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 .
Claim Status
Claims 1-4, 6-9, 11-18 and 22-25 are pending.
Claims 16-18 and 22-25 are withdrawn.
Claims 1-4, 6-9, and 11-15 are under examination.
It is noted that the Examiner of record has changed.
Election/Restrictions
Applicant’s election with traverse of the following invention
Invention
Group I, claims 1-4, 6-9, and 11-15, drawn to a method of producing a cellular composite,
in the reply filed on 24th, July, 2026 is acknowledged.
Applicant’s traversal is on the grounds that the prior art cited of US 2019/0276784 ("Lin") in combination with Watanabe et al., 1999 ("Watanabe") does not render the technical feature obvious.
In response, this is not found persuasive for the reasons stated below.
Concerning the alleged technical feature, first, as set forth below (see rejections under 35 U.S.C. 103 below) claim 1 is obvious over Mao et al. (US-20110202142-A1; see IDS filed 26th, August, 2024; henceforth “Mao”), in view of Emans et al. (US-20130123314-A1; henceforth “Emans”) as well as the combination of Chen et al. (Tissue Eng Part A. 2012 Sep;18(17-18):1902-11. Epub 2012 Aug 8.; see IDS filed 26th, August, 2024; henceforth “Chen”) in view of Emans et al. (US-20130123314-A1; henceforth “Emans”) for the reason set forth below and therefore no technical feature of claim 1 can be novel. Therefore, the technical feature as previously cited (see pg. 4 of the Lack of Unity mailed on 29th, May, 2026), “a cellular composite” comprising mesenchymal stem cells (MSCs) distributed within a three-dimensional (3D) growth material and differentiated into chondrocytes in a cell culture medium supplemented with a HAPLN link protein, wherein the material is coated with a population of osteoblasts” is still not novel because it would be made obvious by Mao in view of Emans or Chen in view of Emans for the reasons set forth below.
Applicant further traverses on the grounds that culturing with HAPLN protein results in advantages which are not obvious over the prior art (pg. 2-3).
In response, this is not persuasive for several reasons. Applicant’s alleged advantages are not recited by, and are therefore not required by instant claims or by the alleged technical feature. Furthermore, Applicant’s alleged advantages appear to require the specific protein of HAPLN1 as well as concentrations and timings and are therefore not commensurate in scope with instant claims and are also not in scope with an alleged shared technical feature.
Claims 16-18 and 22-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Objections
Claim 13 is objected to because of the following informalities:
Claim 13 recites “the gel is a hydrogel.” Claim 13 depend on claim 12, which recites “the porous scaffold comprises a polymer” and depends on claim 11 which recites “a porous scaffold and/or a gel.” While it appears claim 13 intends to require both the porous scaffold and the gel because it depends on claim 12, it is recommended that Applicant amend to indicate that claim 13 requires both the porous scaffold and the gel to improve the clarity and readability of the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 15 is 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.
Claim 15 recites the method step of “further comprising providing a further population of cells” which makes the metes and bounds of the claim unclear and renders the scope of the claim indefinite. There is not a nexus that links the step of “further comprising providing a further population of cells” to the steps recited in claim 1, upon which claim 15 depends, and therefore it is unclear how and where the further population is integrated into the method of producing a cellular composite.
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.
Claims 1, 4, 9 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Mao et al. (US-20110202142-A1; see IDS filed 26th, August, 2024; henceforth “Mao”), in view of Emans et al. (US-20130123314-A1; henceforth “Emans”).
Regarding claim 1, Mao discloses a method of producing a cellular composite (“engineered
tissue modules and methods for their fabrication” para. [0035]) comprising:
distributing a population of mesenchymal stem cells (MSCs) (“tissue progenitor cells” that are mesenchymal stem cells within a three-dimensional (3D) cell growth material (“biocompatible matrix comprising at least two layers” para. [0011]; see also para. [0012-0016, 0020-0022, 0032, 0036-0043, 0049-076, 0080-0082, 0084, 0088, 0090-0091, 0093, 0096-0103, 0105, 0110, 0113-0117, 0120-016) and differentiating the MSCs into chondrocytes (“tissue progenitor cells introduced into a matrix can be progenitor cells that can give rise to cartilage tissue such as MSCs or MSC chondrocytes” para. [0050] and “the tissue module includes a first type of progenitor cells seeded in the first matrix layer” para. [0012]) in cell culture medium ( A suitable medium can be used for in vitro progenitor cell infusion, differentiation”; para. [0099];see also Examples 3-6); and
coating a surface of the 3D cell growth material with a population of osteoblasts (“Osteoblasts or stem cell-derived osteoblasts were seeded in the PCL” para. [0143]; Example 1; “seeded with osteoblasts or stem cell-derived osteoblasts” para. [0145] and Figure 4; “MSC-derived osteoblasts were seeded in PCL” para. [0147]; see also claim 54).
