DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 2-21 are under examination.
Response to Applicants Arguments and Amendments
Because of the amendment made to claim 5, the claim objection has been withdrawn. Thank you for submitting the terminal disclaimers for both patents 9,662,420 and 10,363,341. The double patenting rejections has been removed.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 2-21 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kandel (US 20080119936) in view of Mizuno “Biomechanical and biochemical characterization of composite tissue-engineered intervertebral discs” Biomaterials 27 (2006) 362-370 and Bonassar (US 6,773,713)
Kandel teaches method of fabricating a tissue-engineered intervertebral disc (IVD), said method comprising:
providing a first population of living cells (Paragraph 68 of Kandel);
providing a second different population of living cells and collagen (Paragraph 69 and Table 1 of Kandel);
forming the second gel around a central mandrel structure (the mandrel structure is the plug mentioned in paragraph 69);
storing the second gel under conditions effective for the collagen in the second gel to align circumferentially around the central mandrel structure by self-assembly of collagen due to cell-mediated gel contraction in the second gel (Paragraph 69 and Table 1);
replacing the central mandrel structure with the first cell population (Paragraph 69—the plug is removed and replaced with the nucleus pulposus), wherein the first gel forms a nucleus pulposus structure and the second gel forms an annulus fibrosus structure surrounding and in contact with the nucleus pulposus structure, thereby fabricating a tissue- engineered IVD suitable for total disc replacement in a mammal (Paragraph 69 of Kandel) as in instant Claims 2 and 18.
Kandel does not expressly recite encapsulating the two distinct cell populations in distinct gels. Mizuno teaches that nucleus pulposus forming cells can be encapsulated in alginate for stability purposes (Figure 1 of Mizuno). The nucleus pulposus forming cells/tissue is surrounded by annulus fibrosus tissue. Since the annulus fibrosus cells/tissue are maintained so that they are viable, such cells are able to produce collagen which would form around the circumference of the nucleus pulposus as can be seen in Figure 1 of Mizuno. It would have been obvious to an artisan of ordinary skill at the time of effective filing to have encapsulated the nucleus pulposus cell population of Kandel in the alginate gels taught by Mizuno. An artisan would have been motivated to have encapsulated the nucleus pulposus population in the alginate gel because it provides stability to the cells, encourages the formation of the desired structure, and integrates the nucleus pulposus structure with the annulus fibrosus structure (Figure 1 of Mizuno) to form an intervertebral disc. Since gel encapsulated cells can successfully result in intervertebral disc implant formation, there would have been a high expectation for success (Introduction and Figure 1 of Mizuno) as in instant Claims 2 and 18.
Neither Kandel or Mizuno teach the encapsulation of the annulus fibrosus cells. However, Bonassar teaches the encapsulation of cells used in a living tissue construct. It would have been obvious to an artisan of ordinary skill at the time of effective filing to have placed the annulus fibrosus cells in an alginate gel. An artisan would have been motivated to have placed the annulus fibrosus cells in gel as well because it makes a stable construct and the shape of the annulus fibrosus can be controlled by placing cells in a gel/hydrogel that can then be molded (Abstract and Summary of Bonassar). The second paragraph of the summary of Bonassar even states many different types of cells can be successfully encapsulated in gel/hydrogel material (Summary, 2nd paragraph of Bonassar). An advantage to encapsulating cells in gel/hydrogel is that they can manipulated into a specific shape to fit a specific space (Summary of Bonassar). Because gels/hydrogels can be shaped with injection methods or molds as taught in Bonassar (Summary Bonassar), there would have been a high expectation for success for placing both the annulus fibrosus and the nucleus pulposus cells in gels.
Dependent Claims taught by Kandel
Kandel teaches wherein the first population of cells secrete a proteoglycan (Paragraph 9) as in instant Claim 5. Kandel teaches wherein the first population of cells comprises nucleus pulposus cells (Paragraph 69 of Kandel) as in instant Claim 6. Kandel teaches wherein the cell population further comprises type II collagen (Paragraphs 11,99) as in instant Claim 7. Kandel teaches wherein the nucleus pulposus has an isotropic structure (Paragraphs 69-70) as in instant Claim 8. Kandel teaches wherein the second population of cells comprises annulus fibrosus cells (Paragraphs 69-70) as in instant Claim 9. Kandel teaches wherein the second gel comprises collagen at a concentration of about 1 mg/ml to about 30 mg/ml (Table 1 of Kandel) as in instant Claim 11. Kandel teaches wherein the annulus fibrosus has an anisotropic structure (Paragraphs 53 and 69) as in instant Claim 12. Kandel teaches wherein the IVD is permeable to allow nutrient transport to developing tissue (the configuration taught in Paragraphs 68-69 would allow the nutrients to permeate) as in instant Claim 13. Kandel teaches wherein said forming is carried out by cutting samples from a sheet (Paragraphs 68-69 of Kandel) as in instant Claims 17 and 21. Plastic dish ware/manderals are used in Kandel (Paragraphs 68-69) as in instant Claim 20.
