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 .
This action is responsive to papers filed 04/20/2026.
Claims 8, 10-11, and 20 have been amended. No claims have been newly added or newly canceled.
Claims 1-21 are currently pending.
Claims 1-7, 11-18, and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 08/27/2025.
Claims 8-10 and 19-20 have been examined on their merits.
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.
Claim(s) 8-10 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Kesti et al (WO 2016/092106-from IDS filed 12/19/2022) in view of JP 2016513979 (hereinafter JP ‘979), Jacobs et al (WO 2016/065254) and Zhou et al (EBiomedicine, 2018).
Regarding claims 8 and 20, Kesti disclose a method for preparing a three-dimensional composition by printing bio-ink that contains chondrocytes, gellan gum and alginate in layers onto a surface in the shape of a nose or ear implant to obtain a biopolymer formulation, crosslinking the biopolymer formulation and maturing the three-dimensional composition during 8 weeks of culture thereby allowing the chondrocytes to produce extracellular matrix to form the three-dimensional composition with suitable stability for implantation (pages 18-19, example 1c and example 2). The bioink composition is disclosed as homogenous and mixed with chondrocytes (page 19 example 2) and thus the biopolymer formulation is also deemed to be homogenous. The chondrocytes are disclosed as isolated from bovine tissue (page 19 example 2) would require cell culture expansion steps to arrive at the disclosed cell density for mixing in the bio-ink preparation. Kesti disclose using cell concentrations of 3 x 106 cells/ml – 50 x 106 cells/ml (5 x 107 cells/ml) (page 13 line 9) and wherein their polymer blend was mixed with 6 x 106 cells/ml (page 18 Example 1c), but can contain 106 to 107 cartilage cells per ml (page 7 line 24). This cell concentration falls within the claimed range of Applicant’s three-dimensional composition product (Applicant’s claim 1).
While Kesti do not disclose the E-modulus of their composition, the resulting hydrogel has a high stiffness, the same starting materials and crosslinker and a maturation process of at least 8 weeks and thus the E-modulus would be at least close to the claimed E-modulus of at least 180 kPa and obtainable by routine optimization if not the same.
JP ‘979 disclose a method for printing a bio-ink for printing live tissue for treating a tissue defect (abstract). A suitable elastic modulus for printed cartilage is approximately 200 kPa and higher (page 5, second paragraph). The cell density of the bio-ink is disclosed as about 6 x 106 cell/mL or more (page 5, second paragraph).
One of ordinary skill in the art would have been motivated to optimize the elastic modulus of the Kesti composition to at least 200 kPa or more because JP’979 indicate that this is a suitable elastic modulus for a bio-ink composition intended for printed cartilage. One of ordinary skill in the art would have had a reasonable expectation of success because JP’979 and Kesti are both using bio-ink containing cartilage cells at a density of 6 x 106 cells/ml for printing cartilage tissue for implant use.
Kesti do not disclose using a cell number of at least about 6 x 107 chondrocytes from harvested culture.
JP’979 disclose wherein isolated chondrocytes are seeded into T175 tissue culture flasks at 5 million cells per flask for expansion as monolayers for 1-2 weeks in primary culture and the human chondrocytes are ready for use (e.g. bioprinted) (page 16, last paragraph).
One of ordinary skill in the art would have been motivated to expand isolated chondrocytes in vitro to obtain at least about 6 x 107 chondrocytes from a harvested culture in the method of Kesti because JP’979 teach and suggest that expanding chondrocytes for 1 to 2 weeks is beneficial to provide sufficient number of cells for use in bioprinting. The total number of cells would allow for larger implants and multiple implants and sufficient cells for backups and research. One of ordinary skill in the art would have had a reasonable expectation of success because JP’979 disclose the culture conditions for expansion of chondrocytes.
Regarding claims 9-10, Kesti disclose a bio-ink embodiment comprising 3.5% gellan gum, 3% alginate, tissue particles and 6 X106 chondrocytes/ml and a homogeneous biopolymer formulation and 8 weeks of culture (pages 18-19 example 1c, example 2). In certain embodiments the gellan gum is approximately 3% or 1-6% (w/v) and the alginate is approximately 2% or 0.5-8% (w/v) (page 7 lines 16-24).
With regard to the concentrations of gellan gum and alginate in the composition, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (MPEP 2144.05).
The selection of specific concentrations clearly would have been a routine matter of optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the amount and viability of the cells cultured would have been affected by these concentrations.