However, regarding claim 1, although, as stated above, Mao teaches differentiating MSCs into chondrocytes (“Chondrogenic differentiation” para. [0142]), Mao is silent to differentiating in a cell culture medium supplemented with a protein of protein of the hyaluronan and proteoglycan
binding link protein (HAPLN) family.
Nevertheless, regarding claim 1, Emans teaches HAPLN1 (“cartilage-link protein”; para. [0026]) as a factor that stimulates chondrogenic differentiation and cartilage matrix synthesis (para. [0026]).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Mao, and combine the known prior art element of the HAPLN1 protein of Emans to obtain the predictable result of a method of producing a cellular composite. One of ordinary skill would have been motivated to do so as taught by Emans to stimulate chondrogenic differentiation and cartilage matrix synthesis (para. [0026]). Regarding the reasonable expectation of success, Mao evidences differentiating MSCs into chondrocytes (“Chondrogenic differentiation” para. [0142]).
Regarding claim 4, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), Emans teaches and makes obvious cartilage-link protein which is the same as HAPLN1 (para. [0026]).
Regarding claim 9, further to the discussion of claim 1 above, Mao teaches the chondrocytes and/or osteoblasts are derived from MSCs (“MSC derived chondrocytes” and/or “MSC derived osteoblasts” para. [0030]).
Regarding claim 11, further to the discussion of claim 1 above, Mao teaches the 3D cell growth material is formed from a porous scaffold (“A matrix with a high porosity and an adequate pore
Size” para. [0056]) and/or a gel (“hydrogel” para. [0016, 0029, 0061, 0079, 0091, 0124, 0137, 0145, 0157, 0159).
Regarding claim 12, further to the discussion of claims 1 and 11 above, Mao teaches the porous scaffold comprises a polymer (“polycaprolactone (PCL), a biodegradable polymeric material that simulates the mechanical properties of bone” para. [0026] and Figure 1; see also para. [0028-0029, 0059-0061, 0066, 0092-0093, 0098, 0110, 0123-0125, 0134-0135, 0137, 0141, 0143-0144, 0154]; claim 51).
Regarding claim 13, further to the discussion of claims 1 and 11-12 above, as stated above (see claim 11 rejection above), Mao teaches the gel is a hydrogel (para. [0016, 0029, 0061, 0079, 0091, 0124, 0137, 0145, 0157, 0159).
Regarding claim 14, further to the discussion of claims 1 and 11 above, Mao teaches a specific embodiment of the pores of the porous scaffold are 400 µm (“Pores and channels with a diameter of 400 um” para. [0027]).
Regarding claim 15, further to the discussion of claim 1 above, Mao teaches providing a further population of cells (“in some embodiments, one or more cell types in addition to a first type of bone progenitor cells and a first type of cartilage progenitor cells can be introduced into or onto the matrix material. Such additional cell type can be selected from those discussed above, and or can include…” (para. [0105]).
Hence, the claimed invention as a whole was prima facie obvious.
Claims 1-2, 4, 6, 9, 11-12 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Tissue Eng Part A. 2012 Sep;18(17-18):1902-11. Epub 2012 Aug 8.; see IDS filed 26th, August, 2024; henceforth “Chen”) in view of Emans et al. (US-20130123314-A1; henceforth “Emans”).
Regarding claim 1, Chen discloses a method of producing a cellular composite (“two-dimensional (2D)–three-dimensional (3D) co-interface culture” abstract) comprising: a) distributing a population of mesenchymal stem cells (MSCs) within a three-dimensional (3D) cell growth material and differentiating the MSCs into chondrocytes in a cell culture medium (0.5 million rBMSCs were seeded with 50 mL 0.5% (w/v) RADA peptide (Sigma) solution on each silk scaffold, then cultured for a week in chondrogenic medium” pg. 1903 col. 2 “Cell culture and in vitro 2D–3D interface coculture model design”); and
b) coating a surface of the 3D cell growth material with a population of osteoblasts (“After 1 week of independent culture, the scaffolds with chondrogenic rBMSCs were transferred to the wells containing the osteoblasts and cocultured for 3 weeks in chondrogenic medium”; pg. 1903 col. 2 “Cell culture and in vitro 2D–3D interface coculture model design”)
However, regarding claim 1, although, as stated above, Chen teaches differentiating MSCs into chondrocytes, Chen is silent to differentiating in a cell culture medium supplemented with a protein of protein of the hyaluronan and proteoglycan binding link protein (HAPLN) family.
