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
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/07/2025 has been entered.
Applicant' s amendment and response filed on 10/09/2025 has been received and entered into the case.
Amendments
In the reply filed on 10/09/2025, Applicant has amended claim 18.
Claim Status
Claims 18-20, 34-37 and 39-45 are pending and are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/11/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 18-19, 37, 39 and 41-43 under 35 U.S.C. 103 as being unpatentable over Stratesteffen et al. (Biofabrication. 2017; 9: 045002, p. 1-12. Prior art of record) in view of Zhuang et al. (PLoS ONE. 2019, 14(6):e0216776, p. 1-21. Prior art of record) is withdrawn in light of Applicant’s amendment to claim 18 to recite new limitation “wherein the (meth)acrylated ECM material and the non-(meth)acrylated ECM material comprise collagen”, as Stratesteffen only discloses a GelMA-Collagen composition in which the (meth)acrylated ECM material does not comprise collagen.
The prior rejection of claims 20 and 34-36 under 35 U.S.C. 103 as being unpatentable over Stratesteffen et al. (Biofabrication. 2017; 9: 045002, p. 1-12. Prior art of record) in view of Zhuang et al. (PLoS ONE. 2019,14(6):e0216776, p. 1-21. Prior art of record), as applied to claim 18 above, and further in view of Vila et al., (Biofabrication. 2020; 12: 025008, p. 1-16. Prior art of record) is withdrawn in light of Applicant’s amendment to claim 18 to recite new limitation “wherein the (meth)acrylated ECM material and the non-(meth)acrylated ECM material comprise collagen”, as Stratesteffen only discloses a GelMA-Collagen composition in which the (meth)acrylated ECM material does not comprise collagen.
The prior rejection of claims 40 and 44-45 under 35 U.S.C. 103 as being unpatentable over Stratesteffen et al. (Biofabrication. 2017; 9: 045002, p. 1-12. Prior art of record) in view of Zhuang et al. (PLoS ONE. 2019,14(6):e0216776, p. 1-21. Prior art of record), as applied to claims 18 and 41 above, and further in view of Yue et al., (Biomaterials. 2015; 73: 254-271. Prior art of record) is withdrawn in light of Applicant’s amendment to claim 18 to recite new limitation “wherein the (meth)acrylated ECM material and the non-(meth)acrylated ECM material comprise collagen”, as Stratesteffen only discloses a GelMA-Collagen composition in which the (meth)acrylated ECM material does not comprise collagen.
New Claim Rejections - 35 USC § 103
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 18, 37 and 39-45 are rejected under 35 U.S.C. 103 as being unpatentable over Rothrauff et al., (J Tissue Eng Regen Med. 2018;12:e159-e170) in view of Zhuang et al. (PLoS ONE. 2019, 14(6):e0216776, p. 1-21. Prior art of record).
With respect to claim 18, Rothrauff teaches a method of fabricating a thermoresponsive, photocrosslinkable hydrogel by functionalizing pepsin‐soluble decellularized tendon and cartilage extracellular matrices (ECM) with methacrylate groups (“TendonMA” and “CartilageMA”, e.g., abstract and see Fig 3 for the three-dimensional hydrogel structure), thus teaches a method of manufacturing a three-dimensional article.
In regard to depositing step, Rothrauff teaches cell-seeded hydrogels are distributed at 4 °C to silicone moulds (e.g., p. 162, para 2.9 “In vitro cell culture”), thus teaches depositing a layer of a printable composition (i.e., the hydrogel solution) to a surface to obtain a deposited layer.
In regard to irradiating step, Rothrauff teaches all hydrogel groups are exposed to 2 min of UV light to induce crosslinking between unreacted methacrylate groups (e.g., p. 162, para 2.9 “In vitro cell culture”), thus teaches irradiating the deposited layer.
In regard to the composition comprising a (meth)acrylated ECM material and a non-(meth)acrylated ECM material, the limitation “a (meth)acrylated ECM material” is being examined as the methacryloyl substitution groups on the reactive amine and hydroxyl groups of the amino acid residues of the ECM material (i.e., (meth)acrylated amino acid residues), and the limitation “a non-(meth)acrylated ECM material” is being examined as the amino acid residues that do not react to the methacryloyl substitution groups (i.e., non-(meth)acrylated amino acid residues). Rothrauff teaches an NMR spectrum assay of methacrylate reaction of CartilageMA (p. 163, section 3.2 “DOF”) and teaches the CartilageMA has the methacrylate being 43.1% based on the percentage of aromatic amino acids in the collagen (p. 163, right col, 6th – 3rd line from bottom), thus teaches the composition (i.e., CartilageMA) comprises a methacrylated ECM material (i.e., methacrylated amino acid residues being 43.1% of total amino acids) and a non-methacrylated ECM material (i.e., the remaining non-methacrylated amino acid residues). Rothrauff teaches the methacrylated ECM contains a visible light-sensitive photoinitiator LAP (e.g., p. 161, left col, section 2.5 “Preparation of ECM hydrogels”, para 2).
