Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Applicants' Remarks filed on 06 November 2025 are fully considered here.
The previous rejection of Claims 1-6 under pre-AIA 35 U.S.C. §103(a) as being unpatentable over Sakai et al. as evidenced by Sakai et al. (2012) in view of Lin as evidenced by Seifert et al., and in view of Blanco et al., in the Non-Final Office Action mailed 06 May 2025, is withdrawn in view of Applicants' amendment filed 06 November 2025.
The previous rejection of Claims 7 and 8 under pre-AIA 35 U.S.C. §103(a) as being unpatentable over Sakai et al. as evidenced by Sakai et al. (2012) in view of Lin as evidenced by Seifert et al., and in view of Blanco et al., as applied to claims 1-6 above, and further in view of Shapiro et al., and Gorensek et al., in the Non-Final Office Action mailed 06 May 2025, is withdrawn in view of Applicants' amendment filed 06 November 2025.
This action is a Final Office Action, based on new grounds under 35 U.S.C. §103(a) over Sakai et al. (2013) as evidenced by Sakai et al. (2012) in view of Duntsch et al., Lin, and Blanco et al., necessitated by Applicants’ amendment received on 06 November 2025, specifically, amended claim 1. See MPEP 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
Claims 1-20 are pending. Claims 9-20 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Group II and nonelected species. Election was made without traverse in the reply filed on 18 March 2025 to the Restriction/Election Office Action mailed 18 September 2024. Claims 1-8 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. §119(e) or under 35 U.S.C. §120, §121, or §365(c) is acknowledged. As noted in the Non-Final Office Action mailed on 06 May 2025, Applicant has claimed the benefit of the filing date of the prior application, and designates the instant application as a "CON" of 14/212,038.
Applicant has complied with all of the conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §120 or §365(c).
Claims 1-8 have the effective filing date of 15 March 2013.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04 September 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the Examiner.
Claim Objections
Claim 20 shows an incorrect status identifier. Applicant is reminded that claim 20 should be labeled: “(Withdrawn)”; remaining claims should be identified appropriately (MPEP 714 (II)(C)(A)) (See 37 CFR 1.121 (c)).
Appropriate correction is required. Applicant is required to provide a new claim set showing correct status identifiers in the response to this Office Action.
Claim Interpretations
(1) Claim 1 recites: “…the pharmaceutical composition comprises a discogenic cell population…”
The specification recites: "’Discogenic’, as used herein, refers to the ability to produce disc tissue in vivo. In some embodiments, discogenic cells are able to regenerate disc tissue that is diseased or damaged and/or has lost one or more properties of disc tissue in vivo. ” (originally-filed specification, pg. 7, para [0033]).
Therefore, any cell population cited in the prior art which is described as producing disc tissue in vivo (or, equivalently described as regenerating (a) diseased or damaged intervertebral disc(s)), regardless of the types of cells contained within the cell population, will be considered to describe a discogenic cell population.
(2) Claim 1 recites the relative term ‘about’.
Claim 1 recites: “...comprising one or more of: (i) a viscous non-reactive agent at a concentration of about 0.1% to 1%..., and wherein less than about 40% of the cell population expresses the cell surface markers CD24 and CD105.”
The specification recites: “’About’ as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of less than about ± 20%. In some cases about may refer to variations of 10% or less, or ± 5% or less. In some cases about may refer to variation of ± 1 % - ± 0.1 %” (spec., pg. 7, para. [0036] thru pg. 8, cont. para. [0036]).
Claim Rejections - 35 U.S.C. § 103
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.
The following is a quotation of pre-AIA 35 U.S.C. §103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. §103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. §103(c) and potential pre-AIA 35 U.S.C. §102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. §103(a).
Claims 1-6 are rejected under pre-AIA 35 U.S.C. §103(a) as being unpatentable over Sakai et al. (2013) (Pub. No. WO 2011/122601 A1; see Sakai et al. (2013) (Pub. No. 2013/0078222 A1 as English translation for pg./para./fig. citations) as evidenced by Sakai et al. (2012) (Nature Comm. 2012, 3(1264): 1-11) in view of Duntsch et al. (Pub. No. US 2012/0100607 A1), Lin (Pub. No. WO 2009/092094 A2), and Blanco et al. (Spine, 2010, 35(26): 2259-2265).
