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 .
Applicant’s amendments and arguments of May 20, 2026, are entered.
Claims 1-2, 8-9, 14, and 20 have been amended.
Claims 3-4 and 13 have been canceled.
No new claims have been added.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on March 20, 2026, was filed before the mailing of the Final Office Action on July 25, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Claim Objections
The amendment to claim 6 overcomes the objection, and therefore, the objection is withdrawn.
Double Patenting
Applicant canceled claim 13 rendering the double patent warning moot. Therefore, the double patent waring for claim 13 is withdrawn.
Claim Rejections - 35 USC § 112(b)
Applicant amended claims 8 and 9 overcoming the §112(b) rejections. Therefore, the §112(b) rejections for claims 8 and 9 are withdrawn.
Claim Rejections - 35 USC § 112(d)
Applicant canceled claim 4 rendering the §112(d) rejection moot. Therefore, the §112(d) rejection for claim 4 is withdrawn.
Claim Rejections - 35 USC § 102
In light of Applicant’s amendments to claim 1 and 2, the §102 rejection for claims 1 and 2 are withdrawn.
Claim Rejections - 35 USC § 103
In light of Applicant’s amendments, the §103 rejection for claims 3-22 is withdrawn.
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.
Claims 1-2, 5-12, and 14-22 are newly rejected under 35 U.S.C. §103 as being unpatentable over Li et al. [Chitosan composite scaffolds for articular cartilage defect repair: a review, RSC Adv., 2018], in view of Mouw et al. [Variations in matrix composition and GAG fine structure among scaffolds for cartilage tissue engineering, Osteoarthritis and Cartilage, 2005], in view of Melrose et al. [The cartilage extracellular matrix as a transient developmental scaffold for growth plate maturation, Matrix Biology, 2016], in view of Melrose et al. (Hereinafter Roughley) [The structure, location, and function of perlecan, a prominent pericellular proteoglycan of fetal, postnatal, and mature hyaline cartilage, Journal of Biological Chemistry, 2006], in view of Wikipedia [Ki-67 (protein), https://en.wikipedia.org/wiki/Ki-67_%28protein%29, Wayback Machine, Jan. 2020], in view of Wikipedia [TUNEL assay, https://en.wikipedia.org/wiki/TUNEL_assay, Wayback Machine, Feb. 2020], in view of Hwang and Kim (Hereinafter Hwang) [Chondrocyte apoptosis in the pathogenesis of osteoarthritis, International Journal of Molecular Sciences, 2015], in view of Vinatier and Guicheux (Hereinafter Vinatier) [Cartilage tissue engineering: from biomaterials and stem cells to osteoarthritis treatments, Annals of Physical and Rehabilitation Medicine, 2016], in view of Klangjorhor et al [Hyaluronan production and chondrogenic properties of primary human chondrocytes on gelatin based hematostatic spongostan scaffold, Journal of Orthapaedic Surgery and Research, 2012], in view of Farrell et al. [Functional properties of MSC-based engineered cartilage are unstable with very long term in vitro culture, J Biomech, 2015].
Regarding claim 1, Li et al. teaches a method for producing a cartilage model, comprising the steps of simultaneously culturing a porous natural polymer support and a cartilage cell [Abstract]. However, Li et al. does not teach the limitations where the cartilage model that represents a growth stage, a maturation stage, an aging stage, or a degeneration stage with the relative time periods associated with each stage.
