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 .
Election/Restrictions
Applicants complied with the election of species requirements set forth in the restriction requirement of 6/20/2025 and 9/24/2025. However, upon reconsideration, all election of species requirements are withdrawn.
An error was noted in the original (6/20/2025) restriction requirement. Claims 11 and 12 were included with Group 2 (drawn to a structure for bone repair), however they should have been included in Group 1 (a method of making a structure for bone repair). Thus, the original groups should have been: Group 1: Claims 1-3, 11 and 12, drawn to a method of making a structure
Group 2: Claims 4-9, 13-14 and 16-17, drawn to a structure for bone repair
Group 3: claims 10 and 15, drawn to a method of replacing a tissue
Applicants previously elected Group 2, with traverse. The reasons for traversal were not found persuasive for the reasons addressed in the 9/24/2025 Office Action. The restriction is made final.
Claims 4-9, 13, 14 and 16-17 read on the elected invention and have been considered on the merits. Claims 1-3, 10-12 and 15 are withdrawn from consideration as being directed to non-elected inventions.
Priority
Acknowledgement is made of Applicants’ claim for priority to foreign application CN202111169004.9 (filed 9/30/2021). A certified copy of the foreign priority document is present in the application file.
Claim Objection
Claims 1, 6 and 7 are objected to for minor informalities:
Claim 1 should begin with the article “A”.
Claim 6 “methylacrylylated gelatin” should read methacrylated gelatin.
Claim 7, line 1, ‘comprises’ should be “comprising”.
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.
Claims 4-9, 13, 14, 16 and 17 are 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.
Regarding claim 4: The metes and bounds of the claim are unclear. The preamble appears to use product-by-process language (defining the bone-repair functional module as obtained by the integrated 3D printing method according to claim 1), yet the body of the claim goes on to describe elements that are not inherent to the production method of claim 1 (e.g. pore channels, specific volume ratios, osteoid hard tissue modules), and then also references additional production steps (e.g. wherein a printing method of the pore channel comprises a separation of adjacent hard material bundles and cell bundles, or a printing of a pore forming material… and removal of pore forming material). Overall, it is unclear what physical and/or chemical properties the bone-repair functional module must comprise.
Additionally, in claim 4, it is unclear of the relationship between the bone-repair functional module and an osteoid hard tissue module. It is unclear if these are the same component, or if the osteoid hard tissue module is a component, or something separate.
Additionally, in claim 4, there is insufficient antecedent basis for the limitation the channel forming material (line 12).
Additionally, claim 4 contains the trademark/trade name Pluronic. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe poloxamer 407 and, accordingly, the identification/description is indefinite.
All of claims 5-9, 13, 14, 16 and 17 depend from claim 4, inherit the deficiencies, and are rejected on the same basis.
Regarding claim 5: Additionally, in claim 5 is unclear what is meant by wherein a polymer material used in the composite polymer. Specifically, it is unclear what is meant by “used in”. Does the composite polymer further comprises a polymer material?
Regarding claim 7: It is unclear what characteristic(s) are required to satisfy the limitation “… the bone defect repair material obtained after the in vitro culture is a functional module of bone-repair”.
Additionally, it is unclear if the bone defect repair material comprises the bone-repair functional module according to claim 4 and a bone organoid (as stated in the first 2 lines), or if the bone-repair functional module becomes a bone organoid after culture, and the claim is to the bone organoid thereby obtained. The confusion is caused by the language at lines 10-11, where it reads “and the bone defect repair material obtained is a mineralized bone organoid…”.
Regarding claim 8: Claim 8 refers to an osteocyte. None of the previous claims have limited the type of bone cell present in the material. It is unclear if claim 8 is limiting the cell unit for osteogenic function to an osteocyte.
Regarding claim 9: Claim 9 appears to recite method steps, but it is unclear what method is being referred to and/or how the method steps relate to the bone defect repair material of the parent claims. It is unclear what cells are target cells (e.g. are the target cells the bone cells present in the material? Are they the osteocytes described in claim 8?).
Regarding claim 13: Claim 13 depends from claim 5, and thus should include all limitations of claim 5, but claim 13 only generic references a ‘composite polymer’, as opposed to the specific polycaprolactone or its derived copolymers. It is thus unclear if the mass ratio of 1:9 is limited to hydroxyapatite to polycaprolactone or its derived copolymers, or of any other polymer.
Regarding claims 16-17: Like parent claim 4, claims 16-17 recites methods of making limitations. These limitations do not properly correlate with the method of claim 1. Thus it is unclear if the bone repair functional module is made by the method of claim 1, or by the method steps recited in these claims.
Furthermore, the language of claims 16 and 17 appear to be describing differentiation and/or developmental pathways in cells, but do not clearly define what active method steps must be carried out, or how those steps limit the bone repair functional material currently claimed. Overall, the metes and bounds of the bone repair product of claims 16 and 17 cannot be determined.