Regarding claim 1, pertaining to a method of treating an intervertebral disc of a subject; administering a therapeutic amount of a pharmaceutical composition to the intervertebral disc of the subject; the pharmaceutical composition comprises a discogenic cell population,
Sakai et al. (2013) shows a cell composition characterized by comprising an intervertebral disk nucleus pulposus cell (stem cell and/or progenitor cell). Regarding such a cell composition, for example, those for treatment or prevention of intervertebral disk disorders are preferable (pg. 3, para. [0060]). Said cell composition, for example, is preferably prepared as a pharmaceutical composition formulated such that it may be injected into the intervertebral disk (pg. 7, para. [0096]).
Further regarding claim 1, pertaining to derived from mammalian nucleus pulposus disc tissue,
Sakai et al. (2013) shows that the ‘isolated’ intervertebral disk nucleus pulposus stem cells/progenitor cell (population) refers to the intervertebral disk nucleus pulposus stem cells/progenitor cell (population) taken from the vertebrate body (pg. 6, para. [0088]). The collected human or mouse nucleus pulposus tissues were cut up into small pieces using scissors, etc. (pg. 8, para. [0104]).
Further regarding claim 1, pertaining to the discogenic cell population has been passaged at least one time in an anchorage dependent culture,
Sakai et al. (2013) shows that the nucleus pulposus cells that completed initial culturing in a single layered state of 4 days in a 10% FBS-added aMEM culture medium were used for the mixed culture. Contact culturing between the cells separated by the membrane, i.e., the nucleus pulposus (NP) cells and AHESS-5 cells, was carried out. The NP cells were separated with TrypLE Express (pg. 8, para. [0105]).
Further regarding claim 1, pertaining to transferred to and maintained in-vitro in anchorage independent culture comprising a culture receptacle comprising a viscous non-reactive reagent for seven days in anchorage independent culture,
Sakai et al. (2013) shows that after suspending a given number of mouse or human cells in a methocult H4230 methylcellulose medium, these were put in a culture dish and cultured for 10 days to form spheroid colonies (pg. 8, para. [0106]).
Sakai et al. (2013) does not explicitly show that methylcellulose is a viscous non-reactive agent that induces anchorage independent culture conditions, with regard to claim 1.
Sakai et al. (2012) shows that chondrocytes are unique among non-transformed cells in that they are capable of anchorage-independent growth in soft agar. In the described study, it was found that NP (nucleus pulposus) cells could form clonal spheroid colonies in methylcellulose medium (pg. 6, column 2, lines 4-8).
Further regarding claim 1, pertaining to expresses aggrecan gene and collagen 2 gene,
Sakai et al. (2013) shows that the expression of nine target genes was measured by PCR using reverse-transcribed cDNA (Table 1) (pg. 9, para. [0120]). Table 1 shows that aggrecan and collagen type 2 were measured (pg. 10, Table 1). Figure 4 shows a clonal analysis of human nucleus pulposus cells (CFU-NP) after anchorage independent culture. The generation of collagen type II and proteoglycan was observed in the CFU-NP colonies by immunostaining of the colonies; however, the generation of collagen type II and proteoglycan was negative or very low in (CFU-F) (colony forming unit-fibroblast cells) (Fig. 4-2 c-d) (pg. 4, para. [0070]; and Fig. 4-2 c-d [aggrecan is also known as cartilage-specific proteoglycan core protein; i.e., it is a proteoglycan]).
Further regarding claim 1, pertaining to less than about 40% of the cell population expresses the cell surface marker CD24,
Sakai et al. (2013) shows that the intervertebral disk nucleus pulposus stem cell is characterized by, for example, CD24 negative (pg. 6, para. [0083]). The intervertebral disk nucleus pulposus cell according to claim 2, wherein the surface marker is additionally CD24-negative (pg. 12, column 2, claim 6). Figure 7-2d shows that nucleus pulposus stem progenitor cells are CD24- (pg. 5, para. [0073]; and Fig. 7-2d).
Sakai et al. (2013) as evidenced by Sakai et al. (2012) does not show: 1) a viscous non-reactive reagent at a concentration of about 0.1% to 1% [Claim 1]; 2) the cell population expresses at least 2-fold more aggrecan gene and collagen 2 gene than a population of nucleus pulposus cells derived from mammalian disc tissue grown in anchorage dependent culture [Claim 1]; and 3) less than about 40% of the cell population expresses the cell surface marker CD105 [Claim 1].