Dependent Claims taught by Mizuno
Mizuno teaches that the first gel is an alginate gel comprising about 2% alginate (Page 363, Section 2.2) as in instant Claim 3. Mizuno teaches that the cell suspension was 25 x 106 cells/ml concentration (Page 363, Section 2.2. and Figure 1) as in instant Claim 4. Mizuno teaches that the NP cells are capable of secreting proteoglycan (Abstract, Page 368, first full paragraph) as in instant Claim 5. Mizuno teaches wherein the first population of cells comprise nucleus pulposus cells (Figure 1) as in instant Claim 6, Mizuno teaches wherein the nucleus pulposus has an isotrophic structure (Figure 1) as in instant Claim 8. Mizuno teaches wherein the second population of cells comprises annulus fibrosus cells (Figure 1) as in instant Claim 9. Mizuno teaches wherein the second population of cells are present in the second gel at a concentration of about 50x106 cells/ml (Figure 1) as in instant Claim 10. Mizuno teaches wherein the second gel comprises collagen at a concentration of about 1 mg/ml to about 30 mg/ml; levels are 50% of natural levels in AF (Abstract, Page 368, rt column) as in instant Claim 11. Mizuno teaches wherein the annulus fibrosus has an ansiotrophic structure (Figure 1) as in instant Claim 12.Mizuno teaches that the IVD is permeable to allow nutrient transport to developing tissue (the IVD, alginate, and scaffolding featured in Figure 1 are permeable materials) as in instant Claim 13. Mizuno teaches that the first gel can be crosslinked (Page 363, Section 2.2, 2nd paragraph) as in instant Claim 14. Mizuno teaches that the first gel has a predetermined shape and size (Figure 1) as in instant Claim 19, Mizuno teaches that injection molding can be used to add the NP cells to the construct with the AF cells (Page 363, Section 2.2, last paragraph) as in instant Claim 21.
Dependent Claims taught by Bonassar
Bonassar teaches that hydrogel gel containing cells can be crosslinked. (Column 2, line 45-55). Bonassar teaches that such crosslinked hydrogels can set at body temperatures (Col 6, ln 7-20). Body temperature is about 37°C as in instant Claim 15.
Bonassar teaches wherein the storing is carried out for about 3 to about 28 days (Column 2, line 20-22) as in instant Claim 16. The first paragraph of Example 2 of Bonassar teaches that molds can be manufactured from Silastic which contains plastic as in instant Claim 20.
Kandel teaches a method of making an intervertebral disc. Kandel does not expressly state that the distinct populations of cells which are used to make the nucleus pulposus structure and the annulus fibrosus structures are each placed in a protective gel. However, an artisan would have been motivated to have encapsulated the different cell populations in gel because Mizuno teaches that nucleus pulposus cells in gel assist with forming a tissue engineered disc intervertebral disc. Furthermore, Bonassar teaches that cells can be placed in gels/hydrogels so that they can be intentional shaped. Given the teachings of the cited references and the level of skill of an ordinary skilled artisan at the time of applicants’ invention, it must be considered absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All of the claimed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention (See KSA International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007)). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.s and Ph.D.s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, cell culture, and tissue engineering. Therefore, the level of ordinary skill in this art is high.
Response to Applicants Arguments
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Applicants are arguing that the claimed structure of the intervertebral disc is not taught in the prior art. Paragraph 69 and Table 1 of the Kandel (the primary reference) is relied upon to teach the structure of the intervertebral disc in the prior art rejection. As can be seen below in paragraph 69 of Kandel, Kandel establishes a structure in which the nucleus pulposus tissue/cells are surrounded by annulus fibrosus tissue/cells. The annulus fibrosus tissue/cells are able to secrete collagen.
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Mizuno and Bonassar are applied in the art rejection to teach encapsulating these distinct cell populations in gel.
Mizuno is used to teach the encapsulation of nucleus pulposus cells in gel (Figure 1 of Mizuno). An artisan would have been motivated to have encapsulated nucleus pulposus cells in an alginate gel because the alginate gel containing the nucleus pulposus cells provides support for a composite intervertebral disc as can be seen in Figure 1 of Mizuno.
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Furthermore, the teachings of Bonassar are applicable because Bonassar in the summary section teaches that cells used in an implant can be encapsulated in a gel to provide greater stability and control the shape of the structure containing the therapeutic cells. Therefore, an artisan of ordinary skill in the art would have been motivated to have encapsulated the cells within a gel structure taught in Bonassar.
Applicants further argue that the references do not teach storing the first and second gels under conditions effective for the collagen in the second gel to align circumferentially around the first gel by self-assembly of collagen due to cell-mediated gel contraction in the second gel, wherein the first gel forms a nucleus pulposus structure and the second gel forms an annulus fibrous structure.
In both the Kandel and Mizuno references, the nucleus pulposus/nucleus pulposus cells are surrounded on all sides by cells/tissue of the annulus fibrosus cells/tissue. The annulus fibrosus cells are able to secrete collagen because they are kept in conditions where they remain viable as shown in Figure 1 of Mizuno and as discussed in Paragraph 69 of Kandel. Because the annulus fibrosus cells surround the entire structure of the nucleus pulposus structure/nucleus pulposus cells, the annulus fibrosus cells will be able to inherently secrete collagen around the circumference of the nucleus pulposus. The structure produced would have an inner structure of nucleus pulposus cells/tissue which is surrounded by annulus fibrosus cells/annulus fibrosus structure.
Conclusion
All claims stand rejected.
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.
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LAUREN K. VAN BUREN
Examiner
Art Unit 1638
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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