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 1-15 are pending.
Claims 4-15 are withdrawn.
Claims 1-3 are under examination.
Withdrawn Claim Objections
The objection to claim 3 as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New Claim Objections
Claim 2 is objected to because of the following informalities:
Claim 2 recites “the outer cavity and the inner cavity each comprise a hydrogel” and “the cell aggregate comprises hepatocytes embedded in the hydrogel.” However, claim 1, upon which claim 2 depends, already recites that the outer cavity is formed by printing a first bio-ink comprising vascular endothelial cells and a hydrogel and the cell aggregate is formed by printing a second bio-ink comprising hepatocytes and a hydrogel which already results in the structure of “the outer cavity and the inner cavity each comprise a hydrogel” and “the cell aggregate comprises hepatocytes embedded in the hydrogel.” Therefore, it is unnecessarily redundant to recite “the outer cavity and the inner cavity each comprise a hydrogel” and “the cell aggregate comprises hepatocytes embedded in the hydrogel” in claim 2.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 101
The rejection of claims 1-3 under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring product without significantly more as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the amendment filed on 23rd, October, 2025, claim 1 was amended to recite the following limitations that appear to be new matter:
a “substantially cell-free” oxygen-permeable lumen (claim 1);
These new limitations appear to be new matter.
This limitation contains the negative proviso that the lumen is substantially “cell-free.”
Applicant is directed to MPEP section 2173.05(i) which states any negative limitation or exclusionary proviso must have basis in the original disclosure.
A review of the originally filed specification by the Examiner did NOT find any specific basis for the recited limitation. The disclosure (including the specification, claims and sequence listing) as originally filed, does not contain an explicit or specific recitation of the limitation.
The closest support for the recited limitation is disclosure of the lumen (para. [0073-0074, 0076-0077, 0094-0095]), and there appears to be no basis in the original disclosure for the lumen to be “substantially cell-free.”
As noted by MPEP 608.04(a), new matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method.
In the instant case one skilled in the art would NOT consider the negative limitation to be explicitly, implicitly, or inherently supported by Applicant’s disclosure.
Hence, there is insufficient written descriptions support for the instantly claimed limitation of and Applicant has not shown possession of the invention.
Response to Arguments
Applicant’s arguments, filed 23rd, October, 2025 have been fully considered but are not found persuasive.
Applicant argues “No new matter is presented.”
In response, Applicant has not provided the location of support for the negative limitation of substantially “cell-free.” When filing an amendment an applicant should show support in the original disclosure for new or amended claims. See MPEP §§ 714.02 and 2163.06 ("Applicant should ... specifically point out the support for any amendments made to the disclosure.") The claim is a new or amended claim, the support for the limitation is not apparent, and applicant has not pointed out where the limitation is supported (see MPEP 2163 (I)). Therefore the claims have been rejected under 35 U.S.C. 112 (a) above.
Withdrawn Claim Rejections - 35 USC § 112 (b)
The rejection of claims 1-3 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New 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 3 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 3 recites “the hydrogel comprises at least one selected from the group consisting of collagen and alginate, fibrin gel, carboxymethyl cellulose, heparan sulfate, hyaluronic acid, collagen, dextran, agarose, gelatin, laminin, a basement-membrane extract comprising laminin, collagen IV, entactin, and heparan sulfate proteoglycan, hydroxyapatite, and polyethylene glycol.” However, claim 2, upon which claim 3 depends, already recites “the hydrogel being selected from the group consisting of collagen, alginate, fibrin gel, carboxymethyl cellulose, heparan sulfate, hyaluronic acid, dextran, agarose, gelatin, laminin, and polyethylene glycol.” Claim 3 recites both redundant options for the hydrogel and options that are not recited in claim 2. Therefore, the scope of the claim is unclear because it is uncertain which options are encompassed by the claim.
Generally, when the claims are indefinite, vague or unclear, they cannot be construed without speculation or conjecture; therefore, the indefinite claims are not treated on the merits with respect to prior art. See In re Steele, 305 F.2d 859, 862 (CCPA 1962) (A prior art rejection cannot be sustained if the hypothetical person of ordinary skill in the art would have to make speculative assumptions concerning the meaning of claim language.); see also In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970) ("If no reasonably definite meaning can be ascribed to certain terms in the claim, the subject matter does not become obvious-the claim becomes indefinite."). Notwithstanding Steele, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution.
New Claim Rejections - 35 USC § 112 (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3 recites “the hydrogel comprises at least one selected from the group consisting of collagen and alginate, fibrin gel, carboxymethyl cellulose, heparan sulfate, hyaluronic acid, collagen, dextran, agarose, gelatin, laminin, a basement-membrane extract comprising laminin, collagen IV, entactin, and heparan sulfate proteoglycan, hydroxyapatite, and polyethylene glycol.” However, claim 2, upon which claim 3 depends, already recites “the hydrogel being selected from the group consisting of collagen, alginate, fibrin gel, carboxymethyl cellulose, heparan sulfate, hyaluronic acid, dextran, agarose, gelatin, laminin, and polyethylene glycol.” Claim 3 recites redundant options for the hydrogel including collagen, alginate, fibrin gel, carboxymethyl cellulose, heparan sulfate, hyaluronic acid, dextran, agarose, gelatin, laminin, and polyethylene glycol that are already recited in claim 2 and therefore cannot further limit claim 2 because they are already recited. Claim 3 also recites the options of basement-membrane extract comprising laminin collagen IV, entactin, and heparan sulfate proteoglycan, hydroxyapatite which are not recited in claim 2 and cannot further limited because the hydrogel is already defined in claim 2.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claims 1-3 under 35 U.S.C. 102(a)(1) as being anticipated by Shepard et al. (US-20140274802-A1; henceforth “Shepard”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claims 1-3 under 35 U.S.C. 102(a)(1) as being anticipated by Ho et al. (Lab Chip. 2013 Sep 21;13(18):3578-87.; henceforth “Ho”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claims 1-3 under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al. (Adv Mater. 2012 Oct 9;24(39):5339-44. Epub 2012 Aug 24.; henceforth “Lee”).