Duntsch et al. discloses a neo-engineered disc comprising nucleus pulposus cells, and related methods of production and methods of use (pg. 1, para. [0002] [nexus to Sakai et al. (2013)- treating an intervertebral disc using nucleus pulposus cells]). The method of producing nucleus pulposus cells comprises the step of growing one or more discospheres (pg. 1, para. [0011] [nexus to Sakai et al. (2013)- producing a population of discogenic cells]).
Regarding claim 1, pertaining to a viscous non-reactive reagent at a concentration of about 0.1% to 1%,
Duntsch et al. discloses that the composition comprising disc stem cells further comprises methylcellulose supplemented to the media (Example 1). The composition comprising disc stem cells further comprises 0.5-10% methylcellulose supplemented to the media (pg. 7, para. [0070]).
Lin shows a method for treating damage at a site of cartilage injury comprising administering a composition that increases expression of bone morphogenic proteins (pg. 3, para. [0008]). The site of cartilage injury is an intervertebral disc (pg. 9, para. [0050] [nexus to Sakai et al. (2013)- method of treating an intervertebral disc]). Nucleus pulposus cells of lumbar intervertebral discs from Sprague-Dawley rats were harvested. Cells were trypsinized and subcultured in 12-well plate or embedded and cultured in alginate beads (so-called 3D culture) (pg. 32, para. [0155]-[0156] [nexus to Sakai et al. (2013)- culture cells in anchorage dependent and anchorage independent conditions]).
Regarding claim 1, pertaining to the cell population expresses at least 2-fold more aggrecan gene and collagen 2 gene than a population of nucleus pulposus cells derived from mammalian disc tissue grown in anchorage dependent culture,
Lin shows the effect of culture time on aggrecan and collagen type II mRNA expression in rat IVD (intervertebral disc) cells cultured in alginate beads (pg. 9, para. [0055]; and Fig. 3). After IVD cells were embedded in alginate beads, the mRNA expression of aggrecan and type II collagen reached their maximal levels at day 14 (pg. 36, para. [0173]; and Fig. 3). Figure 3 shows that there was an at least 2-fold increase in aggrecan and collagen type II gene expression at day 14 compared to day 3 (Fig. 3). In another embodiment, in monolayer culture, both aggrecan and collagen II mRNA expression in the treated (simvastatin) group did not show a difference compared with the control. In 3-D culture, the data showed that simvastatin continuously elevated BMP-2 mRNA expression from day 3 up to day 7, when the peak level was present (5-fold). As a consequent responsiveness to elevated BMP-2, aggrecan was expressed increasingly from day 3 to day 21 by 11-fold. (Figure 1). While collagen type II showed slight delay in the increase after day 7, the increase was sustained to day 21 by 16 fold (Figure 2) (pg. 32, para. [0160] thru pg. 33, cont. para. [0160]; and Figs.1 and 2 [nexus to Sakai et al.- expression of aggrecan and collagen type 2 is increased when cells are cultured under anchorage independent conditions]).
Blanco et al. shows that the nucleus pulposus (NP) contains mesenchymal stem cells, which are similar to bone marrow (BM) mesenchymal stem cells (MSC) (pg. 2259, column 2, Conclusion [nexus to Sakai et al. (2013)- discogenic cells from nucleus pulposus]). MSC obtained from BM were able to differentiate in all cases to, minimally, chondrocytes. NP-MSC and BM-MSC all expressed the following important genes in NP and other chondrogenic tissues: aggrecan, collagen type II, COMP, SOX6 and SOX9 (pg. 2262, column 2, para. 1-2 thru pg. 2263, column 1, line 1 [nexus to Sakai et al. (2013) and Lin- NP cells express aggrecan and collagen type 2]). Mature NP cells are quite similar to chondrocytes (pg. 2261, column 2, para. 4).
