DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 4/27/2026 to claims 1, 21, 22, and 27 have been entered. Claims 3, 10-15, 20, and 23 are canceled. Claims 1, 2, 4-9, 16-19, 21, 22, and 24-27 remain pending, of which claims 1, 2, 4-8, 16-19, 21, 22, and 24-27 are being considered on their merits. Claim 9 remains withdrawn from consideration. References not included with this Office action can be found in a prior action.
The instant claim amendments have overcome the 35 U.S.C. § 112(b), 102, and 103 rejections of record, which are withdrawn.
Any other rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
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 1, 2, 4-7, 16-19, 21, and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Prestwich et al. (US 2013/0172985; provided in the IDS dated 5/18/2023) in view of Anseth et al. (WO 2012/1063445; provided in the IDS dated 5/18/2023).
Prestwich teaches a method of making a 3D organ construct, the method comprising (a) providing a reservoir containing an extrudable hydrogel composition, said composition comprising a cross-linkable prepolymer (i.e. hyaluronic acid (HA) or gelatin), a post-deposition crosslinking group (i.e. an excess of methacrylic anhydride), live cells (HepG2 C3A, Intestine 407, or NIH 3T3 cells), (b) depositing said hydrogel composition onto a substrate (e.g., by extrusion through a syringe); and then (c) cross-linking said prepolymer with said post-deposition crosslinking group by an amount sufficient to increase the stiffness of said hydrogel and form said three-dimensional organ construct (see the single working example at ¶0067-0079 HA-MA/gelatin-MA extrudable hydrogel made by UV crosslinking in a stacked ring pattern), reading in-part on claim 1, the embodiment of photoinitiated crosslinking for claim 2, and claim 4, the embodiment of stacked rings for claim 6, the embodiment of a first ring for the supporting polymer in an adjacent position for claim 7, Prestwich teaches that the hydrogel has a stiffness (e.g. G’ or elastic modulus) of 10 or 20 Pa (¶0076), reading on the embodiment of (i) for claim 5. Prestwich teaches adding 2,2-dimethoxy-2-phenyl-acetophenone in NVP as a species of photoinitiator (¶0070), reading on claims 16 and 17. Prestwich teaches that the hydrogel compositions are formed from aqueous buffered solutions (e.gh. comprising water; ¶0070), reading on claim 19. Prestwich teaches that the hydrogel has an elastic modulus of about 100 Pa (e.g. 80-90 Pa; ¶0076), reading on claim 26. Prestwich teaches cell aggregates (e.g. 3D organ constructs) comprising embryonic cells and/or stem cells (¶0056), reading in-part on claims 20, 21, and 23-25. Prestwich further teaches that the hydrogel composites produced therein are advantageous in downstream methods of tissue engineering (¶0051). Prestwich teaches adding extracellular matrix secreted from cells or obtained from genetically-manipulated cells (e.g. decellularized; ¶0057-0058), reading on claim 18. Prestwich teaches that an elastic modulus of 80-90 Pa is effective to yield a hydrogel enough like a fluid to be pulled into a syringe and extruded through a needle tip without visibly damaging the hydrogel structure yet solid enough to temporarily retain shape when printed before the secondary photocrosslinking step (¶0076), reading on claim 26.
Regarding claim 26, generally, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case, Prestwich teaches that the elastic modulus of the hydrogel composition is a known result-effective variable, being enough like a fluid to be pulled into a syringe and extruded through a needle tip without visibly damaging the hydrogel structure yet solid enough to temporarily retain shape when printed before the secondary photocrosslinking step. Thus, the burden is shifted back to establish criticality of the claimed elastic modulus range by objective evidence.
Regarding claim 1, Prestwich does not teach wherein said cross-linkable prepolymer is formed from a reaction of: (i) a thiol-substituted polymer and (ii) a first thiol-reactive crosslinking agent, wherein the reaction at least partially crosslinks the thiol-substituted polymer and the first thiol- reactive crosslinking agent. Regarding claim 1, Prestwich does not teach wherein said post-deposition crosslinking group comprises an alkyne. Regarding claim 21, Prestwich does not teach wherein said thiol-substituted polymer is selected from the group consisting of thiolated hyaluronic acid, thiolated gelatin, and a combination thereof, and wherein said first thiol-reactive crosslinking agent is selected from the group consisting of a polyalkylene glycol diacrylate, a polyalkylene glycol 4-arm acrylate, and a combination thereof. Regarding claim 24, Prestwich does not teach wherein said post-deposition crosslinking group comprises a multi-arm thiol-reactive crosslinking agent and/or polyethylene glycol dialkyne. Regarding claim 25, Prestwich does not teach wherein said post-deposition crosslinking group is a PEG 4-arm alkyne or PEG 8-arm alkyne.