For these limitations, Mouw et al. discloses culturing cartilage constructs using different scaffolds that resulted in changes in extracellular matrix composition and glycosaminoglycan structure that showed progress in biochemical and phenotypic characteristics of cartilage in a growth stage [Results ¶ 1]. Because of this, a person of ordinary skill would have recognized that cartilage model cultured over time would exhibit phenotypic changes corresponding to different developmental stages. For the limitations where the culturing is performed 2-3 months, 5-7 months, 7-9 months, or 10-12 months depending on cartilage stage, Mouw et al. also teaches culturing cartilage constructs for 20-40 days which is within the 2-3 months [Results ¶ 1]. Additionally, Mauck et al. demonstrates that extended in vitro culture of engineered cartilage constructs was well known in the art. Specifically, Mauck et al. cultured mesenchymal stem cell-derived cartilage constructs for up to 112 days, approximately 16 weeks, evaluating the constructs at multiple time points. Mauck et al. further recognized that cartilage constructs continue to mature and change during prolonged culture [Abstract]. Thus, Mauck et al. establishes that extending cartilage culture beyond initial growth periods results in progressively more mature tissue [Discussion ¶ 6]. Here, a person of ordinary skill would understand that extending culture duration beyond the 20-40 days, as taught by Mauck et al., would allow further matrix development, maturation, and tissue remodeling. Because of this, it is prima facie obvious to a person of ordinary skill in the art before the before the filing of the claimed invention to modify the systems and methods of Li et al. where the authors discussed various methods in culturing cartilage with a 3D porous natural polymer scaffold with the teachings of Mouw et al. where it was disclosed early-stage matrix formation, including the formation of glycosaminoglycan chains. Because of this, there is a reasonable expectation of success that a person of ordinary skill would recognize the teachings of both Li et al. combined with Mouw et al. and Mauck et al. where culture conditions could be extended in order for the cartilage model to achieve later developmental stages withing the claimed temporal ranges. Lastly, citing MPEP § 2112.01(I), “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977)”. Mouw et al. and Li et al. establish a cartilage construct that is produced using substantially the same tissue-engineering techniques with Mauck et al. disclosing that engineered cartilage can be cultured for extended periods to include roughly 16 weeks.
For claim 2 where the natural polymer further comprises hyaluronic acid, Klangjorhor et al. discloses a porous natural polymer that contains hyaluronic acid [Scanning electron microscopy ¶ 1, HA assay ¶ 1, Figure 2].
For claim 5 where method further comprises confirming changes to the thickness in the outer layer in the cultured cartilage model, Mouw et al. teaches histological analysis and structural assessment of the cultured tissued constructs [Table 1]. Although not specifically measuring outer layer thickness, a person of ordinary skill would recognize the changes in tissue structure and extracellular matrix deposition would inherently affect tissue thickness and using routine methods, it would have been prima facie obvious to a person of ordinary skill to confirm changes in thickness that included increased thickness in the outer layer of the cartilage model.
For claim 6 where the cartilage is selected based on the different stages by confirming the thickness of the outer layer of the cartilage model, Mouw et al. discloses the assessment of matrix composition, extracellular matrix deposition, and structural differences among scaffolds over time. Histological analysis in Mouw et al. would provide the data on changes in tissue morphology and overall construct thickness allowing a person of ordinary skill to determine what growth stage the cartilage model is based on cultured conditions and culture duration.
For claim 7 that comprises confirming the presence of collagen type I or type II in the cultured cartilage model, Mouw et al. discloses culturing chondrocytes in various scaffolds and assessing the extracellular matrix deposition and matrix development over time [Results]. Here, a person of ordinary skill would recognize that extracellular matrix growth in cartilage constructs inherently implies the presence of collagen type II, and in some context collagen type I. This is because collagen is an essential structural component of cartilage extracellular matrix. Therefore, Mouw et al. suggests to a person of ordinary skill the presence of cartilage tissue producing collagen as a normal part of the extracellular matrix formation process.
For claim 8 where collagen type II is expressed and collage type I is hardly expressed, Mouw et al. discloses the formation of the extracellular matrix in articular cartilage. A person of ordinary skill would understand that collagen type II is the main component in the hyaline cartilage extracellular matrix [Results].
For claim 9 where collage type I is expressed and collagen type II is hardly expressed, Melrose et al., discussing cartilage extracellular matrix development, teaches that chondrocytes are tightly regulated at all stages including initial limb bud and rudiment cartilage stages of development [Abstract]. Melrose et al. further teaches that type I collagen is lad down by fibrocytic cells and replaces type II collagen in later stages of limb joint formation where it creates a transpositional replacement of type I and type II collagens [Collagens ¶ 1]. Based on this, it is prima facie obvious to a person of ordinary skill in the art that a person of ordinary skill measuring collagen expression profiles in cultured cartilage could select cartilage exhibiting higher type I/lower type II expression where it represented later, non-hyaline stage of development given the known transitional behavior of cartilage extracellular matrix and skeletogenesis taught by Melrose et al.