In regarded to collagen, Rothrauff teaches the decellularized tendon and cartilage comprise collagen (see Fig 1K) and teaches calculating CartilageMA methacrylate being 43.1% based on the percentage of aromatic amino acids in the collagen (p. 163, right col, 6th – 3rd line from bottom). Additionally, Rothrauff teaches CartilageMA constructs similarly displayed dark staining indicative of the collagen type II of the native cartilage tissue (Figure 7e, o) (p. 166, right col, para 1). Thus, Rothrauff teaches the composition (i.e., CartilageMA) comprises a methacrylated collagen (i.e., methacrylated amino acid residues of collagen) and a non-methacrylated collagen (i.e., the remaining non-methacrylated amino acid residues of collagen).
In regard the weight ratio, as stated supra, Rothrauff teaches the CartilageMA methacrylate being 43.1% based on the percentage of aromatic amino acids in the collagen (p. 163, right col, 6th – 3rd line from bottom), thus teaches a weight ratio of the methacrylated collagen (amino acids) to the non-methacrylated collagen (amino acids) being 43.1% : 56.9%, i.e., about 1:1.1, within the claimed range.
However, Rothrauff is silent on repeating the depositing and irradiating steps until the deposited layers form the 3D article.
Zhuang teaches a method of manufacturing a 3D construct using a layer-by-layer method (abstract). Zhuang teaches a methacrylated ECM-based hydrogel layer is deposited to a surface and is irradiated by a UV source to crosslink the hydrogel, and these depositing/irradiating steps are repeated to eventually achieve fabrication of complex 3D structures with high aspect ratio (see e.g. Fig 1 left panel for depositing/irradiating, and the right panel for repeating the steps to form the final 3D structure). Zhuang teaches this layer-by-layer ultraviolet assisted bioprinting provides a novel strategy to develop soft tissue constructs with desirable structure integrity (abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of manufacturing a 3D article by depositing and irradiating a layer of printable composition disclosed by Rothrauff, by combining repeating the layer-by-layer printing steps taught by Zhuang with a reasonable expectation of success. Since Rothrauff aims to manufacture a 3D article by depositing and irradiating a methacrylated ECM-based material for cartilage tissue engineering (see e.g., abstract), and since Zhuang teaches the layer-by-layer ultraviolet assisted bioprinting provides a novel strategy to develop soft tissue constructs with desirable structure integrity (abstract), one of ordinary skill in the art would have had a reason to combine repeating the depositing and irradiating steps taught by Zhuang in order to enable the fabrication of 3D structures for cartilage tissue engineering envisioned by Rothrauff.
With respect to claim 37 directed to the composition comprising RGD peptide, as stated supra, Rothrauff teaches the composition (i.e., CartilageMA) comprises collagen (e.g., Fig 1K, p. 163, right col, 6th – 3rd line from bottom and p. 166, right col, para 1). One of ordinary skill in the art would have immediately expected that collagen would comprise RGD peptide sequence.
With respect to claim 39 directed to the methacrylated ECM material having a degree of methacrylation of about 5 to about 95 percent, it is noted that the specification defines the term “about” being equal to ±10% of that numerical value ([0110]), thus the claimed range encompasses a degree being 100 percent. As stated supra, the limitation “a (meth)acrylated ECM material” is being examined as the (meth)acrylated amino acid residues of the ECM material, thus the degree of methacrylation of the (meth)acrylated amino acid residues of the ECM material would be 100%, within the claimed range.
With respect to claim 40 directed to the methacrylated ECM material including a mono-methacrylated ECM material, Rothrauff teaches using 1H NMR to confirm derivatization with the methacrylate group and to calculate the degree of functionalization (DOF) (p. 161, left col, para 2.6 “NMR analysis”) and teaches vinyl protons of the methacrylate bound to collagen (peak #1) (in Fig 2 and p. 163, left col, para 3.2 “DOF”). One of ordinary skill in the art would have immediately expected that the methacrylate group bound to collagen would result in a mono-methacrylated ECM material.
With respect to claim 41 directed to the composition further comprising PBS, Rothrauff teaches “As with non‐methacrylated ECM hydrogels, the methacrylated hydrogel solutions were pH and salt balanced”, and teaches the non‐methacrylated ECM hydrogels are prepared in PBS (by adding one‐ninth digest volume of 10× PBS) (p. 161, left col, para 2.5 “Preparation of ECM hydrogels”), thus teaches the composition further comprises PBS.