Regarding claim 19, Kesti disclose wherein their cells are autologous, human cells, specifically autologous chondrocytes (page 12 lines 20-29). Auricular cartilage is disclosed as a suitable source for tissue particles used with the bio-ink (page 17 lines 24-35) and the products printed are indicated for patient specific auricular grafts (page 9 lines 24-30). While Kesti is silent with regard to the specific site of the source of the chondrocytes used in their bio-ink method, one of ordinary skill in the art would have been motivated to use auricular chondrocytes in the method of Kesti because Kesti suggest that this is a suitable source for the tissue particles in their bio-ink. One of ordinary skill in the art would have had a reasonable expectation of success because Kesti indicate that their bio-ink graft products can be used to repair damaged auricular tissue.
Regarding claims 8-10 and 19-20, Kesti state that cartilage extracellular matrix production was evaluated after 8 weeks in culture (page 18 lines 11-23, page 23 lines 17-20) but do not specifically disclose how long after 8 weeks this evaluation is performed. Kesti do not specifically disclose maturing or culturing the three-dimensional composition for 10 to 24 weeks.
Jacobs disclose compositions and methods for cartilage replacement (Title). Jacobs disclose that including an in vitro culture period before transplantation would provide a more controlled environment in which the tissue-engineered cartilage could more effectively evolve and differentiate, locking in cartilaginous properties prior to subsequent implantation for additional change and maturation in cartilage morphology (page 20 lines 13-19). Jacobs in vitro culture period was determined by optimization to be about 12 weeks (page 20 lines 22-23, page 21 lines 1-9).
Zhou disclose methods for in vitro regeneration of patient-specific ear-shaped cartilage for auricular reconstruction (Title) and include wherein the ear-shaped (three-dimensional) cartilage construct was generated via in vitro expansion (page 288, bottom of column 2) and harvested at 12 weeks (page 293, column 2, Figure 3, page 297, section 3.2).
One of ordinary skill in the art would have been motivated to increase the culture time to at least about 12 weeks for the method of Kesti because Jacobs teach and suggest that this is an optimal time period for in vitro culture of a tissue-engineered cartilage replacement construct to provide a more controlled environment in which the tissue-engineered cartilage could more effectively evolve and differentiate, locking in cartilaginous properties prior to subsequent implantation for additional change and maturation in cartilage morphology. One of ordinary skill in the art would have had a reasonable expectation of success because Zhou disclose in vitro culture methods wherein a three-dimensional cartilage construct was harvested at 12 weeks.
Therefore, the combined teachings of Kesti, JP’979, Jacobs et al and Zhou et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant's arguments filed 04/20/2026 have been fully considered but they are not fully persuasive in view of the new rejection above.
Applicant argues that the subject matter of pending claim 8 differs from the Kesti reference method as the claimed method comprises maturing the three-dimensional composition for 10 to 24 weeks.
This is found persuasive. The previous rejection has been withdrawn and replaced with a new rejection above.
Applicant argues that the present inventors have surprisingly found that a long maturation of greater than 10 weeks improves both the cell viability and the mechanical stability of the resulting three-dimensional composition and point to evidence in their Specification at Examples 4.3 and 4.4 and Figures 2 and 3. Applicant asserts that cell viabilities over 70%, an elastic modulus of 180 kPa or higher and no bacterial or mycoplasma contamination despite the long maturation was surprising.
This is not found persuasive. The newly cited references of Jacobs and Zhou indicate that longer in vitro culture times of greater than 10 weeks are advantageous for the generation of an engineered cartilage construct as described above.
Applicant argues that the Kesti reference method is limited to maturation times of up to a maximum of 8 weeks and that there is no suggestion whatsoever in Kesti that longer maturation times may increase mechanical stability or improve cel viability. Applicant asserts that given the risk of contamination with increasing maturation times and the fact that no advantage of longer maturation times was suggested in any way, the skilled person would not have been motivated to increase the maturation time in the method of Kesti.
This is not found persuasive. Kesti state that cartilage extracellular matrix production was evaluated after 8 weeks in culture (page 18 lines 11-23, page 23 lines 17-20), but do not specifically disclose how long after 8 weeks this evaluation is performed. Kesti do not specifically disclose maturing or culturing the three-dimensional composition for 10 to 24 weeks, but also do not indicate that 8 weeks is a maximum time period for maturation.
Applicant argues that JP ‘979 does not disclose any maturation period of structures from bio-ink and thus cannot remedy the deficiencies in the teachings of Kesti.
This is not found persuasive. The newly cited references of Jacobs and Zhou indicate that longer in vitro culture times of greater than 10 weeks are advantageous for the generation of an engineered cartilage construct as described above.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Mauck et al., “Chondrogenic differentiation and functional maturation of bovine mesenchymal stem cells in long-term agarose culture”, OsteoArthritis and Cartilage, (2006) Vol. 14, pp. 179-189.
Mauck disclose in vitro culture of 3D cartilage constructs for greater than 10 weeks. (page 180, 185).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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