Claim 10 where lacuna or glycosaminoglycan presence is confirmed in the cartilage culture, Melrose et al. teaches that hyaluronan, the simplest glycosaminoglycan, has a widespread distribution in both cartilage and bone [Hyaluronan ¶ 1, 2], and that it is responsible for providing weight bearing properties [Id.]. Additionally, Melrose et al. discloses that chondrocyte arrangement within lacunae as a normal part of growth plate cartilage maturation [Introduction, MMPs ¶ 2]. Although Melrose et al. does not specifically teach the measuring either lacuna or glycosaminoglycans, confirming the presence and/or measuring the presence of these factors would have been obvious to assess the presence of glycosaminoglycans or lacuna-like structures given it could be used to evaluate the tissue development and extracellular matrix formation where both of these limitations are inherent features of cartilage extracellular matrix.
For claim 11 the cultured cartilage model is selected in a mature stage where the lacuna structure is maintained or the glycosaminoglycans is formed, Roughly et al. discloses that perlecan, a proteoglycan carrying glycosaminoglycan chains, is associated with matrix structures primarily in fetal and mature hyaline cartilage [Introduction ¶ 1]. Based on this, it would have been prima facie obvious to a person of ordinary skill to understand the presence of extracellular matrix components like glycosaminoglycan-rich proteoglycans are hallmarks of mature cartilage, and that this feature would also correlate with an organized lacunae along with other established extracellular structures.
For claim 12 where Ki-67 presence is confirmed, Wikipedia discloses that Ki-67 is a well-known marker in proliferating cells and can be used in immunohistochemistry to confirm the presence of cellular proliferation given that Ki-67 is “strictly” associated with cell proliferation [Use as a marker of proliferating cells ¶ 1].
For claim 14 where a cartilage model is selected that hardly expresses Ki-67, Wikipedia discloses that Ki-67 is a nuclear protein marker of cellular proliferation that is expressed during actively cycling cells, i.e. G1, S, G2, and M phases, would also mean that Ki-67 is absent in quiescent cells, i.e. G0 cells [Use as a marker of proliferating cells ¶ 1]. Combine this with the teachings in Roughly et al., a person of ordinary skill would understand that selecting a cartilage model that hardly expresses Ki-67, the cartilage culture would be made up of non-actively cycling cells, e.g. mature cartilage.
For claim 15 where a TUNEL assay is performed to confirm the presence of apoptosis of cartilage cells in the cartilage culture, Wikipedia discloses that TUNEL assays, i.e. terminal deoxynucleotidyl transferase dUTP nick end labeling, is a method for detecting DNA fragmentation by labeling the 3’-hydroxyl termini in the double-stranded DNA breaks generated during apoptosis [TUNEL assay]. Given this, it is prima facie obvious to a person of ordinary skill prior to the filing of the claimed invention that an artisan would select a TUNEL assay in order to determine the presence of apoptosis of chondrocytes in a cartilage culture based on TUNEL assays being widely used for identifying and quantifying apoptotic cells [Method].
Claim 16 where a cartilage culture is selected where apoptosis is not observed, Mouw et al. discloses cartilage cultures where apoptosis is not present given the cartilage cultures in Mouw et al. are actively expanding based on the presence of glycosaminoglycans that help form the extracellular matrix in cartilage which signifies the growth stage [Design ¶ 1].
Claim 17 where a cartilage model in which an apoptosis-positive cell begins to appear as a cartilage model in a mature stage, Hwang discloses that apoptosis is a marker of cartilage state and that once apoptosis is confirmed, selecting the specific model, e.g. mature stage, would be the next logical step given that apoptosis occurs as cartilage progresses toward later stages, including degeneration, where a person of ordinary skill would correlate the cartilage culture as “mature” [Graphical Abstract].
