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 .
Withdrawal of Rejections
The response and amendments filed on 11/05/2025 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality corrections and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous 35 U.S.C. 103 rejections for obviousness have been withdrawn necessitated by Applicant’s amendments; however, new grounds of rejection are set forth below.
The previous non-statutory double patenting rejection has been withdrawn necessitated by Applicant’s amendments to independent claim 5.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 5-7, 10, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Detamore (US 2016/0235892; Date of Publication: August 18, 2016 – previously cited) in view of Huang (Fabrication of Novel Hydrogel with Berberine-Enriched Carboxymethylcellulose and Hyaluronic Acid as an Anti-Inflammatory Barrier Membrane; 2016 – newly cited) and Leonardis (Use of cross-linked carboxymethyl cellulose for soft-tissue augmentation: preliminary clinical studies; 2010 – previously cited).
Detamore’s general disclosure relates to compositions comprising decellularized cartilage tissues powders for treating osteochondral defects (see, e.g., Detamore, abstract). Moreover, Detamore discloses that the cartilage tissue powder can be used for “treating full and partial-thickness cartilage defects caused by traumatic injury and osteoarthritis. This cartilage or bone tissue powder could also be used in tendon, ligament, meniscus, and TMJ regenerative applications. Preferably, the decellularized cartilage (DCC) fragment or powder is a chondroinductive material, meaning that it induces chondrogenesis” (see, e.g., Detamore, [0006]).
Regarding claim 5 pertaining to a composition for regeneration of cartilage, Detamore teaches a decellularized cartilage tissue powder, wherein the powder particulates range in size from about 1 nm to about 500 µm (see, e.g., Detamore, [0007]). The claimed range of the powder diameter overlaps with the teachings of Detamore; therefore, a prima facie case of obviousness exists (see, e.g., MPEP 2144.05(I)). Additionally, Detamore teaches a composition comprising cartilage powder particulates ranging from between about 10 w/v % and about 90 w/v % (see, e.g., Detamore, [0012]).
Regarding claim 7 pertaining to the micronized cartilage powder, Detamore teaches that the cartilage powder contains at least 85% glycosaminoglycans (see, e.g., Detamore, [0009]). Moreover, Detamore teaches a composition comprising “solubilized decellularized cartilage powder particulates ranging from between about 10 w/v % and about 90 w/v %, and Methacrylated Hyaluronic Acid (MeHA) ranging from between about 10 w/v % and about 90 w/v %” (see, e.g., Detamore, [0012]). One of ordinary skill in the art would readily recognize that MeHA is a glycosaminoglycan.
However, Detamore does not teach: a crosslinked product of hyaluronic acid and carboxymethylcellulose (claim 5); or wherein the crosslinked product of hyaluronic acid and carboxymethylcellulose is in an amount of 50 to 80 parts by weight relative to the total weight of the composition (claim 5); or wherein the composition has a complex viscosity of 35,000 to 45,000 Pa
∙
s (claim 5); or wherein the hyaluronic acid and carboxymethylcellulose are crosslinked by 1,4-butanediol diglycidyl ether (BDDE) (claim 10).
Huang’s general disclosure relates to carboxymethylcellulose (CMC) incorporated in a hydrogel membrane with hyaluronic acid (HA) for anti-inflammatory properties (see, e.g., Huang, abstract). Additionally, Huang discloses “carboxymethylcellulose (CMC) incorporated with hyaluronic acid (HA) as an antiadhesion barrier membrane and drug delivery system has been reported to provide excellent tissue regeneration and biocompatibility” (see, e.g., Huang, abstract). Furthermore, Huang discloses “Hyaluronic acid is a natural component found in abundance in the extracellular space [16] and load-bearing joints [17, 18] that has been reported to play an important role in wound healing and for retaining skin moisture [19]. In addition, it has anti-inflammatory, antioxidant, and antibacterial effects for the treatment of periodontal diseases [20]. However, the lubricating effect of HA is generally short lived and the duration of its bioeffects is not predictable. To address these issues, a semisynthetic natural polymer obtained from the CMC combined with HA has been developed that can generate a new hybrid membrane for use as a tissue barrier [1, 14, 21]. The CMC can cross-link with HAby1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) with a various cross-linking degree [22]. This hybrid membrane can thus prolong the drug release function” (see, e.g., Huang, Introduction, pg. 2).