Anseth teaches a thiol-yne polymeric material and methods for producing said polymers (Abstract). Anseth teaches that the polymers described herein can be used as a substrate for the growth of various cell types (p9, lines 1-5), reading in-part on claims 20-25. Anseth teaches the polymer formulated as a hydrogel (claim 6), reading in-part on claims 1, 21, 24, and 25. Anseth teaches a thiol-substituted polymer comprising hyaluronic acid or gelatin (claim 5), reading on claim 1. Anseth teaches that a thiol-reactive crosslinking agent comprising 4-arm thiolated PEG (Example 3) further modified to comprise vinyl functional monomers such as acrylates (p7, lines 11-16), reading on claim 21. Anseth teaches a thiol-reactive crosslinking agent comprising an alkyne (claim 1), and a 4-arm PEG alkyne (paragraph spanning p1-2), reading on claims 1, 24, and 25. Anseth teaches that there is a need in this art for materials in tissue regeneration that are low cost, versatile, and easily prepared (p1, lines 10-15), reading on claims 1, 21, 24, and 25. Anseth teaches that the thiol-yne polymeric material may be used as a substrate for cell and stem cell growth (p9, lines 1-5), reading on claims 1, 21, 24, and 25.
Regarding claims 1, 21, 24, and 25, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the thiolated hyaluronic acid or thiolated gelatin and the thiolated 4-arm PEG alkyne of Anseth for the hyaluronic acid or gelatin and crosslinkable methacrylate groups of Prestwich in Prestwich’s methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Anseth and Prestwich are directed towards crosslinked hyaluronic acid and/or gelatin hydrogel compositions for either the culturing/manufacture of a stem cell aggregate (e.g. 3D organ construct) for Prestwich or culturing of stem cells for Anseth, and because both Anseth and Prestwich are directed towards downstream methods of tissue engineering/regeneration. The skilled artisan would have been motivated to do so because Anseth teaches that the thiolated hyaluronic acid or thiolated gelatin and the thiolated 4-arm PEG alkyne are predictably advantageous by being low cost, versatile, and easily prepared, and would thus improve upon the downstream methods of tissue engineering/regeneration taught by Prestwich.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Prestwich and Anseth as applied to claim 1 above, and further in view of Cosson et al. (Scientific Reports (March 2014), 4:4462).
The teachings of Prestwich and Anseth are relied upon as set forth above. Prestwich further teaches cell aggregates (e.g. 3D organ constructs) comprising embryonic cells and/or stem cells (¶0056), reading in-part on claim 8.
Regarding claim 8, Prestwich and Anseth do not teach wherein said substrate comprises a microfluidic device having at least one chamber, and said depositing is carried out in said at least one chamber; or said substrate comprises a first planar member, said depositing step is carried out on said planar member, and said method further comprises the step of inserting said planar member into a chamber of a microfluidic device.
Cosson teaches a hydrogel microfluidic system for both adherent or aggregate-based cell culture (p2, left column, paragraph starting “We reasoned…”). Cosson teaches that the substrate comprises a microfluidic device having at least one chamber, and said depositing of hydrogel is carried out in said at least one chamber and further comprises embryonic stem cells (Fig. 1 and p2, right column, subheading “ESC culture on hydrogel chip surface.”), reading on claim 8. Cosson teaches that the microfluidic device is advantageous to deliver biomolecules in a tightly controlled fashion to embryonic stem cells such that the embryonic stem cells differentiate into neural stem cells (p3-4, subheading starting “Spatiotemporarlly controlled…”, Fig. 3, and p4, 1st paragraph of the “Conclusion”), reading on claim 8.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to add the microfluidic device of Cosson to the methods of Prestwich. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because towards methods of making embryonic stem cell aggregates in-part by culturing said cells with a hydrogel composition, The skilled artisan would have been motivated to do so because Cosson teaches that the microfluidic device is advantageous to deliver biomolecules in a tightly controlled fashion to embryonic stem cells such that the embryonic stem cells differentiate into neural stem cells, thus improving the methods of Prestwich to make neural stem cells from embryonic stem cells.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Prestwich and Anseth as applied to claim 1 above, and further in view of Prestwich et al. (US 2010/0330143; hereafter referred to as “the Prestwich ‘143 pre-grant publication”).