With respect to claim 42 directed to the photoinitiator and irradiating, Rothrauff teaches adding LAP (p. 161, left col, para 2.5 “Preparation of ECM hydrogels”), which is a visible light-sensitive photoinitiator (p. 161, left col, para 2.4). One of ordinary skill in the art would have immediately expected that the LAP is a UV dye with light absorbance peak around 370–375 nm, within the claimed range of 300 nm to 420 nm. Rothrauff teaches photocrosslinking was induced by exposure to UV light (LED bulbs, 390-395 nm, 0.5 W) for 2 min (p. 161, left col, para 2.4), thus teaches irradiating the deposited layer comprises illuminating with light having a wavelength of 300 nm to 420 nm.
With respect to claim 43 directed to the article supporting cell proliferation, Rothrauff teaches mesenchymal stem cells are seeded in methacrylated tendon (TendonMA) or CartilageMA and are cultured up to 42 days (p. 162, left col, para 2.9 “In vitro cell culture”, see Fig. 4 for cell-mediated contraction and Fig. 5 for gene expression of cells in the constructs), thus teaches the article supports cell proliferation.
With respect to claim 44 directed to the article being a 3D article of an organ, and claim 45 directed to the organ being a mammalian organ, Rothrauff teaches the aim is to study the efficacy of the thermoresponsive, photocrosslinkable hydrogels derived from decellularized tendon and cartilage extracellular matrix (i.e., the TendonMA or CartilageMA) for cartilage tissue engineering (e.g., see title) and contemplates the clinical translation as a point-of-care therapeutic (see Introduction in p. 160, para 1). Thus, Rothrauff suggests the 3D article being a 3D article of an organ (i.e., a cartilage tissue) and the organ being a mammalian organ (e.g., a human cartilage tissue as a clinical therapeutic).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 10/09/2025 are acknowledged.
Applicant argues that Stratesteffen and Zhuang in the prior rejection do not teach or suggest a composition including a (meth)acrylated ECM material and a non-(meth)acrylated ECM material both including collagen, and there would have been no reasonable expectation of success for modifying Stratesteffen’s construct to include metharylated collagen based on the teaching of Stratesteffen, and one of ordinary skill in the art would not be motivated to replace the gelatin (GelMA) with collagen (methacrylated collagen) based on the teaching of Stratesteffen. (Remarks, p. 6).
Applicant’s arguments have been fully considered and they are persuasive. Therefore, the prior rejection based on Stratesteffen has been withdrawn. However, as necessitated by amendment, a new ground of rejection has been made over Rothrauff in view of Zhuang. Specifically, as stated supra, the limitation “a (meth)acrylated ECM material” is being examined as the methacryloyl substitution groups on the reactive amine and hydroxyl groups of the amino acid residues of the ECM material (i.e., (meth)acrylated amino acid residues), and the limitation “a non-(meth)acrylated ECM material” is being examined as the amino acid residues that do not react to the methacryloyl substitution groups (i.e., non-(meth)acrylated amino acid residues). Rothrauff teaches methacrylated decellularized cartilage (CartilageMA) that includes methacrylated collagen, with 43.1% of methacrylation. Thus, Rothrauff teaches a (meth)acrylated ECM material (i.e., (meth)acrylated amino acid residues of collagen) and a non-(meth)acrylated ECM material (i.e., non-(meth)acrylated amino acid residues of collagen), both including collagen.
Applicant further argues that the claimed method exhibits surprising advantages, in particular providing improved cell interactive features to aid in cell attachment and proliferation. Specifically, Example 4 and Figs 5A and 5B indicate that the printable composition including the combination of (meth)acrylated collagen and non-(meth)acrylated collagen (201 and 202) provides statistically significant increases in cell attachment as compared to a composition without this combination (203) (Remarks, end of p. 6 – p. 7).
Applicant’s arguments have been fully considered but they are not persuasive.
As a first matter, MPEP § 2145 states that a showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements that claimed compound possesses unusually low immune response or unexpected biological activity that is unsupported by comparative data held insufficient to overcome prima facie case of obviousness). In this case, Applicant’s argument is not supported by side-by-side comparative data. Specifically, only one of the two compositions including the combination of (meth)acrylated collagen and non-(meth)acrylated collagen (i.e., 201) has statistically significant increase in cell attachment as compared to control 203, while the similar composition 202 does not show increase, but decrease, in cell attachment compared to control (see Fig 5A attached here). Furthermore, in cell proliferation assessment in Fig 5C, both 201 and 202 show decrease compared to Ctrl, with 201 being the worst (see Fig 5C attached here). Thus, Applicant’s purported surprising advantages to aid in cell attachment and proliferation, are not supported by side-by-side comparative data.