Regarding claim 5 pertaining to the crosslinked product of hyaluronic acid and carboxymethylcellulose, Huang teaches a novel hydrogel comprised of crosslinked hyaluronic acid and carboxymethylcellulose (see, e.g., Huang, Introduction, pg. 2 & Materials and Methods, Section 2.4, pgs. 2-3). Moreover, Huang teaches “The PE-CMC (10mg/mL), HA (30mg/mL), TWEEN80, seed oil, and berberine-enriched CMC were added and mixed with a magnetic stirrer” (see, e.g., Huang, Section 2.4, pg. 3).
Leonardis’ general disclosure relates to chemically treating sodium carboxymethyl cellulose by a crosslinking process for use as a hydrogel for soft-tissue augmentation through injection with thin needles (see, e.g., Leonardis, abstract). Moreover, Leonardis discloses that carboxymethyl cellulose is a biosynthetic substance that is present in its native, non-crosslinked state, for dermal fillers and carriers, and carboxymethyl cellulose allows for a wider range of use compared to other alternative substances, such as calcium hydroxylapatite and poly-L-lactic acid (see, e.g., Leonardis, Introduction, pg. 318). Furthermore, Leonardis discloses that native carboxymethyl cellulose has “specific characteristics for visco-supplementation, densification, and drug delivery”, and is free of mutagenic or carcinogenic outcomes while exhibiting bactericidal activity, (see, e.g., Leonardis, Discussion, pg. 320); however, crosslinking carboxymethyl cellulose results in increased performance characteristics (see, e.g., Leonardis, Discussion, pg. 320).
Regarding claim 5 pertaining to the content of the total weight of carboxymethylcellulose, Leonardis teaches that the concentration of carboxymethyl cellulose for making the crosslinked biopolymer is 20 mg/g (see, e.g., Leonardis, “Preparation of cross-linked carboxymethyl cellulose hydrogel”, pg. 318). One of ordinary skill in the art would readily recognize that one can produce a composition wherein the crosslinked biocompatible polymer is 10 to 90 parts by weight of the composition, wherein the crosslinked biopolymer is 20 mg/g, as taught by Leonardis.
Regarding claim 5 pertaining to the viscosity, Leonardis teaches that the viscosity of the crosslinked sodium carboxymethyl cellulose polymer is 380 Pa
∙
s (see, e.g., Leonardis, “Specifications of cross-linked carboxymethyl cellulose hydrogel”, pg. 318).