Regarding claim 1, pertaining to less than about 40% of the cell population expresses the cell surface marker CD105,
Blanco et al. shows that the immunophenotypic characterization of MSC from both NP and BM tissue was carried out using FITC (fluorescein isothiocyanate)-labeled cell markers, including CD105. For each antigen, besides percentage of positive cells, mean fluorescence intensity (MFI) ratio was calculated (pg. 2261, column 1, para. 2). Results of flow cytometric immunophenotyping showed that various cell markers, including CD105, were significantly lower in the IVD-MSC group than in the BM-MSC group (pg. 2262, column 2, lines 12-20; and Supplemental Data, after the last page of the document). The graph presented in the Supplemental Data shows that NP-MSC are less than 40% of the total number of cells that express CD105 (Supplemental Data, after pg. 2265 of the document).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time that the claimed invention was made, to have modified the method of treating an intervertebral disc of a subject by administering a pharmaceutical composition comprising a discogenic cell population to the intervertebral disc (IVD) of the subject, as shown by Sakai et al. (2013) as evidenced by Sakai et al. (2012), by incorporating a viscous non-reactive reagent (such as methylcellulose) into the culture medium at a concentration of about 0.1% to 1% [Claim 1], as shown by Duntsch et al., with a reasonable expectation of success, because Duntsch et al. shows the cultivation of a discogenic cell population, which is the cultivation method, shown by Sakai et al. (2013) (MPEP 2143 (I)(G)).
It would have been further obvious to have propagated the discogenic cell population in anchorage independent culture, so that the cells express at least 2-fold more aggrecan gene and collagen 2 gene when compared to the cells grown in anchorage dependent culture [Claim 1], as shown by Lin, with a reasonable expectation of success, because Lin shows the propagation of IVD cells (i.e., cells recovered from the nucleus pulposus (NP) of intervertebral discs) in anchorage dependent (monolayer) and anchorage independent (alginate beads/3D culture) conditions, which are the culture conditions shown by Sakai et al. (2013) as evidenced by Sakai et al. (2012) for the same type of cells; i.e., discogenic cells (MPEP 2143 (I)(G)).
In addition, although not measured as a fold increase in gene expression, Sakai et al. (2013) shows that both the aggrecan proteoglycan and collagen type II proteins are expressed at an increased level in NP cells grown under anchorage independent conditions (compared to similarly grown fibroblast cells) (Figure 4c-d).
One of ordinary skill in the art would have been motivated to have made that modification, because Sakai et al. (2013) teaches that the major role of NP cells is the production of ECM (extracellular matrix) configured from type II collagen and proteoglycan [aggrecan] (pg. 11, para. [0130]). That is, one of ordinary skill in the art of treating the IVD of a subject would prefer to administer NP cells that express the greatest amount of aggrecan and collagen type 2 gene product by way of optimizing the therapeutic composition comprising said cells used to treat a damaged or injured IVD.
It would have been further obvious to have propagated a discogenic cell population comprising cells that express less than about 40% of the cell marker CD105 [Claim 1], as shown by Blanco et al., with a reasonable expectation of success, because Blanco et al. shows that intervertebral disc cells comprising NP cells, which are the cells shown by Sakai et al. (2013), are/contain mesenchymal stem cell-like cells, which exhibit a CD105 expression level that is less than 40% of the total number of NP-MSCs (MPEP 2143 (l)(G)).
One of ordinary skill in the art would have been motivated to have made that modification, because Blanco et al. teaches that the findings of the described study suggest that intervertebral disc degeneration may be treated by cell therapy, and by stimulating endogenous MSC from NP (pg. 2259, column 2, Conclusion). That is, with regard to therapeutic use, a cell having stem cell-like characteristics (i.e., a low level of CD105) would be attractive as a therapeutic tool to, for example, replace degraded NP tissue. Therefore, the ability to identify cells with a desired level of cell surface marker presentation (e.g., less than about 40% CD105) would have the ability to differentiate into chondrocytes, CD105 having chondrogenic potential.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Regarding claim 2, pertaining to serum, Lin shows cell culture in alginate beads (i.e., anchorage independent conditions or low adhesion). Beads were cultured in DMEM/F12 medium with 10% FBS (fetal bovine serum), glutamine and vitamin C (pg. 34, para. [0164]).
Regarding claim 3, Lin shows, in one embodiment, that in monolayer culture, both aggrecan and collagen II mRNA expression in the treated (simvastatin) group did not show a difference compared with the control. In 3-D culture, the data showed that simvastatin continuously elevated BMP-2 mRNA expression from day 3 up to day 7, when the peak level was present (5-fold). As a consequent responsiveness to elevated BMP-2, aggrecan was expressed increasingly from day 3 to day 21 by 11-fold. (Figure 1). While collagen type II showed slight delay in the increase after day 7, the increase was sustained to day 21 by 16 fold (Figure 2) (pg. 32, para. [0160] thru pg. 33, cont. para. [0160]; and Figs.1 and 2).