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Furthermore, MPEP 716.02(d), states that unexpected results must be commensurate in scope with the claimed invention. In the instant case, the purported surprising advantages presented by the Applicant (i.e., compositions 201 and 202) were compositions comprising the combination of (meth)acrylated collagen and non-(meth)acrylated collagen (in a narrow weight ratio range of about 1:3 to 1:1.6) as well as PEG600DM (i.e., further comprising a poly(ethylene glycol) di-(meth)acrylated monomer having a Mw of 600 Daltons) (see Table 2 in Example 4, [0083]). Thus, it is not commensurate in scope with the claimed method using a printable composition comprising a (meth)acrylated ECM material and a non-(meth)acrylated ECM material wherein the (meth)acrylated ECM material and the non-(meth)acrylated ECM material comprise collagen, in a claimed range of weight ratio of about 5:1 to about 1:5.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Rothrauff et al., (J Tissue Eng Regen Med. 2018;12:e159-e170) in view of Zhuang et al. (PLoS ONE. 2019, 14(6):e0216776, p. 1-21. Prior art of record), as applied to claim 18 above, and further evidenced by Zhang et al., (Cartilage. 2012;3(3):267-277).
Claim 19 is directed to the ECM material further comprising fibronectin.
Rothrauff teaches hyaline cartilage of the femoral condyles were harvested from juvenile (6–8 weeks old) cow hindlimbs (p. 160, left col, para 2.1 “Decellularization of tendon and cartilage ECM”). Zhang evidences that fibronectin (FN) and fibronectin fragments (FN-fs) are comprised in the articular cartilage from 4 different load-bearing regions (Fig. 1) of bovine femoral condyles (p. 273, section “FN and FN-fs in Bovine Knee Cartilage” and see Figure 6). Thus, one of ordinary skill in the art would have immediately expected that Rothrauff’s cartilage (i.e., the ECM material) would further comprise fibronectin as evidenced by Zhang.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 10/09/2025 are acknowledged and have been discussed above.
Claims 20 and 34-36 are rejected under 35 U.S.C. 103 as being unpatentable over Rothrauff et al., (J Tissue Eng Regen Med. 2018;12:e159-e170) in view of Zhuang et al. (PLoS ONE. 2019, 14(6):e0216776, p. 1-21. Prior art of record), as applied to claim 18 above, and further in view of Cosgriff-Hernandez et al., (Acta Biomaterialia. 2010; 6: 3969-3977).
Claims 20 and 34-36 are directed to the composition further comprising a PEGDA monomer.
However, Rothrauff and Zhuang are silent on the composition further comprising a PEGDA monomer in claim 20, or the Mw or percentage in claims 34-36.
Cosgriff-Hernandez teaches bioactive hydrogels based on designer collagens (streptococcal collagen-like (Scl) proteins, see e.g., title and abstract) as well as collagen. Cosgriff-Hernandez first functionalizes the Scl2 proteins and collagen with photocrosslinking sites to enable incorporation into a hydrogel matrix (p. 3970, right col, para 2.3) and then fabricates bioactive hydrogels by combining the functionalized Scl2 proteins and collagen with poly(ethylene glycol) diacrylate (PEGDA) (p. 3972, section 2.6. “Preparation of biologically active PEG-Scl2 hydrogels”, and p. 3975, section 3.4. “Bioactive hydrogels with cell-specific adhesion”, also see Fig 2 for the PEGDA-Scl2 hydrogel and see Fig 9 for each tested cell type spread on PEG-collagen gel in the last row), related to claim 20. Cosgriff-Hernandez teaches the PEGDA is synthesized by PEG (3.4 kDa) (p. 3972, section 2.6.), thus teaches the PEGDA monomer has a weight average molecular weight of about 3400 Da, within the claimed ranges in claim 34 and claim 35. Cosgriff-Hernandez teaches the PEGDA is added to 5 wt.% (e.g., p. 3972, right col, para 1), within the claimed range of about 1 wt.% to about 20 wt.% in claim 36. Cosgriff-Hernandez teaches these results highlight the potential of this novel biomaterial platform in the development of improved tissue engineered vascular grafts (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of manufacturing a 3D article for tissue engineering using a composition comprising functionalized collagen as suggested by Rothrauff in view of Zhuang, by combining with PEGDA so as to fabricate a bioactive hydrogel (PEGDA-collagen-F) as suggested by Cosgriff-Hernandez with a reasonable expectation of success. Since Rothrauff aims to use the method for tissue engineering (e.g., title and abstract) and since Cosgriff-Hernandez teaches PEGDA is selected due to the broad tunability of PEG gel mechanical properties (p. 3975, last para) and the novel biomaterial platform has potential in the development of improved tissue engineered grafts (e.g., abstract), one of ordinary skill in the art would have had a reason to combine PEGDA in the printable composition of Rothrauff in view of Zhuang in order to take advantage of the broad tunability of PEG gel mechanical properties and to improve tissue engineering.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 10/09/2025 are acknowledged and have been discussed above.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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