Claim Interpretation
For purposes of compact prosecution, the best interpretation for comparison to the prior art is as follows: Claim 4. A bone-repair functional module comprising:
a ‘material unit for mechanical scaffolds’, which comprises a biomedical material with a compression strength of 2MPa or above,
a ‘cell unit’ which will have potential for some osteogenic function, and
a pore channel,
wherein a ratio of (i) : (ii) is 1: 0.5-2, and
wherein the product has a porosity of 20%-80%. (The manner of making the pores is a product-by-process limitation which does not change the final product structure)
Claim 5. The bone-repair functional module of claim 4, wherein the (i) material unit comprises hydroxyapatite particles having a nano-meter size, wherein the material unit further comprises polycaprolactone or its derived copolymers, and wherein the mass ratio of the hydroxyapatite to polycaprolactone or its derived copolymers is 1: (4-9).
Claim 6. The bone-repair functional module of claim 4, wherein the (ii) cell unit comprises a cell encapsulated in a hydrogel or a bioink, wherein the density of the cells in the hydrogel is from 1 x 105 to 1 x 107 cells/mL, the bioink or hydrogel comprises methacrylated gelatin.
Claim 7. A bone defect repair material, comprising the bone-repair functional module of claim 4 cultured so as to form a mineralized bone organoid. The details regarding the culture conditions are product-by-process limitations that do not clearly further limit the final structure.
Claim 8. The bone defect repair material of claim 7, wherein the material comprises an osteocyte.
Claim 9. (no additional structural or physical limitations can be discerned from claim 9). Claim 9 will be included in any prior art rejection of claim 8.
Claim 13: The bone-repair functional module of claim 5, wherein the (i) material unit comprises hydroxyapatite and an additional polymer, and the mass ratio is 1:9.
Claim 14. The bone-repair functional module of claim 6, wherein the cells are present in the hydrogel or bioink at a density of 1 x 106 cells/mL.
Claim 16. (no additional structural or physical limitations can be discerned from claim 16). Claim 16 will be included in any prior art rejection of claim 4.
Claim 17. The bone-repair functional module of claim 4, wherein the biomedical material has a melting temperature of between 30 and 200oC.
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.
Claims 4, 6, 14, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al (CN109381749; cited on 7/5/2023 IDS), in view of Roohani-Esfahani et al (Scientific Reports, 2016), Gleadall et al (Burns & Trauma, 2018), and evidenced by Mechanical Tribology- Materials, Characterization, and Applications, 2004.
Xu et al is in the Chinese language. A translation from the PatentScope website is relied upon, citations are made to the translation.
Xu et al is directed to bone tissue engineering applications, including bone tissue repair ink, bone tissue repair compositions, bone tissue repair scaffolds and bone tissue repair kits (See Xu et al ¶0005-0009). The bone tissue repair scaffold will be relied upon for this rejection.
Regarding claims 4 and 16: Xu et al teach a bone tissue repair scaffold comprising a plurality of layers of fiber layers, wherein the fiber layers are arranged in parallel. Each layer of the fiber layers includes a ‘stent structure’ made of bone tissue repair ink and a ‘stent structure’ made of a bioactive carrier material ink (See ¶0117-0118). The term ‘stent structure’ is understood to refer to a bioprinted filament (See Figs. 1 and 4). The bone tissue repair scaffold reads on a bone-repair functional module.
The ‘bone tissue repair ink’ is made of a biodegradable material that can include, inter alia, hydroxyapatite, polycaprolactone (PCL), and combinations thereof (See Xu et al ¶0035-0043). Example 6 (¶0156+) uses a combination of hydroxyapatite and PCL. The ‘stent structure’ made of the bone tissue repair ink reads on a material unit for mechanical scaffolds.
The ‘bioactive carrier material ink’ is made of a bioactive hydrogel and a bioactive factor (See Xu et al ¶0058). Cells can further be included in the bioactive carrier ink (See ¶0068). Example 6 (¶0156+) uses a bioactive carrier ink comprising osteoblasts in collagen type I. The ‘stent structure’ made of the bioactive carrier material ink reads on a cell unit for an osteogenic function, noting that osteoblasts are osteogenic cells.
The printing configurations in Fig. 4 A-2 show the ‘stent structure’ made of bone tissue repair ink (white) and ‘stent structure’ made of bioactive carrier ink (black) adjacent to one another, and show spaces between neighboring stent structures made of bone tissue repair ink (spaces between the white filaments). The spaces between neighboring stent structures made of bone tissue repair ink read on pore channels. There are multiple pore channels, which read on multiple holes.
In the configuration of Fig. 4A-2 there is a 2:1 ratio of the stent structures made of bone tissue repair ink to stent structures made of bioactive carrier material ink. This reads on a volume ratio of the material unit and the cell unit being 1:0.5. Hydroxyapatite, on its own, has a compressive strength of 350-450 MPa (See Mechanical Tribology, Table 1). This satisfies the limitation that the (i) ‘material unit for mechanical scaffolds’, comprises a biomedical material with a compression strength of 2MPa or above. It is emphasized the claim does not clearly limit the compressive strength of the bone-repair functional module, per se.
The scaffold of Xu et al differs from the instant claim in that Xu et al does not teach the overall porosity of the scaffold.