Regarding claim 4, pertaining to greater than 70% of the discogenic population produces cell surface marker CD44, and CD44 gene product, Sakai et al. (2013) shows, in one embodiment, that the expression of other surface molecules in the human nucleus pulposus cell was determined. Other surface molecules were investigated by three fractionations from among A (Tie2-GD2-), B (Tie2+GD2+), and C (Tie2-GD2+). Expressions of, minimally, CD44 were observed in 80% or more A, B, and C fractionations of the nucleus pulposus cells (pg. 5, para. [0078]).
Regarding claims 5 and 6, transplantation to the mouse caudal vertebra was performed. Purified human nucleus pulposus cells were suspended in PBS and subsequently injected into an insulin syringe with 27 gauge needles. Said cell suspension was injected and transplanted into the caudal vertebra of an injured NOD/SCID mouse, where the nucleus pulposus tissues had been absorbed with the same 27 gauge needles (pg. 9, para. [0116]). That is, the cells were injected into the same location in the vertebra that mouse NP tissue had been previously collected (pg. 7, para. [0102]); i.e., the nucleus pulposus.
Claims 7 and 8 are rejected under 35 U.S.C. §103(a) as being unpatentable over Sakai et al. (2013) as evidenced by Sakai et al. (2012) in view of Duntsch et al., Lin, and Blanco et al., as applied to claims 1-6 above, and further in view of Shapiro et al. (Pub. No. WO 03/068149 A2), and Gorensek et al. (Cell. Molec. Biol. Ltrs. 2004, 9: 363-373).
Sakai et al. (2013) as evidenced by Sakai et al. (2012) in view of Duntsch et al., Lin, and Blanco et al. do not show: 1) the discogenic population is frozen before administration [Claim 7]; and 2) the discogenic population is frozen after growth in the anchorage dependent culture and before growth in the anchorage independent culture [Claim 8].
Shapiro et al. and Gorensek et al. provide information from which one of ordinary skill in the art would have understood that the discogenic cell population (comprising nucleus pulposus (NP) cells) could have been frozen before administration, as well as after anchorage dependent culture growth but before anchorage independent culture, by way of addressing the limitations of claims 7 and 8.
Regarding claims 7 and 8, Shapiro et al. shows novel compositions and methods for the treatment of degenerative intervertebral disc disease involving implanting nucleus pulposus cells into the nucleus pulposus space of a degenerated disc (pg. 1, para. [0002] [nexus to Sakai et al. (2013)- treat an intervertebral disc with discogenic cells isolated from the nucleus pulposus]). The end plate, annulus, and nucleus pulposus tissue fragments were suspended in, minimally, Triton-X 100 in PBS. The extracts were polytron homogenized and stored at -80°C until they were analyzed (pg. 25, para. [0113]).
Regarding claims 7 and 8, Gorensek et al. teaches that basic research on nucleus pulposus reinsertion has been conducted. Researchers found that using a rat model in which a disc herniation was induced in the caudal vertebrae of rats, the reinsertion of either fresh or cryopreserved nucleus pulposus was found to prevent the progression of IVD (intervertebral disc) degeneration (pg. 370, para. 1).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time that the claimed invention was made, to have modified the method of treating an intervertebral disc of a subject by administering a pharmaceutical composition comprising a discogenic cell population to the intervertebral disc (IVD) of the subject, as shown by Sakai et al. (2013) as evidenced by Sakai et al. (2012) in view of Duntsch et al., Lin, and Blanco et al., as applied to claims 1-6 above, by: 1) freezing the discogenic cell population before administration [Claim 7]; and/or 2) freezing the discogenic cell population after the anchorage dependent culture step but before the anchorage independent culture step [Claim 8], with a reasonable expectation of success, because Gorensek et al. shows that cryopreserved nucleus pulposus (which contains the described discogenic cell population) was as successful as fresh tissue in preventing IVD degeneration (MPEP 2143 (I)(G)).
Therefore, barring a showing of criticality for the specific limitation, it would have been obvious (in view of the additional information, shown by Shapiro et al., that nucleus pulposus tissue could be frozen prior to the extraction of its cells for their successful use as a therapeutic in treating an IVD) to have frozen the discogenic cell population derived from mammalian nucleus pulposus disc tissue at any point prior to its administration to a subject, e.g., before or after anchorage independent cell culture [Claims 7 and 8], with the reasonably predictable expectation that said administration would have treated the IVD of a subject (e.g., a subject with a damaged or injured IVD) (MPEP 2144 (III)).