Nevertheless, regarding claim 1, Emans teaches HAPLN1 (“cartilage-link protein”; para. [0026]) as a factor that stimulates chondrogenic differentiation and cartilage matrix synthesis (para. [0026]).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Chen, and combine the known prior art element of the HAPLN1 protein of Emans to obtain the predictable result of a method of producing a cellular composite. One of ordinary skill would have been motivated to do so as taught by Emans to stimulate chondrogenic differentiation and cartilage matrix synthesis (para. [0026]). Regarding the reasonable expectation of success, Chen evidences differentiating MSCs into chondrocytes (pg. 1903 col. 2 “Cell culture and in vitro 2D–3D interface coculture model design”).
Regarding claim 2, further to the discussion of claim 1 above, Chen teaches the surface of the 3D cell growth material with the population of osteoblasts is coated after MSCs have been differentiated into chondrocytes (“subsequently placed in contact and co-cultured” abstract; “Cell culture and in vitro 2D–3D interface coculture model design” pg. 1903 col. 1-2; see also “After 1 week of independent culture, the scaffolds with chondrogenic rBMSCs were transferred to the wells containing the osteoblasts and cocultured for 3 weeks in chondrogenic medium”; pg. 1903 col. 2 “Cell culture and in vitro 2D–3D interface coculture model design”).
Regarding claim 4, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), Emans teaches and makes obvious cartilage-link protein which is the same as HAPLN1 (para. [0026]).
Regarding claim 6, further to the discussion of claim 1 above, Chen teaches the chondrocyte differentiation step of the Chondrocytes is for one week (pg. 1903 col. 2 “Cell culture and in vitro 2D–3D interface coculture model design”) and therefore it would have been obvious to apply the HAPLN1 taught and suggested by Emans above during this step which falls within the claimed range of “from about day 0 to about day 28” and thereby makes it obvious.
Notably, regarding claim 6, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
Regarding claim 9, further to the discussion of claim 1 above, Chen teaches the chondrocytes are derived from MSCs (“0.5 million rBMSCs were seeded with 50 mL 0.5% (w/v) RADA peptide (Sigma) solution on each silk scaffold, then cultured for a week in chondrogenic medium” pg. 1903 col. 2 “Cell culture and in vitro 2D–3D interface coculture model design”).
Regarding claims 11-12, further to the discussion of claim 1 above, Chen teaches the 3D cell growth material is formed from a porous scaffold (instant claim 11) which is a polymer (instant claim 12) (“silk fibroin sponge” pg. 1903 col. 1).
Regarding claim 14, further to the discussion of claims 1 and 11 above, Chen teaches the pores of the porous scaffold are 150 ± 20 µm diameter (“Scaffolds were found to have interconnected sponge structures with uniform pores of 150 ± 20 µm diameter” pg. 1905 col. 1 “Scaffold characterization”).
Hence, the claimed invention as a whole was prima facie obvious.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Mao et al. (US-20110202142-A1; see IDS filed 26th, August, 2024; henceforth “Mao”), in view of Emans et al. (US-20130123314-A1; henceforth “Emans”) as applied to claim 1 above, and in further view of Barksby et al. (Arthritis Rheum. 2006 Feb;54(2):540-50.; henceforth “Barksby”).
The teachings of Mao and Emans above are incorporated herein in their entirety.
Regarding claims 7-8, further to the discussion of claim 1 above, although Mao teaches the tissue construct made by the method can be used as a model (abstract), Mao teaches additional agents can be added the medium periodically (after step b), ( “additional agents added periodically” para. [0100]), and Mao teaches the method further comprise additional agents introduced into or onto the matrix (para. [0113), Mao is silent to contacting the population of chondrocytes with IL1-α and/or oncostatin M.
Nevertheless, regarding claims 7-8, Barksby teaches contacting a population of chondrocytes with medium containing IL-1 (0.02 ng/ml) and/or OSM (10 ng/ml) (pg. 541 col. 2 3rd para. “Cell culture and RNA extraction”; see also “stimulation with IL-1 plus OSM” pg. 548 col. 2 2nd para.) for about 1 day (24 hours; “stimulated with medium alone (control), IL-1 (0.02 ng/ml), OSM (10 ng/ml), or IL-1 α OSM for 24 hours; Figure 1 legend). Barksby teaches the potent proinflammatory cytokine combination of IL-1 plus OSM synergistically and coordinately up-regulates many genes and several MMPs and provides insight into the complex processes that mediate joint disease in the inflammatory arthritis (abstract). Barksby teaches the combination of IL-1 and OSM induces a marked inflammatory arthritis in vivo (pg. 541 col. 1).