For bone repair scaffolds, overall porosity between 60% and 90% with an average pore size of >150µm and compressive strength comparable to natural cortical bone (100 to 150 MPa) is ideal (See Roohani-Esfahani et al, Pg 1, 1st paragraph).
Therefore, while Xu et al does not report on the overall porosity of their scaffold, given that Roohani-Esfahani et al teach 60-90% porosity is ideal for bone scaffolds, one would have been motivated to make the overall porosity of the scaffold of Xu et al within this range. Furthermore, Roohani-Esfahani et al teach how to adjust the filament pattern and spacing to affect pore size and overall porosity (See Roohani-Esfahani et al Fig. 1). Gleadall et al also teach in 3D printed scaffolds, the size of the printed filaments, as well as printing pattern (i.e. space between neighboring filaments, and directly between filaments of adjacent layers) directly affects the pore geometry and overall porosity (See Gleadall et al, Pg. 5, col. 2). Therefore, one having ordinary skill in the art would have had a reasonable expectation of successfully manipulating the printing parameters (filament size, spacing, orientation) to obtained the desired porosity range (60-90%). While 60-90% extends slightly beyond the claimed range, the substantial overlap is considered to render the claimed range prima facie obvious. See MPEP 2144.05.
Regarding claims 6 and 14: Following the discussion of claim 1 above, Xu et al disclose the bioactive carrier ink of Example 6 contains 4 x 105 cells/mL. This is slightly lower than the density required by claims 6 and 14; however it is submitted that the density of cells is a result effective variable. Higher number of cells will affect the rate of growth factor production, mineralization and tissue regrowth.
Regarding the hydrogel material: while Example 6 uses collagen type I, Xu et al also teach that methacrylate gelatin (GelMA) (reads on methylacrylated gelatin) is an acceptable hydrogel material for use in the bioactive carrier (See Xu et al, ¶0062).
Regarding claim 17: Following the discussion of Xu et al above, the bone tissue repair ink includes polycaprolactone. The polycaprolactone reads on a biomedical material. Official notice is taken that the melting point of polycaprolactone is about 60oC, which is within the claimed range.
Claims 4-9, 13, 14, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al (CN109381749; cited on 7/5/2023 IDS), in view of Roohani-Esfahani et al (Scientific Reports, 2016), Gleadall et al (Burns & Trauma, 2018), further in view of Kuss et al (J Biomed Mater Res Pt B, 2018), evidenced by Mechanical Tribology- Materials, Characterization, and Applications, 2004.
The teachings of Xu et al, Roohani-Esfahani et al, Gleadall et al and Mechanical Tribology are set forth above. The combination of teachings render obvious claims 4, 6, 14, 16 and 17.
Regarding claims 5 and 13: Following the discussion of claim 4 above, Xu et al teach the (i) material unit comprises a mixture of hydroxyapatite and polycaprolactone. Xu et al does not teach the particle size of any hydroxyapatite used to generate the bioink.
However, Kuss et al teach nanocrystals of hydroxyapatite are appropriate for forming a bioink of PCL-hydroxyapatite (See Kuss et al, Pg 1789, “3D printing and scaffold characterization”). Nanocrystals of hydroxyapatite reads on wherein a particle size of the hydroxyapatite is nanometer-scale . It would have been prima facie obvious to have looked to Kuss et al for details on how to generate the hydroxyapatite-PCL bioink. This conclusion of obviousness is based on a teaching in the art when the primary reference is silent about a detail. There would have been a reasonable expectation of successfully using 100 nm hydroxyapatite nano-crystals based on the teachings of Kuss et al.
In Example 6 of Xu et al, they teach a 1:1 ratio of PCL: hydroxyapatite (See et al ¶0158). However, Xu et al teach that the mass ratio of hydroxyapatite to other polymers present in the bone tissue repair ink can vary from 10:0 to 0:10 (See Xu et al, ¶0052-0055). Selection of any ratio within this range, including 1:9 is considered prima facie obvious as a matter of routine optimization.
Regarding claims 7-9: Xu et al teaches culturing the constructs of Example 6 (constructs of all of Examples 1-6) in culture medium for 7 days (See Xu et al, ¶0161); however Xu et al do not report on mineralization or effect of the culture.
However, given that the purpose of the bone tissue repair scaffolds of Xu et al are to repair bone tissue, it would have been prima facie obvious to have cultured the bone tissue repair scaffolds under conditions effective to generate mineralized bone tissue. At the time the invention was made osteogenic media appropriate for inducing differentiation to osteogenic cells and mineralization was known in the art. Specifically, media comprising dexamethasone, ß-glycerophosphate and ascorbic acid (Vitamin C) was known as an osteogenic media (See Kuss et al, Pg. 1789 “Cell culture and differentiation”). Therefore, it would have been prima facie obvious to have cultured the bioprinted bone tissue repair scaffold of Xu et al, which contains osteoblasts (or in Examples 2-5 bone marrow mesenchymal stem cells) in osteogenic media for the purpose of differentiating the cells into osteocytes which secrete endogenous mineralized scaffolding. The mineralized tissue thereby created reads on the bone defect repair material of claims 7-9.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
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/ALLISON M FOX/ Primary Examiner, Art Unit 1633
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