Regarding claim 10 pertaining to the crosslinking agent, Leonardis teaches that sodium carboxymethyl cellulose is chemically treated with BDDE in order to produce a crosslinked sodium carboxymethyl cellulose polymer (see, e.g., Leonardis, “Preparation of cross-linked carboxymethyl cellulose hydrogel”, pg. 318).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Detamore’s composition comprising a micronized cartilage powder with Huang’s crosslinked hyaluronic acid and carboxymethylcellulose composition. One would have been motivated to do so because Huang teaches “carboxymethylcellulose (CMC) incorporated with hyaluronic acid (HA) as an antiadhesion barrier membrane and drug delivery system has been reported to provide excellent tissue regeneration and biocompatibility” (see, e.g., Huang, abstract). Furthermore, Huang discloses “Hyaluronic acid is a natural component found in abundance in the extracellular space [16] and load-bearing joints [17, 18] that has been reported to play an important role in wound healing and for retaining skin moisture [19]. In addition, it has anti-inflammatory, antioxidant, and antibacterial effects for the treatment of periodontal diseases [20]. However, the lubricating effect of HA is generally short lived and the duration of its bioeffects is not predictable. To address these issues, a semisynthetic natural polymer obtained from the CMC combined with HA has been developed that can generate a new hybrid membrane for use as a tissue barrier [1, 14, 21]” (see, e.g., Huang, Introduction, pg. 2). Moreover, Detamore teaches “The present invention provides decellularized cartilage (DCC) fragments or powder as a raw material component to be utilized for scaffolds, such that it provides a microenvironment similar to that of native cartilage tissue. The decellularized cartilage powder described herein provides a platform technology upon which many cartilage, or even bone, tissue engineering scaffolds could be based on. It revolutionizes the field of treating full and partial-thickness cartilage defects caused by traumatic injury and osteoarthritis. This cartilage or bone tissue powder could also be used in tendon, ligament, meniscus, and TMJ regenerative applications. Preferably, the decellularized cartilage (DCC) fragment or powder is a chondroinductive material, meaning that it induces chondrogenesis” (see, e.g., Detamore, [0006]). Therefore, based on the teachings of Detamore and Huang, it would have been obvious to combine a micronized cartilage product with a composition comprising hyaluronic acid and carboxymethylcellulose because this would produce a composition for cartilage regeneration that has anti-inflammatory, antioxidant, and antibacterial effects. One would have expected success because Detamore and Huang both teach hydrogel compositions for protection and/or regeneration of tissues.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Detamore composition comprising a micronized cartilage powder and Huang’s composition comprising crosslinked hyaluronic acid and carboxymethylcellulose, wherein the hyaluronic acid and carboxymethylcellulose are crosslinked using 1,4-butanediol diglycidyl ether (BDDE), as taught by Leonardis. One would have been motivated to do so because Leonardis teaches that BDDE allows for crosslinking of carboxymethylcellulose to produce a crosslinked hydrogel (see, e.g., Leonardis, Materials and methods, pg. 318). Detamore teaches producing a hydrogel cartilage composition through a water-soluble cross-linked network of polymer chains (see, e.g., Detamore, [0011]). Moreover, Huang teaches “The CMC can cross-link with HAby1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) with a various cross-linking degree” (see, e.g., Huang, Introduction, pg. 2). Additionally, Huang teaches production of a hyaluronic acid and carboxymethylcellulose crosslinked product as a tissue barrier (see, e.g., Huang, Introduction, pg. 2). Therefore, based on the teachings of Huang and Leonardis, it would have been obvious to use BDDE to crosslink. One would have expected success because Detamore, Huang, and Leonardis all teach production of cross-linked compositions.
Regarding claims 15-18, these claims are product-by-process claims; therefore, determination of patentability is based on the product itself, namely the composition recited in claim 5 (see, e.g., MPEP 2113(I)). Therefore, the combined prior art of Detamore, Leonardis, and Huang, as discussed above, renders obvious claims 15-18.
Regarding claim 5’s limitation pertaining to the complex viscosity of the composition, this limitation is a matter of judicious selection and routine optimization (see, e.g., MPEP 2144.05). For example, Leonardis states that native CMC (i.e., non-cross-linked) have lower performance characteristics than crosslinked hyaluronic acids (see, e.g., Leonardis, Discussion, pg. 320). Moreover, Leonardis states that the crosslinked sodium carboxymethyl is “a material whose structure is very strong even at high deformation, with an identical variation of its elastic and viscous properties at different stress conditions applied (Figures 1 and 2)” (see, e.g., Leonardis, “Specifications of cross-linked carboxymethyl cellulose hydrogel”, pg. 318). Furthermore, Detamore states that crosslinking can occur to form the composition into a gel (also called a hydrogel) (see, e.g., Detamore, [0114]). Furthermore, Detamore teaches that the addition of the crosslinked polymer with MeHA increases the overall viscosity of the composition (see, e.g., Detamore, Figure 8); therefore, one of ordinary skill in the art would expect that the addition of the micronized cartilage powder to the crosslinked carboxymethyl cellulose hydrogel will result in a composition with even greater viscosity. Therefore, based on the teachings of Detamore and Leonardis, one of ordinary skill in the art would reasonably understand that crosslinking of the biopolymer will increase the viscosity of the composition and form a strong composition whose structure is resistant to deformation. This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Furthermore, this is motivation for someone of ordinary skill in the art to test the crosslinking parameters and conditions to increase the viscosity of the composition in order to form a hydrogel composition that is strong and resistant to deformation. Absent any teaching of criticality by the applicant concerning the viscosity, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variables which can be met as a matter of routine optimization.