For claims 18 and 19 where the cartilage model is where most of the cells exhibit an apoptotic state where the cartilage model is in an aging state and degenerative state, Hwang, discussing the role of apoptosis in osteoarthritis and the dysregulation of apoptosis leads to the degenerative pathological state [Abstract]. And because articular cartilage depends on resident cells, i.e. the chondrocytes, for the maintenance of the extracellular matrix, the apoptosis of chondrocytes would lead to the failure of the articular cartilage [Abstract]. Because of this, a person of ordinary skill in the art would understand the presence of increasing apoptosis would be indicative of either an aging stage or a degenerative stage.
For claim 20 where a cartilage model is produced by the method of claim 1, Li et al. provides various methods where a cartilage model is produced where chondrocytes are cultured simultaneously with a porous natural polymer such as chitosan, gelatin, or alginic acid [Abstract].
For claim 21 where it involves testing the activity or toxicity of a test substance, comprising the step of treating the cartilage model according to claim 20 with the test substance, Vinatier discloses the use of combining mesenchymal stem cells and biomaterials capable of releasing proautophagic drugs as a means for improving osteoarthritis treatments to help with cartilage homeostasis [Conclusion ¶ 1].
For claim 22 where the activity is a measurement of drug metabolic activity or an assessment of drug interaction, Vinatier discloses the use of combining mesenchymal stem cells and biomaterials capable of releasing proautophagic drugs as a means for improving osteoarthritis treatments to help with cartilage homeostasis [Conclusion ¶ 1]. This would inherently involve assessment of drug interactions between the released proautophagic compound carried by the mesenchymal stem cells and the effects it had on articular cartilage as it relates to osteoarthritis, a degenerative disease that affects cartilage.
Therefore, it is prima facie obvious for a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Li et al. with the additional teachings of Vanatier where it was disclosed the potential use of mesenchymal stem cells and other biomaterials as a delivery mechanism for delivery of proautophagic drugs as a means for improving osteoarthritis degeneration affecting joint cartilage. Because of this, there is a reasonable expectation of success that a person of ordinary skill in the art would recognize the need to assess the effects of drug toxicity and/or drug interaction that is being administered to cartilage.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Argument
Applicant’s fundamental argument is found on pg. 17 of Applicant’s response submitted on May 20, 2026 where Applicant argues that essentially none of the references discloses a configuration in which a cartilage model is classified into four stages made up of a growth stage with a culture period of 2-3 months, a maturation stage with a culture period of 5-7 months, a aging stage with a culture period of 7-9 months, and a degeneration stage with a culture period consisting of 10-12 months. Applicant further states none of the references present the technical concept of configuring such time-based cartilage state definition as a functional in vitro platform for use in evaluating drug efficacy, toxicity, drug metabolic activity, or drug interaction.
Examiner appreciates Applicant’s argument. However, the examiner does not find this argument persuasive.
Mouw et al., in view of Mauck et al. teaches engineered cartilage constructs cultured over progressively longer periods, thereby recognizing the temporal maturation of engineered cartilage. Additionally, Applicant’s claim is directed to “wherein the cartilage model is a cartilage model in a growth stage, a maturation stage, an aging stage, or a degeneration stage”. As discussed above, Mouw et al. combined with Mauck et al., at the very least, disclose a growth stage within Applicant’s defined ranges. Furthermore, Applicant has not identified any structural or functional distinction between the claimed stages and the prior art constructs other than assigning descriptive stage names and associated culture conditions. Applicant has defined certain temporal culture conditions to encompass growth, maturation, aging, and/or degeneration. However, these definitions along with the assigned length of culture conditions does not distinguish the claimed subject matter over the prior art. Because of this, claims 1-2, 5-12, and 14-22 are newly rejected under 35 U.S.C. §103 as being obvious over the cited art.
Conclusion
No claims allowed.
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 JOHN DAVID MOORE whose telephone number is (703)756-1887. The examiner can normally be reached M-F 8-5.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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