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
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This Action is in response to the papers filed on December 31, 2025 for a Request for Continued Examination. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 31, 2025 has been entered.
Pursuant to the amendment filed on December 31, 2025, claims 1, 3-6 are currently pending of which claims 1, 4, and 6 have been amended.
The Declaration filed under 37 C.F.R. § 1.132 by Dr. Sung Won Kim on August 22, 2025 (“Kim Decl. ”), and filed on August 22, 2025 has been previously acknowledged.
Therefore, claims 1, and 3-6 are currently under examination to which the following grounds of rejection are applicable.
Priority
The instant application claims foreign priority 35 U.S.C. 119(a)-(d) to Republic of Korea applications 10-2018-0095658 filed on August 16, 2018 and 10-2019-0099786 filed on August 14, 2019, both filed prior to PCT/KR2019/010438 filed on August 16, 2019. Receipt is acknowledged of untranslated certified copies of papers required by 37 CFR 1.55.
Thus, the earliest possible priority for the instant application is August 16, 2018.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 103
In view of Applicants' amendment to the claims dated December 31, 2025, wherein claims 1,4, and 6 are amended, the rejection to claims 1, 3 and 4 rejected under 35 U.S.C. 103 as being unpatentable over Mumme et al. in view of Stuart et al. and Funayama et al. are withdrawn.
In view of Applicants' amendment to the claims dated December 31, 2025, wherein claims 1,4, and 6 are amended, the rejection to claims 5 and 6 rejected under 35 U.S.C. 103 as being unpatentable over Mumme et al. in view of Stuart et al. and Funayama et al., as applied to claims 1 and 4, and further in view of Shafiee et al. and Schmal et al. are withdrawn.
The reasoning behind the withdrawn rejections is in view of the amended claims 1 and 4, and in view of the Remarks filed on December 31, 2025. In particular, the Applicant describes Mumme teaching collagen scaffold/membrane in combination with nasal chondrocytes for treatment of cartilage damage, yet Stuart teaching a scaffold-free approach with chondrocytes spheroids wherein Stuart describes a scaffold, e.g. a hydrogel, impairs cell-to-cell interactions. Therefore, it can be understood that the references do work in combination, and as such these rejections have been withdrawn accordingly.
Applicants' arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
New Grounds of Rejection
Claim Rejections - 35 USC § 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 (i.e., changing from AIA to pre-AIA ) 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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Stuart et al. (Stem Cells International, 2017; of record IDS filed on February 16, 2021; hereinafter ‘Stuart’) in view of Funayama et al. (J Orthop Sci (2008) 13:225–232; hereinafter ‘Funayama’; of record) and Chen et al. (Cell and Tissue Banking 19.1 (2018): 35-46; hereinafter ‘Chen’).
Regarding claim 1, Stuart teaches a method of obtaining cartilage progenitor cells (CPCs) from human nasal septum cartilage in which CPCs are formed into spheroids for scaffold-free cartilage engineering (abstract; Figure 1). The advantages of spheroids as opposed to a scaffold/monolayer approach are described as being lower in cost, absence of exogenous stimuli, and a high cell viability, all of which amount to an optimized delivery system for tissue engineering (abstract, Fig. 3). Figure 7 depicts the CPC spheroids after spontaneous chondrogenesis (21-day culture) as retaining fusion capacity. Stuart describes in view of applicability that “Delivering CPC spheroids introduce a great promise to improve retention in cartilage tissue implantation site” (Conclusion). Figure 1 depicts the process of obtaining cell spheroids using molds.
Stuarts’s cartilage progenitor cells (CPCs) are similar to the claimed nasal chondrocytes claimed in view of the Specification, page 9 that states, “In the present invention, the chondrocyte is a concept that also includes chondroprogenitor cells, which are cells whose differentiation direction has been determined as chondrocytes.”
Stuart does not teach a method of treating articular cartilage damage comprising administering a pharmaceutical composition comprising a mixture of nasal septum chondrocytes (NSCs) and collagen support as an active ingredient into a subject in need thereof, wherein the pharmaceutical composition is formulated as an injection.