Regarding claim 5’s limitations pertaining to the weights of the micronized cartilage powder and the crosslinked product of hyaluronic acid and carboxymethylcellulose to the total weight of the composition, those working in the biological and/or pharmaceutical arts would understand that the adjustments of particular conventional working conditions (e.g., concentration or amount of a compound) is deemed a matter of judicious selection and routine optimization, which is within the purview of the skilled artisan (see, e.g., MPEP 2144.05). For example, the disclosure of Detamore states that if the “cartilage powder particulates are suspended at a high concentration, the particulates can form a composition that is putty-like, and if suspended at a somewhat lower concentration, it can form a composition that is paste-like” (see, e.g., Detamore, [0012]). Moreover, Detamore teaches a composition comprising cartilage powder particulates ranging from between about 10 w/v % and about 90 w/v % (see, e.g., Detamore, [0012]), and Huang teaches a hyaluronic acid (HA) and carboxymethylcellulose (CMC) crosslinked product comprising PE-CMC (10mg/mL) and HA (30mg/mL) (see, e.g., Huang, Section 2.4, pg. 3). Additionally, Leonardis teaches that the concentration of carboxymethyl cellulose for making the crosslinked biopolymer is 20 mg/g (see, e.g., Leonardis, “Preparation of cross-linked carboxymethyl cellulose hydrogel”, pg. 318). One of ordinary skill in the art would readily recognize that one can produce a composition wherein the crosslinked biocompatible polymer is 10 to 90 parts by weight of the composition, wherein the crosslinked biopolymer is 20 mg/g, as taught by Leonardis. Therefore, based on these concentrations and percentages, one of ordinary skill in the art would readily understand how to form a composition comprising micronized cartilage, hyaluronic acid, and carboxymethylcellulose by weight relative to the total weight of the composition. Furthermore, this is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the applicant concerning the percentage, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variables which can be met as a matter of routine optimization.
Regarding claims 7’s limitations pertaining to the percentage and/or weight ratios of the cartilage powder and/or glycosaminoglycans within the composition, those working in the biological and/or pharmaceutical arts would understand that the adjustments of particular conventional working conditions (e.g., concentration or amount of a compound) is deemed a matter of judicious selection and routine optimization, which is within the purview of the skilled artisan (see, e.g., MPEP 2144.05). For example, the disclosure of Detamore states that if the “cartilage powder particulates are suspended at a high concentration, the particulates can form a composition that is putty-like, and if suspended at a somewhat lower concentration, it can form a composition that is paste-like” (see, e.g., Detamore, [0012]). Furthermore, Detamore states that retaining glycosaminoglycans within the powdered cartilage composition is crucial as the size of the micronized cartilage versus the coarse ground cartilage is more ideal to incorporate into 3D scaffolds, such as pastes, hydrogels, and microspheres (see, e.g., Detamore, [0169]). Therefore, one of ordinary skill in the art would reasonably understand that the amount of cartilage powder within the composition influences the viscosity and resulting composition (i.e., putty vs paste). This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the applicant concerning the percentage, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variables which can be met as a matter of routine optimization.