One of ordinary skill in the art would have been motivated to have made that modification, because the knowledge that the discogenic cell population could be frozen without damaging their therapeutic value, would allow the practitioner to compile a large stock of ready-to-administer cells over time, thereby expediting the treatment of a subject with a damaged or injured IVD, without relying on the potentially unfavorable logistics of producing the discogenic cell population for 'just-in-time' administration.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP 2159. See MPEP 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/ patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/ patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 9-11 of Patent No. 11,891,626 B2.
The claimed subject matter of instant Application No. 18/416,244 is:
Claim 1. A method of treating an intervertebral disc of a subject. The method comprises administering a therapeutic amount of a pharmaceutical composition to the intervertebral disc of the subject. The pharmaceutical composition comprises a discogenic cell population derived from mammalian nucleus pulposus disc tissue.
The discogenic cell population has been passaged at least one time in an anchorage dependent culture, then is transferred to and maintained in-vitro in anchorage independent culture comprising one or more of: (i) a viscous non-reactive reagent at a concentration of about 0.1% to 1% or (ii) low adhesion coating on a culture receptacle.
The cell population expresses at least 2-fold more aggrecan gene and collagen 2 gene than a population of nucleus pulposus cells derived from mammalian disc tissue grown in anchorage dependent culture, and less than about 40% of the cell population expresses the cell surface markers CD24 and CD105, after seven days in anchorage independent culture.
Claim 2. The anchorage independent culture comprises a media comprising one or more additives selected from EGF, bFGF, and serum.
Claim 3. Expression of the aggrecan gene and collagen 2 gene is at least 5-fold greater than the same genes expressed in a population of nucleus pulposus cells derived from mammalian disc tissue grown in anchorage dependent culture.
Claim 4. Greater than 70% or less than 40% the population further produces one or more cell surface markers selected from the group comprising CD34, CD44, CD73, CD90, CD166, Stro-1, HIF1, nestin, CK8, and HLA proteins, and one or more genes or gene products selected from the group comprising GAPDH, SDHA, HPRT1, B2M, Sox9, Col1, nestin, CK8, Sox1, CD44, ALP1, and PPARG.
The claimed subject matter of Patent No. 11,891,626 is:
Claim 1. A discogenic cell population. The discogenic cell population is derived from mammalian nucleus pulposus disc tissue.
The discogenic cell population has been passaged at least one time in an anchorage dependent culture, then is transferred to and maintained in-vitro in anchorage independent culture comprising methylcellulose at a concentration of about 0.1% to about 5% or a low adhesion coating.
The cell population expresses at least 2-fold more aggrecan gene and collagen 2 gene than a population of nucleus pulposus cells derived from mammalian disc tissue grown in anchorage dependent culture, and less than about 40% of the cell population expresses the cell surface markers CD24 and CD105, after seven days in anchorage independent culture.
Claim 2. The anchorage independent culture comprises a media comprising one or more additives selected from EGF, bFGF, and serum.
Claim 3. The cell population is passaged in a culture receptacle comprising a low adhesion coating.
Claim 4. Expression of the aggrecan gene and collagen 2 gene is at least 5-fold greater than the same genes expressed in a population of nucleus pulposus cells derived from mammalian disc tissue grown in anchorage dependent culture.
Claim 5. The population further produces one or more cell surface markers selected from the group comprising CD34, CD44, CD73, CD90, CD166, Stro-1, HIF1, nestin, CKS, and HLA proteins.
Claim 6. The percentage of the cells producing the one or more cell surface markers of claim 5 is greater than 70% or less than 40%.
Claim 7. The population expresses one or more genes or gene products selected from the group comprising GAPDH, SDHA, HPRT1, B2M, Sox9, Col1, nestin, CKS, Sox1, CD44, ALP1, and PPARG.
Claim 9. A method of using the discogenic cell population of claim 1 to treat at least one disc in a subject in need thereof comprising: administering a therapeutic amount of the discogenic cell population of claim 1 to the subject, thereby treating the subject.
Claim 10. A method of treating a subject having at least one diseased or damaged intervertebral disc, comprising: administering to the subject the discogenic cell population of claim 1, in an amount effective to treat the disease or damage.
