therefore, It would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to provide a population of nucleus pulposus progenitor cells derived from a nucleus pulposus tissue upon enzymatic digestion of the tissue, culturing digested cellular material and selecting a population of progenitor cells as based on a higher expression of stem cell markers such as Nanog, Oct-4 and SOX2 relatively to the other cell population risen from the cultured digested cellular material of nucleus pulposus tissue. A specific quantitative threshold for expression of stem cell markers Nanog, Oct-4 and SOX2 by a population of stem cells including nucleus pulposus progenitor cells would be established or optimized by one of skill in the art depending of experimental techniques or instrumentations as intended to isolate a population of nucleus pulposus progenitor cells because the nucleus pulposus progenitor cells are characterized by a higher expression of stem cell markers Nanog, Oct-4 and SOX2 and because these cells are considered to be clinically significant for treatments of interverbal disk disorders as taught by US 2013/0078222 (Sakai et al)
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
As applied to claim 2 as amended: in the method of US 2013/0078222 (Sakai et al) the staring nucleus pulposus tissue is cut into “small pieces” that would be small enough or comparable to the claim-recited 1 cubic mm as intended for enzymatic digestion of the tissue.
As applied to claim 3 as amended: in the method of US 2013/0078222 (Sakai et al) enzymatic treatment is performed with trypsin product “TrypLE” and collagenase for a total time of about 3 hours (par. 0104, lines 3-5) and further culturing for 4 days and/or 7 days (par. 0105). One of skill in the art would optimize enzymatic digestion time depending of specific enzymes, experimental techniques and/or instrumentations as intended to digest tissue for further culturing and isolation of populations of nucleus pulposus cells including progenitor cells.
As applied to claim 6 as amended: in the method of US 2013/0078222 (Sakai et al) the NP progenitor cell populations were screened for expression of genes CD44, CD73, CD90 and CD105 (par. 0078).
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited document US 2013/0078222 (Sakai et al). Therefore, the claims are properly rejected under 35 USC § 103.
Claims 1-4 and 6 as amended are rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0078222 (Sakai et al) in view of Kalluri et al (Journal of Clinical Investigation, 2009. Vol. 119, No. 6, pages 1420-1428).
The cited US 2013/0078222 (Sakai et al) is relied upon as explained above for the disclosure of a method for isolating (par. 0104) and characterizing nucleus pulposus progenitor cells for expression of embryonic stem cell genes including Nanog, Oct3/4 (same as Oct-4) and SOX2 (par. 0134, par. 0072), for expression of mesenchymal stem cell genes using markers CD44, CD73, CD90 and CD105 (par. 0078) and for capabilities of NP cell populations for differentiation to osteocytes, adipocytes and chondrocytes (par. 0122). The cited US 2013/0078222 (Sakai et al) teaches the use of NP progenitor cells for tissue regeneration in treating intervertebral disk (IVD) disorders (abstract).
As applied to claim 4: The cited US 2013/0078222 (Sakai et al) is silent about screening the NP progenitor cells for expression of genes N-cadherin, vimentin, beta-catenin and snail protein.
However, the reference by Kalluri teaches that cell markers commonly used by researches for detection of cell differentiation or transition towards mesenchymal phenotype include N-cadherin, vimentin, beta-catenin and snail protein (figure 1) and that this transition is associated with tissues regeneration (page 1421, col. 1).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to provide further screening of NP progenitor cell populations in the method of US 2013/0078222 (Sakai et al) for expression of genes N-cadherin, vimentin, beta-catenin and snail protein with a reasonable expectation of success in isolating and characterizing NP progenitor cell populations suitable for tissue regeneration in treating intervertebral disk disorders because these cell markers are commonly used by researches for detection of cell differentiation/transition towards mesenchymal phenotype and because the mesenchymal cell transition is associated with tissue regeneration as taught/suggested by Kalluri. Thus, one of skill in the art would be motivated to further characterize NP progenitor cells in the method of Sakai as being intended to provide cells suitable for tissue regeneration in treating intervertebral disk disorders.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Claims 1-6 as amended are rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0078222 (Sakai et al) in view of Kalluri et al (Journal of Clinical Investigation, 2009. Vol. 119, No. 6, pages 1420-1428) as applied to claims 1-4 and 6 above, and further in view of Brisby et al (Stem Cells and Development. 2013, Vol. 22, No. 5, pages 804-814).