Funayama teaches the repair of full-thickness articular cartilage defects using injectable type II collagen gel embedded with cultured chondrocytes (title; “Chondrocyte/type II collagen solution mixed with PTE-TSG was injected via an 18-gauge needle into the right knee of each rabbit in the transplanted group until the defect was filled.” (p 226, col 2, par 3)). Funayama teaches that the results indicate that type II collagen gel is suitable for injection into cartilage defects without any covering of a graft and offers a useful scaffold during chondrocyte transplantation (p 225, col 2 , par 1)). Funayama further elucidates collagen as being the principal component of a natural matrix in articular cartilage wherein using collagen in scaffolds has advantageous properties (p 230, col 2, par 1). Lastly, the reference describes “Chondrocyte transplantation with type I collagen gels reportedly induces synthesis of type II collagen and proteoglycans in gels in vitro,8,16 and favorable results have been reported in vivo.” (p 229, col 2).
Funayama does not teach the injection comprising specifically nasal chondrocytes, but rather chondrocytes isolated from the shoulder, knee, and hip joints of rabbits, and moreover the collagen was prepared from the nasal septa of cattle (p 226, col 1).
Chen teaches the delivery of nasal chondrocytes via injection to treat articular cartilage damage that have been expanded in a hydrogel. The outcomes for this treatment group was “superior and more hyaline-like repaired tissue both at 3 and 6 months after surgery. Mechanical analysis showed that the repaired tissue in the Alg+ NC group possessed similar mechanical properties to the native cartilage” (abstract, title).
In reference to the “spheroidal pellet” limitation, the Stuart reference describes the pellet culture as being formed by an external force, e.g. centrifugation, and furthermore, “In contrast to aggregates formed by external forces, spheroids are formed by self-assembling process using nonadherent hydrogel molds or platforms such as hanging-drop, 96-well plate, and recently micromolded nonadhesive hydrogels” (p 2, col 1). Funayama teaches forming a chondrocyte pellet prior to resuspension in culture medium via centrifugation (p 226, col 1, par 3). However, based on the entirety of the Specification, specifically Example 3, it appears that the use of the term “pellet” does not require an external force since the spheroidal shapes are formed by seeding cells inside the StemFIT 3D (Microfit) without an external force applied. Consequently, there appears to be no difference in the structure of the spheroids described by Stuart than the spheroidal pellets claimed.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the chondrocytes of Funayama that are delivered in combination with injectable grade collagen with the spheroidal nasal chondrocytes taught by Stuart to obtain the predictable outcome of treating articular cartilage damage as is shown by Funayama. This substitution is obvious in view of Stuart’s spheroids being shown to retain fusion capacity, having high cell viability, and described as having a purpose in treating cartilage damage. Additionally, it would be obvious for the spheroids to be delivered with collagen based on Funayama teachings that the protein is suitable for injection into cartilage defects without any covering of a graft (of note spheroids do not require a graft), is a principle component of articular cartilage, and it being shown that chondrocyte transplantation with collagen gels induces the synthesis of collagen and proteoglycans. Altogether, it would be obvious to inject spheroidal nasal chondrocytes with collagen to treat articular cartilage damage based on the combined teachings of Stuart and Funayama, and moreover Chen further supports that nasal chondrocytes can treat such damage when used in with an injectable hydrogel, or rather without a fixed membrane graft.
Regarding claim 3, dependent on claim 1, Stuart teaches wherein the NSCs express collagen type 2 or SOX9 (collagen: Fig. 6c, Sox9: Fig. 6h).
Regarding claim 4, the claim is directed to a method of making of the pharmaceutical composition described in the claim 1 rejection above.
Stuart teaches a method of producing human cartilage progenitor cells spheroids by isolating cartilage fragments from the nasal septum which are then expanded in culture flask containers comprising bovine serum albumin. The cells are then harvested for further culturing in media comprising bovine serum in hydrogel molds to obtain spheroidal shapes which were recovered after 2 days or 21 days (p 2, col 2, par 2- p 3, par 1; Fig. 1). Stuart teaches the advantages of spheroids as opposed to a scaffold/monolayer approach as lower in cost, absence of exogenous stimuli, and a high cell viability all of which amount to an optimized delivery system for tissue engineering (abstract, Fig. 3). Stuart describes in view of applicability that “Delivering CPC spheroids introduce a great promise to improve retention in cartilage tissue implantation site” (Conclusion).
Stuart does not teach combining spheroids with collagen, and consequently does not teach the spheroids mixed with a collagen support after recovery, and prior to injection.