Examiner’s Response to Arguments
Applicant's arguments filed 11/05/2025 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments pertaining to the cited prior art failing to teach or suggest the newly added limitation of a cross-linked product of hyaluronic acid and carboxymethylcellulose (HA-CMC) (remarks, pages 11-13), this argument is not persuasive because, as discussed above, the newly cited prior art of Huang was used to teach this limitation; therefore, Applicant’s argument regarding the teachings of Detamore and Leonardis failing to teach this limitation is moot.
Regarding Applicant’s argument pertaining to the cited prior art failing to teach or suggest an optimal micronized cartilage powder and crosslinked HA and CMC ratio (remarks, pages 13-15), this argument is not persuasive because, as discussed above, these ratios can be met as a matter of routine optimization. Furthermore, Detamore teaches that if the “cartilage powder particulates are suspended at a high concentration, the particulates can form a composition that is putty-like, and if suspended at a somewhat lower concentration, it can form a composition that is paste-like” (see, e.g., Detamore, [0012]). Moreover, Detamore teaches a composition comprising cartilage powder particulates ranging from between about 10 w/v % and about 90 w/v % (see, e.g., Detamore, [0012]), and Huang teaches a hyaluronic acid (HA) and carboxymethylcellulose (CMC) crosslinked product comprising PE-CMC (10mg/mL) and HA (30mg/mL) (see, e.g., Huang, Section 2.4, pg. 3). Additionally, Leonardis teaches that the concentration of carboxymethyl cellulose for making the crosslinked biopolymer is 20 mg/g (see, e.g., Leonardis, “Preparation of cross-linked carboxymethyl cellulose hydrogel”, pg. 318). One of ordinary skill in the art would readily recognize that one can produce a composition wherein the crosslinked biocompatible polymer is 10 to 90 parts by weight of the composition, wherein the crosslinked biopolymer is 20 mg/g, as taught by Leonardis. Therefore, based on these concentrations and percentages, one of ordinary skill in the art would readily understand how to form a composition comprising micronized cartilage, hyaluronic acid, and carboxymethylcellulose by weight relative to the total weight of the composition.
Regarding Applicant’s argument pertaining to the cited prior art failing to teach or suggest the optimal viscosity (remarks, page 15), this argument is not persuasive because, as discussed above, this viscosity can be met as a matter of routine optimization (see, e.g., MPEP 2144.05). Furthermore, Leonardis states that native CMC (i.e., non-cross-linked) have lower performance characteristics than crosslinked hyaluronic acids (see, e.g., Leonardis, Discussion, pg. 320). Moreover, Leonardis states that the crosslinked sodium carboxymethyl is “a material whose structure is very strong even at high deformation, with an identical variation of its elastic and viscous properties at different stress conditions applied (Figures 1 and 2)” (see, e.g., Leonardis, “Specifications of cross-linked carboxymethyl cellulose hydrogel”, pg. 318). Furthermore, Detamore states that crosslinking can occur to form the composition into a gel (also called a hydrogel) (see, e.g., Detamore, [0114]). Furthermore, Detamore teaches that the addition of the crosslinked polymer with MeHA increases the overall viscosity of the composition (see, e.g., Detamore, Figure 8); therefore, one of ordinary skill in the art would expect that the addition of the micronized cartilage powder to the crosslinked carboxymethyl cellulose hydrogel will result in a composition with even greater viscosity. Therefore, based on the teachings of Detamore and Leonardis, one of ordinary skill in the art would reasonably understand that crosslinking of the biopolymer will increase the viscosity of the composition and form a strong composition whose structure is resistant to deformation (see, e.g., Leonardis, “Specifications of cross-linked carboxymethyl cellulose hydrogel”, pg. 318 & Discussion pg. 320) (see, e.g., Detamore, [0114] & Figure 8).
Regarding Applicant’s argument pertaining to the non-statutory double patenting rejection (remarks, pages 15-16), as discussed above, this rejection has been withdrawn necessitated by Applicant’s amendments to independent claim 5.
Conclusion
Claims 5-7, 10, and 15-18 are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653