The cited US 2013/0078222 (Sakai et al) amd Kalluri et al teach and suggest characterization and screening of a population of nucleus pulposus progenitor cells for markers including Nanog, Oct3/4 (same as Oct-4) and SOX2 (Sakai par. 0134, par. 0072), for expression of mesenchymal stem cell genes using markers CD44, CD73, CD90 and CD105 (Sakai par. 0078) and expression of genes N-cadherin, vimentin, beta-catenin and snail protein (Kalluri).
But the cited references are silent about screening the NP progenitor cells for STRO-1 and JAGGED.
However, the reference by Brisby et al teaches that progenitors cell populations derived from intervertebral disks (IVD) are also characterized by STRO-1 and JAGGED markers in addition to embryonic stem cell marker OCT3/4 and mesenchymal stem markers CD105 and CD90 (table 3 and page 805, col.1, lines 5-16). The reference by Brisby also teaches that STRO-1 marker associated with tissue growth and regeneration (page 805, col.1, lines 12-13).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to provide further screening of NP progenitor cell populations in the method of US 2013/0078222 (Sakai et al) for expression of genes STRO-1 and JAGGED in addition to embryonic stem cell marker OCT3/4 with a reasonable expectation of success in isolating and characterizing NP progenitor cell populations suitable for tissue regeneration in treating intervertebral disk disorders because these cell markers are knonw and used by researches for characterization of progenitor and stems cells in IVD cell populations and because the mesenchymal stem cell markers are associated with tissue regeneration as taught/suggested by Brisby. Thus, one of skill in the art would be motivated to further characterize NP progenitor cells in the method of Sakai as being intended to provide cells suitable for tissue regeneration in treating intervertebral disk disorders.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0078222 (Sakai et al), Kalluri et al (Journal of Clinical Investigation, 2009. Vol. 119, No. 6, pages 1420-1428) and Brisby et al (Stem Cells and Development. 2013, Vol. 22, No. 5, pages 804-814) and as applied to claims 1-6 above, and further in view of Liu et la (Mediators and Inflammation, 2021, article ID 2933199, pages 1-10).
The cited US 2013/0078222 (Sakai et al) is relied upon as explained above for the disclosure of a method for isolating (par. 0104) and characterizing nucleus pulposus progenitor cells for expression of embryonic stem cell genes including Nanog, Oct3/4 (same as Oct-4) and SOX2 (par. 0134, par. 0072), for expression of mesenchymal stem cell genes using markers CD44, CD73, CD90 and CD105 (par. 0078) and for capabilities of NP cell populations for differentiation to osteocytes, adipocytes and chondrocytes (par. 0122). The cited US 2013/0078222 (Sakai et al) teaches the use of NP progenitor cells for tissue regeneration in treating intervertebral disk (IVD) disorders (abstract).
As applied to claim 7: The cited US 2013/0078222 (Sakai et al) is silent about screening the NP progenitor cells for inflammation related genes.
However, the reference by Liu teaches that expression and upregulation of COX2, an inflammation and/or pain marker, in NP cell populations from intervertebral disks (abstract). The reference teaches that assays for expression of COX2 involve treatment of cells with degeneration inductors such as IL-1beta and TNF-alpha (page 2, col. 1, last par.).