Claim 11. A method of treating an indication selected from the group consisting of degenerative disc disease, herniated disc, and injured disc, comprising: administering a therapeutic amount of the discogenic cell population of claim 1, thereby treating the indication.
Although the claims are not identical, they are not patentably distinct from each other because, as demonstrated above in the claim sets from each application, the discogenic cell population and the methods for its use, described in Patent No. 11,891,626 B2 anticipates the method of treating an intervertebral disc of a subject, described in instant Application No. 18/416,244.
Response to Arguments
Applicant’s arguments, pp. 7-11, filed on 06 November 2025, with respect to the prior art references cited in the 35 U.S.C. §103(a) rejections, have been fully considered but they are either not persuasive or are moot because the arguments do not apply to the references as they are applied in the context of the current rejection, or as new grounds necessitated by Applicant’s amendment, in which claim 1 was amended.
1. Applicant remarks (pg. 8, para. 2) that independent claim 1 is presently amended. Amended claim 1 is neither taught nor suggested by the cited art. First, Sakai's colony forming culture system, and its requirement for addition of angiopoietin, are distinct from the claimed manufacturing conditions and phenotype. That is, Sakai's "colony assay" is distinct, at least because it is not intended to expand the cell population, from Applicant's anchorage independent culture method. Sakai (¶ 0091) expressly conditions viability of its cells on the presence of angiopoietin. This statement, alone, would have "discouraged" the skilled artisan from following Applicants' path which neither include, let alone requires angiopoietin.
However, in response to Applicant, first, Sakai et al. (2013) does show that nucleus pulposus stem cells are cultured and proliferate under the conditions described (pg. 6, para. [0087]). Second, there is no description in the claimed subject matter of a complete list of the ingredients in the culture medium used to culture the nucleus pulposus (NP) cells apart from the use of a viscous non-reactive agent to encourage anchorage-independent culture [Claim 1] and the one or more additives described in claim 2 that the medium/media may comprise. That is, there is no description of those ingredients that are required (nor of those which are not required or not allowed). On the other hand, the instant originally-filed specification recites that angiopoietin can be added to the claimed culture media (spec., pg. 10, para. [0054]).
2. Applicant remarks (pg. 8, last para. thru pg. 9) that Sakai also fails on the claimed marker phenotype. Sakai's cell surface marker signature is the opposite of the present requirement that less than about 40% of the population expresses CD105, and it is reported in a different gel-entrapment modality and timeline than is claimed. Fig. 12 depicts CD105 at approximately 96-98%.
However, in response to Applicant, Sakai et al. (2013) is not a "102-type" reference; i.e., the reference is part of a combination of references which address the limitations of the claimed subject matter. In addition, it is not clear that the culture conditions described by Sakai et al. (2013) and those described by the claimed subject matter are the same nor is it clear how similar the culture conditions may be. On the other hand, Sakai et al. (2013) shows that the expression of CD105 was observed in 80% or more of the different fractionations of the cells from the culture medium (pg. 5, para. [0078]). That is, 20% of the cells did not express CD105; and, therefore, one of ordinary skill in the art could have selected those cells out of the population if there was a criticality shown that less than about 40% of the NP cells should express CD105.
There are many different types of cell surface markers which are expressed by any particular population of cells; e.g., Sakai et al. (2013) shows that the cell surface markers CD44, CD49f, CD56, CD73 and CD90 were expressed by the described NP cells (pg. 5, para. [0078]). Therefore, one of ordinary skill in the art of screening a(n) NP cell population could have gated said cells with a flow cytometry protocol that could select cells expressing any cell marker or combination thereof. For example, the instant specification recites: "Cell surface markers that may aid in characterizing a discogenic cell population may include, without limitation, CD24, CD34, CD44, CD73, CD90, CD105, CD166, Stro-1, HIF1, nestin, CK8, and HLA proteins (Human Leukocyte Antigen, e.g. HLA-A, -B, -C, HLA-DQ, and HLA-DR) (spec., pg. 14, para. [0062]). Therefore, the inclusion of CD24 and CD105 in the claimed subject matter appear to be arbitrary, with no criticality shown for these specific cell markers.