The teachings of Prestwich and Anseth are relied upon as set forth above.
Regarding claim 22, Prestwich does not teach wherein said thiol-substituted polymer comprises thiolated hyaluronic acid and said first thiol-reactive crosslinking agent comprises polyethylene glycol diacrylate.
The Prestwich ‘143 pre-grant publication teaches a hydrogel composition comprising thiolated hyaluronic acid and PEDGA (i.e. CarbylanTM-SX) (¶0188, ¶0291, and ¶309), reading on claim 22. The Prestwich ‘143 pre-grant publication teaches that the hydrogel composition is advantageous as post-op adhesion barrier that is resorbable, easy to use, and stay in place after application (¶0253), reading on claim 22. The Prestwich ‘143 pre-grant publication teaches culturing a plurality of cells or cell aggregates (e.g. 3D organ construct) in the hydrogel composition and for downstream use in methods of tissue engineering (¶0266-0268), reading on claim 22
It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the thiolated hyaluronic acid and PEDGA (i.e. CarbylanTM-SX) of the Prestwich ‘143 pre-grant publication for the hyaluronic acid and crosslinkable methacrylate groups of Prestwich in Prestwich’s methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both the Prestwich ‘143 pre-grant publication and Prestwich are directed towards crosslinked hyaluronic acid hydrogel compositions for either the culturing/manufacture of a cell aggregate (e.g. 3D organ construct), and because both the Prestwich ‘143 pre-grant publication and Prestwich are directed towards downstream methods of tissue engineering/regeneration. The skilled artisan would have been motivated to do so because the Prestwich ‘143 pre-grant publication teaches that the thiolated hyaluronic acid and PEDGA (i.e. CarbylanTM-SX) hydrogen composition would be predictably advantageous as post-op adhesion barrier that is resorbable, easy to use, and stay in place after application, and would thus improve upon the downstream methods of tissue engineering/regeneration taught by Prestwich.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Prestwich and Anseth as applied to claim 1 above, and further in view of Tirella et al. (Tissue Engineering: Part C (2011), 17(2), 229-237).
The teachings of Prestwich and Anseth are relied upon as set forth above. Prestwich further teaches a crosslinkable macromolecule/polymer comprising alginic acid (¶0042), reading in-part on claim 27.
Regarding claim 27, Prestwich and Anseth do not teach the embodiment of extruding the hydrogel composition through a needle having a needle gauge range of 20-30G.
Tirella teaches methods of making cell-incorporated alginate scaffold with piston-assisted microsyringe (PAM2) (Abstract). Tirella teaches extruding the alginate hydrogel through a 29 gauge needle (the paragraph spanning p230-231), reading on claim 27. Tirella teaches loading the alginate hydrogel composition with HepG2 cells (p230, right column, paragraph starting “HepG2 cell line”), reading in part on claim 27. Tirella teaches that the PAM2 system and methods fabricates well-defined 3D scaffolds using materials with high viscosity, typically hydrogels (paragraph spanning p230-231) and is capable of yielding hydrogel compositions in a hexagonal grid shape which mimics the hepatic lobule (p231 subheading “Cell-incorporated alginate scaffolds”, and Fig. 2), reading on claim 27.
Regarding claim 27, it would have been obvious to a person of ordinary skill in the art before the invention was filed to further extrude the hydrogel composition of Prestwich with the needle gauges of Tirella. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Tirella and Prestwich are directed towards methods of extrudable cell-incorporated hydrogel scaffolds. The skilled artisan would have been motivated to do so because the further extrusion of Prestwich’s hydrogel would be predictably advantageous to yield the HepG2 cells of Prestwich formulated as in a hexagonal grid shape which mimics the hepatic lobule.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 6-13 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
In response to applicant's argument on pages 8-11 of the reply regarding the combination of Anseth with Prestwich, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this case, Applicant appears to be bodily incorporating the teachings of Anseth into Prestwich and which is an improper test of obviousness. That Prestwich does not teach every element of claim 1 as instantly amended is not disputed, but Prestwich is not applied alone under 35 U.S.C. § 102 anymore but in combination with Anseth under 35 U.S.C. § 103 and the claimed invention becomes obvious when the references are considered together as a whole rather than each alone. None of Applicant’s arguments address the specific statement of a reasonable expectation of success and the motivation to combine Anseth with Prestwich.
Conclusion
No claims are allowed. No claims are free of the art.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at 571-272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Sean C. Barron/Primary Examiner, Art Unit 1653
Prosecution Insights