The cited above reference by Kalluri also teaches that differentiation/transition towards mesenchymal cell phenotype in is associated with inflammation which ceases once inflammation is attenuated (page 1421, col.1, par. 2, lines 6-7). It recognizes that expression of MMP3 is related to inflammation (page 1423, col. 2).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to provide further screening of NP progenitor cell populations in the method of US 2013/0078222 (Sakai et al) for expression of genes related to inflammation including COX2 with a reasonable expectation of success in isolating and characterizing NP progenitor cell populations suitable for tissue regeneration in treating intervertebral disk disorders because inflammation related COX2 markers are present in NP cell populations from intervertebral disks and they used for characterization of NP cell populations as taught by Liu. One of skill in the art would be motivated to further characterize NP progenitor cells with inflammation related markers in the method of Sakai as intended to provide progenitor cell population suitable for tissue regeneration in treating intervertebral disk disorders because differentiation/transition towards mesenchymal cell phenotype is associated with inflammation, which ceases once inflammation is attenuated, and because differentiation/transition towards mesenchymal cell phenotype is associated with tissue regeneration as taught/suggested by Kalluri.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
The claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Response to Arguments
Applicant's arguments filed on 6/10/2026 have been fully considered but they are not all found persuasive.
The rejection of claim under 35 U.S.C. 102 (a) (1) as being anticipated by US 2013/0078222 (Sakai et al) has been withdrawn because the cited document does not expressively teach a specific quantitative threshold for expression of Nanog, Oct-4 and SOX2 by a population of nucleus pulposus progenitor cells being greater than 1.5 relative to the other nucleus pulposus cells.
Nevertheless, the cited document US 2013/0078222 (Sakai et al) clearly teaches that stem cell markers such as Nanog, Oct-4 and SOX2 are “highly expressed” by a population of nucleus pulposus progenitor cells “compared to the other cell populations” (par. 0135) and the cited document clearly recognizes a clinical significance of this population of nucleus pulposus progenitor cells (abstract; par. 0135-00136).
With regard to claim rejected under 35 USC § 103 as based on the disclosure by the primary reference US 2013/0078222 (Sakai et al) Applicants’ main argument is drawn to a specific quantitative threshold for expression of Nanog, Oct-4 and SOX2 by a population of nucleus pulposus progenitor cells being greater than 1.5 relative to the other or control nucleus pulposus cells.
This argument is not found persuasive because the cited document US 2013/0078222 (Sakai et al) clearly teaches that stem cell markers such as Nanog, Oct-4 and SOX2 are “highly expressed” by a population of nucleus pulposus progenitor cells “compared to the other cell populations” (par. 0135) and the cited document clearly recognizes a clinical significance of this population of nucleus pulposus progenitor cells (abstract; par. 0135-00136). In the instant case and in view of specification disclosure, the threshold value of 1.5 appears to be randomly selected by Applicants and the specification does not demonstrate correlation of this value with any benefits and/or clinical significance.
Applicants also argue that the method of Sakai does not teach or suggest culturing “tissue blocks” or “enzyme-treated tissue blocks” in order to allow cell population to migrate away from blocks and to form a plurality of clusters that are further separately cultured and screened for selected markers.
This argument is not convincing because Sakai clearly teach enzymatic digestion of tissue as intended for further culturing and selection/isolation of a population of progenitor cells. Although the degree of enzymatic digestion or disintegration of original tissues might have some differences as disclosed by Sakai and as intended by Applicants, the digested cellular materials of Sakai is reasonably considered to provide for the same starting cells derived from the same nucleus pulposus cells as intended for the instant claims.
Some of the applicants’ arguments are based on Sakai disclosure of cells positive for markers Tie2 and GD2 in a method for separation of progenitors cells which is not encompassed by the claimed method. Nevertheless, the method of Sakai further comprises the use of the same markers or expression of stem cell genes including Nanog, Oct3/4 (same as Oct-4) and SOX2 for characterization and selection of nucleus pulposus progenitor cells. Moreover, the claimed method is open to applications of other markers by the open language “method .. comprising”. The final cells of Sakai are characterized by a high expression of the same 3 markers as claimed when compared to the other cells.
No claims are allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VERA AFREMOVA whose telephone number is (571)272-0914. The examiner can normally be reached Monday-Friday: 8.30am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Vera Afremova
August 17, 2026
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653
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