Funayama teaches the repair of full-thickness articular cartilage defects using injectable type II collagen gel embedded with cultured chondrocytes (title; “Chondrocyte/type II collagen solution mixed with PTE-TSG was injected via an 18-gauge needle into the right knee of each rabbit in the transplanted group until the defect was filled.” (p 226, col 2, par 3)). Funayama teaches that the results indicate that type II collagen gel is suitable for injection into cartilage defects without any covering of a graft and offers a useful scaffold during chondrocyte transplantation (p 225, col 2 , par 1)). Funayama further elucidates collagen as being the principal component of a natural matrix in articular cartilage wherein using collagen in scaffolds has advantageous properties (p 230, col 2, par 1).
In reference to the limitation “spheroidal pellet” this is addressed in claim 1 rejection above, wherein it appears that the claimed pellet it similar in structure to that taught by Stuart.
Lastly, Chen teaches the delivery of nasal chondrocytes via injection to treat articular cartilage damage that have been expanded in a hydrogel. The outcomes for this treatment group was “superior and more hyaline-like repaired tissue both at 3 and 6 months after surgery. Mechanical analysis showed that the repaired tissue in the Alg+ NC group possessed similar mechanical properties to the native cartilage” (abstract, title).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the chondrocytes of Funayama that are delivered in combination with injectable grade collagen with the spheroidal nasal chondrocytes taught by Stuart to obtain the predictable outcome of obtaining a pharmaceutical composition comprising nasal chondrocytes (NSCs) and collagen, wherein the NCs are spheroidal in shape. The substitution is obvious in view of Stuart’s spheroids being shown to retain fusion capacity, having high cell viability, and described as having a purpose in treating cartilage damage. Additionally, it would be obvious for the spheroids to be delivered with collagen based on Funayama teachings that the protein is suitable for injection into cartilage defects without any covering of a graft (of note spheroids do not require a graft), is a principle component of articular cartilage, and it being shown that chondrocyte transplantation with collagen gels induces the synthesis of collagen and proteoglycans. Therefore, these teaching would have led one of ordinary skill in the art to combine the prior art reference teachings to arrive at the claimed invention.
Claims 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Stuart et al. (Stem Cells International, 2017; of record IDS filed on February 16, 2021; hereinafter ‘Stuart’) in view of Funayama et al. (J Orthop Sci (2008) 13:225–232; hereinafter ‘Funayama’; of record) and Chen et al. (Cell and Tissue Banking 19.1 (2018): 35-46; hereinafter ‘Chen’) as applied to claim 4, and further in view of Shafiee et al. (Stem Cells and Dev., Vol 20, No. 12, 2011; hereinafter ‘Shafiee’; of record) and Schmal et al. (Tissue Engineering, Vol 12, No. 4, 2006; hereinafter ‘Schmal’; of record).
Regarding claim 4, the disclosure of Stuart in view of Funayama and Chen is applied as in the 103 rejections above, the content of which is incorporated herein, in its entirety.
Regarding claim 5, dependent on claim 4, Funayama teaches the method step of using a filter after collagenase treatment to remove undigested fragments; however, Funayama does not teach the claimed filter size of a 40 to 50-nm filter, but rather a 100-mm filter (p 226, col 1, par 3).
Shafiee teaches “The cartilage specimens were cut into small pieces, digested with 0.2% protease solution…, followed by incubation in 0.2% w/v collagenase type I and II … then passed through 70 μm filters prior to culturing” (p 2078, par 3).
Schmal teaches that P0 and P2 chondrocytes were estimated to be in a range of 9 to 30 µm (average sizes of 12.99 + 0.22 and 12.64 + 0.31 µm, respectively (p 747, par 1)), which is larger than the pore size of the claimed filter.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Stuart in view of Funayama by utilizing a filter after dissociating a tissue/cell cluster prior to culturing wherein cellular debris is captured by the filter and chondrocytes pass through. In particular, by using a 50 um filter chondrocytes would be harvested based on their size being well-known in the art as discussed in Schmal. Altogether, this method step is well-known in the field of cell culturing where tissues are dissociated by chemical or physical means then captured/purified by filtration and/or centrifugation which is described in Funayama, Schmal, and Shafiee. The use of a 50 um filter is understood as optimization based on the target cell, as previously described in view of Schmal teachings and in view of Shafiee teaching a comparable filter size of 70 um for chondrocytes. Therefore, these teaching would have led one of ordinary skill in the art to combine the prior art reference teachings to arrive at the claimed invention.