3. Applicant remarks (pg. 9, para. 1-2) that Lin and Seifert cannot compensate for the failures of the Sakai references. Lin cultures cells by encapsulation in alginate beads - a crosslinked hydrogel entrapment system - while employing exogenous interventions to drive cell identity. Alginate bead entrapment is not a low-adhesion surface or a low-percent, non-reactive viscous suspension format, and Lin's results rely on pharmacologic cues not required or recited here. It is not reasonable to expect that one of skill in the art would substitute Lin's gel entrapment for the claimed low-adhesion/low-viscosity modalities, while also predicting the present seven-day expression levels of aggrecan/collagen II and surface marker levels. Lin explicitly teaches that it is unreasonable to expect to achieve Applicant's gene expression levels. Figure 3 demonstrates that Lin's cells achieve higher expression only after 14 days growth in alginate beads - indeed, after 7 days growth in alginate beads - Aggrecan gene expression is reduced, and Collagen type II expression is unchanged.
However, in response to Applicant, the reference of Seifert et al. (cited in the Non-Final Office Action mailed 06 May 2025 and on the record) teaches that alginate bead cell propagation is an example of anchorage-independent cell culture, and that the alginate gel could be interpreted as a 'low-adhesion surface'. In addition, Lin shows that after 14 days in culture there is an at least 2-fold increase in aggrecan and collagen type II gene expression; i.e., it is clear that the described NP cells have the potential to achieve the instantly-claimed levels. If a criticality can be established that the NP cells reach the claimed aggregan and collagen 2 gene expression after seven (as opposed to 14) days in culture, one of ordinary skill in the art would use routine optimization to optimize the culture parameters so as to achieve the claimed expression levels in less than fourteen days.
4. Applicant remarks (pg. 9, last para. thru pg. 10) that Blanco cannot compensate for the failures of Sakai and Lin. The Office relies on Blanco for CD105, but Blanco's MSC-like immunophenotypes are not predictive of the downstream distribution that might result after Applicant's processing, particularly in light of the recited seven-day aggrecan/collagen II expression levels. Applicants note that general "optimization" cannot bridge the significant differences between the cited arts' culture methods and phenotypes. The suggestion that a skilled artisan would simply "optimize" anchorage independent culture ignores the material differences between gel entrapment systems described by the cited art and the presently claimed low adhesion/low viscosity modalities.
However, in response to Applicant, the comment made by Applicant (that Blanco's MSC-like immunophenotypes are not predictive of the downstream distribution that might result after Applicant's processing, particularly in light of the recited seven-day aggrecan/collagen II expression levels) appears to be so-called "opinion evidence". It is well known that in assessing the probative value of an expert opinion, the examiner must consider the nature of the matter sought to be established, the strength of any opposing evidence, the interest of the expert in the outcome of the case, and the presence, or absence of factual support for the expert's opinion (MPEP 716.01 (c)(llI)).
In addition, routine optimization of cell cultures generally involves adjusting cell culture medium components, which can, in turn, apply to any type of anchorage-independent cell culture system, whether it be alginate beads or low adhesion/low viscosity systems. For example, Jiang et al. (BioProc. Intl. 2012, pp. 1-9 (provided here)) teaches that, in general, for a fed-batch cell culture process, optimization can be achieved by development efforts addressing one or more of three major elements: basal medium, feed medium, and process settings. Given the large sets of variables in these systems, establishing a cost- and time-efficient approach for process optimization is desired but challenging (pg. 1, para. 2). That is, routine optimization encompasses three major areas as standard practice optimization regardless of the goals of the cell culture system. With regard to process settings, optimization can include adjusting the length of time that cells are in culture, as well as other parameters such as incubation temperature.
5. Applicant remarks (pg. 10, para. 3-4) against the rejection of dependent claims 7 and 8. Shapiro and Gorensek are not cited for teaching nor do they teach the aspects of claim 1 missing from the Sakai 2013, Sakai 2012, Lin, Seifert, and Blanco. Shapiro's handling of tissue extracts and Gorensek' s tissue reinsertion models do not address freezing of Applicants cell culture-created discogenic cell population characterized by the present seven-day comparative gene-expression benchmark and dual-marker thresholds under the claimed culture modalities.
However, in response to Applicant, Shapiro et al. and Gorensek et al. were cited to address the limitations of dependent claims 7 and 8, which describe freezing the discogenic cell population before administration and during the culturing process (i.e., after anchorage dependent growth and before anchorage independent growth). The cited prior art of Sakai et al. (2013), Duntsch et al., Lin, and Blanco et al. address the limitations of at least claim 1.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/SMP/Examiner, Art Unit 1657