Therefore, regarding claims 7-8, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Mao in view of Emans, and combine the known prior art element of contacting a population of chondrocytes with medium containing IL-1 (0.02 ng/ml) and/or OSM (10 ng/ml) for about 1 day of Barkby to obtain the predictable result of chondrocyte stimulation. One of ordinary skill would have been motivated to do so as taught by Barksby to model and provide insight into the complex processes that mediate joint disease in the inflammatory arthritis (abstract and pg. 541 col. 1). Regarding the reasonable expectation of success, Barksby evidences contacting a population of chondrocytes with medium containing IL-1 (0.02 ng/ml) and/or OSM (10 ng/ml) (pg. 541 col. 2 3rd para. “Cell culture and RNA extraction”; see also “stimulation with IL-1 plus OSM” pg. 548 col. 2 2nd para.) for about 1 day (24 hours; “stimulated with medium alone (control), IL-1 (0.02 ng/ml), OSM (10 ng/ml), or IL-1 α OSM for 24 hours; Figure 1 legend).
Hence, the claimed invention as a whole was prima facie obvious.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Tissue Eng Part A. 2012 Sep;18(17-18):1902-11. Epub 2012 Aug 8.; henceforth “Chen”) in view of Emans et al. (US-20130123314-A1; henceforth “Emans”), as applied to claim 1 above, and in further view of Barksby et al. (Arthritis Rheum. 2006 Feb;54(2):540-50.; henceforth “Barksby”).
The teachings of Chen and Emans above are incorporated herein in their entirety.
Regarding claims 7-8, further to the discussion of claim 1 above, although Chen teaches the tissue construct made by the method can be used as a model of the ostochondral interface for the purpose of osteochondral tissue engineering (abstract), Chen is silent to contacting the population of chondrocytes with IL1-α and/or oncostatin M.
Nevertheless, regarding claims 7-8, Barksby teaches contacting a population of chondrocytes with medium containing IL-1 (0.02 ng/ml) and/or OSM (10 ng/ml) (pg. 541 col. 2 3rd para. “Cell culture and RNA extraction”; see also “stimulation with IL-1 plus OSM” pg. 548 col. 2 2nd para.) for about 1 day (24 hours; “stimulated with medium alone (control), IL-1 (0.02 ng/ml), OSM (10 ng/ml), or IL-1 α OSM for 24 hours; Figure 1 legend). Barksby teaches the potent proinflammatory cytokine combination of IL-1 plus OSM synergistically and coordinately up-regulates many genes and several MMPs and provides insight into the complex processes that mediate joint disease in the inflammatory arthritis (abstract). Barksby teaches the combination of IL-1 and OSM induces a marked inflammatory arthritis in vivo (pg. 541 col. 1).
Therefore, regarding claims 7-8, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Chen in view of Emans, and combine the known prior art element of contacting a population of chondrocytes with medium containing IL-1 (0.02 ng/ml) and/or OSM (10 ng/ml) for about 1 day of Barkby to obtain the predictable result of chondrocyte stimulation. One of ordinary skill would have been motivated to do so as taught by Barksby to model and provide insight into the complex processes that mediate joint disease in the inflammatory arthritis (abstract and pg. 541 col. 1). Regarding the reasonable expectation of success, Barksby evidences contacting a population of chondrocytes with medium containing IL-1 (0.02 ng/ml) and/or OSM (10 ng/ml) (pg. 541 col. 2 3rd para. “Cell culture and RNA extraction”; see also “stimulation with IL-1 plus OSM” pg. 548 col. 2 2nd para.) for about 1 day (24 hours; “stimulated with medium alone (control), IL-1 (0.02 ng/ml), OSM (10 ng/ml), or IL-1 α OSM for 24 hours; Figure 1 legend).
Hence, the claimed invention as a whole was prima facie obvious.
Pertinent Art
He
The prior art of He et al. (Stem Cells Int. 2018 Jan 30:2018:3217895. eCollection 2018.; henceforth “He”) made of record but not relied upon, is considered pertinent to Applicant’s disclosure.
He teaches a method of differentiating Cartilage stem/progenitor cells (CSPCs) into chondrocytes by culturing the CSPSCs in LPP at a concentration of 50 ng/mL (pg. 3 col. 2 “2.10. Chondrogenic Differentiation Assay”). He teaches Link protein N-terminal peptide (LPP) (amino acid sequence of “DHLSDNYTLDHDRAIH”; pg. 2 col. 1 “2.1. Peptide Synthesis”) which is the consensus sequence of human N-terminal link protein (which is also known as HAPLN1), and was thought to be the functional fragment of link protein as the cross-linker.
Allowable Subject Matter and Claim Objections
Claims 3 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is allowable.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANA N EBBINGHAUS whose telephone number is (703)756-4548. The examiner can normally be reached M-F 9:30 AM to 5:30 PM ET.
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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