It is noted the filter size claimed is 40-50 nm, as opposed to 40-50 uM or 40-50 mm. The obviousness rejection is in view of a filter being larger than the known sizes of chondrocytes as described by Schmal, wherein the cells would pass through. However, in view of the filter being smaller than the known sizes of chondrocytes, it would remain obvious to use in order to separate the cells from the filtrate which contains enzymes, buffer solutions and antibiotics, to successfully obtain chondrocyte cells. Clarification is further required in view of this limitation, as seen in the 112(b) rejection below.
Regarding claim 6, dependent on claim 4, Stuart teaches spheroids being formed in hydrogel molds (Figure 1), and Funayama teaches a chondrocyte/collagen solution mixed with 100 μl of 5 mM pentaerythritol PEG ether tetrasuccinimidyl glutarate (PTE-TSG), and further describes other hydrogels being used to improve retention during injections by preventing leakage (p 225, par 5), and Chen teaching using an alginate hydrogel with nasal chondrocytes for delivery via injection (abstract). Lastly, Funayama describes developing “a type II collagen gel scaffold by chemically reacting type II collagen with a crosslinker in which the main ingredient is polyethylene glycol (PEG). The mixture of type II collagen and PEG-based crosslinker becomes liquid immediately after the crosslinking reaction, forming a gel within several minutes. This allows direct injection of chondrocytes with type II collagen gel into a cartilage defect.” (p 226, par 2).
Response to Applicants’ Arguments as they apply to rejection of claims 1, 3-6 under 35 USC § 103 over Mumme, Stuart and Funayama.
Starting on page 4 of the remarks filed on December 31, 2025, Applicants essentially argue the following:
The presence of a scaffold impacts the cell-to-cell interactions, and therefore Mumme’s chondrocytes could not possibly form spheroids as they are fixed to a membrane scaffold. Applicant then states, “Stuart clearly points out that a scaffold (such as a hydrogel) impairs cell-to-cell interactions. The spheroid compaction of Stuart is a cell-driven self-assembling process mediated by N-cadherin. In contrast, the cells of Mumme that are already embedded in an ECM or attached to a collagen membrane are confined by a physical substrate thereby blocking the direct cell-to-cell contact and aggregation that are essential for spheroid formation.”
The cell differentiation state between Mumme and Stuart are different, and would not perform the same. Stuart uses cartilage progenitor cells (CPCs) and Mumme uses mature chondrocytes.
The purposes or rather the problems being solved between Stuart and Mumme are different.
There is inconsistency in timing and sequence between Stuart and Mumme.
In response to these arguments they have been fully considered but are not persuasive due to the following reasons:
Regarding all the arguments presented, the new grounds of rejection no longer employ the reference of Mumme. The rejections were withdrawn in view of the amended claim 1 and 4, and in view of the argument pertaining to cell-to-cell interactions being limited with the scaffold of Mumme, and consequently interactions between spheroids would be limited.
The new rejection maintains that Stuart teaches nasal chondrocytes in spheroidal shape and in view of Funayama teaching the combination of chondrocytes with collagen for injections to treat articular cartilage damage, and providing in vivo teachings. The new rejection now uses Chen that teaches treating articular cartilage damage with specifically nasal chondrocytes in combination with a hydrogel for delivery via injections. Altogether, the new rejections make obvious the limitations listed in claims 1, 3-6.
In reference to the second argument presented pertaining to the cell types used, it is described above in the claim 1 rejection that the spheroidal chondrocyte progenitor cells that are isolated from nasal septums as described by Stuart are similar to the ones claimed in the instant application, as it is supported in the Specification on page 9, par 1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 5 is 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 5 is indefinite in the recitation of “in Step a), the NSCs are harvested after filtration with a 40 to 50-nm filter”, as it is unclear if the filter is being used to pass the cells through for collection or rather for the cells to be collected from the surface of the filter for the pharmaceutical composition.
Clarification is required based on the rather small size of the filter claimed, i.e. 40-50 nm, that is smaller than the average size of the chondrocytes. Therefore, passing the cells suspension through the filter, and using the filtrate would likely be unsuccessful based on the composition comprising dead/ruptured cells. However, if the cells collected on the surface of the filter are used then a different outcome would be expected, and as such this step should be reflected in the claims. Lastly, if the size of the filter is incorrect, then this should be amended; however, it is noted by the Examiner that the Specification only supports 30-50 nm, and such change would present a “New Matter” rejection under 112(a) (pages 4, 12, and 14).
Conclusion
Claims 1, 3-6 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634