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.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Adv Mater. 2012 Oct 9;24(39):5339-44. Epub 2012 Aug 24.; henceforth “Lee”) in view of Shepard et al. (US-20140274802-A1; henceforth “Shepard”).
Regarding claim 1, Lee discloses a liver organoid (“liver-lobule architecture”; Figure 2) comprising:
a tubular outer cavity having an inner space divided into a plurality of radial compartments, the outer cavity vascular endothelial cells (human umbilical vein endothelial cells (HUVEC); pg. 5340 col. 1 2nd para. and Figure 2) and a hydrogel (“hydrogel layers” pg. 5339 col. 1; “hepatocyte-containing hydrogel layers” Figure 2; “hydrogel matrix” pg. 5341; Experimental Section “Construction of Three-Dimensional Engineered Tissues” pg. 5342 col-2 - pg. 5343 col 2);
a cell aggregate filling each of the plurality of the compartments, the cell aggregate comprising hepatocytes and a hydrogel (“hepatocyte-containing hydrogel layers” Figure 2); and
an inner cavity disposed within and surrounded by the tubular outer cavity comprising a hydrogel (“hydrogel layers” pg. 5339 col. 1; Figure 2; “hydrogel matrix” pg. 5341; Experimental Section “Construction of Three-Dimensional Engineered Tissues” pg. 5342 col-2 - pg. 5343 col 2),
wherein the organoid comprises a through-hole extending along a longitudinal center of the inner cavity creating a substantially cell-free lumen, and
wherein the organoid comprises blood vessels between an outer surface of the outer cavity and each of the plurality of compartments and on an outer circumferential surface of the through-hole, where the organoid is vascularized (it comprises blood vessels and vascular endothelial cells as discussed above) (see annotated Figure 2 of Lee below).
PNG
media_image1.png
431
1267
media_image1.png
Greyscale
(Figure 2 of Lee with annotations of corresponding structures).
Regarding the recited limitation that the lumen is “oxygen-permeable,” the lumen of Lee does not comprise cells or hydrogel and appears to be oxygen permeable. Additionally, a specific amount of oxygen permeability is not required by instant claims, so instant limitations are met as long as some oxygen can permeate the lumen.
However, regarding claim 1, although Lee appears to teach the required structures of the liver organoid, as discussed above, Lee does not teach that the liver organoid is fabricated by three-dimensional printing.
Nevertheless, regarding claim 1, Shepard teaches fabrication of liver organoids by three-dimensional printing (bioprinted; para. [0004, 0006-0011, 0015-0030, 0037, 0051-0052, 0055, 0060, 0074-0077, 0079-0080, 0083-0085, 0090-0091, 0094, 0096, 0098, 0115, 0121, 0126, 0130-0131, 0138, 0140-0141, 0143, 0160-0164, 0170-0171, 0173-0174, -176, 0181-0182, 0185-0193, 0197-0200]; Figures 2-19; see in particular Example 1; Examples 2-3, 5; claims 1-2, 14-15, 26-27, 37-38, 47-48, 59-60, 67-68, 74-76) using bio-inks comprising vascular endothelial cells, hydrogels, and hepatocytes, to overcome both inherent challenges (planar/ laminar geometry and cell density) through the spatially-defined deposition of bio-ink comprised of cells and enable the incorporation of cells at a density that mimics native tissue (para. [0094]).
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 prepare the liver organoid of Lee, and simply substitute the known prior art element of fabrication by three-dimensional printing of Shepard for the preparation steps of Lee to obtain the predictable result of a 3D-printed organoid. One of ordinary skill would have been motivated to do so as taught by Shepard to overcome inherent challenges of geometry and cell density through the spatially-defined deposition of bio-ink comprised of cells and enable the incorporation of cells at a density that mimics native tissue (para. [0094]). Regarding the reasonable expectation of success, Shepard evidences the fabrication of liver organoids by three-dimensional printing (Examples 1-5).
Furthermore, regarding claim 1, this is a product-by process claim. Applicant is reminded that product-by process claims are not limited by the manipulation of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (see MPEP 2113). In the instant case, Lee teaches the structures of the claimed organoid and Shepard makes obvious fabricating the organoid by printing using bio inks, and therefore the structure of the claimed organoid is obvious as discussed above.
Regarding the thereby clause of claim 1, Lee in view of Shepard suggest the structural limitations of instant claims as discussed above and Shepard teaches and makes obvious fabricating the organoid by three-dimensional printing using bio inks with the claimed cell types and hydrogel and therefore the suggested organoid would result as “a vascularized and oxygen-permeable lobule-type liver organoid distinct from natural liver tissue” in view of this suggested preparation (See MPEP 2111.04).
Regarding the recited limitations of claim 1 that the cavities are formed by printing with specific bio-inks (“the outer cavity being formed by printing a first bio-ink comprising vascular endothelial cells and a hydrogel,” “the inner cavity being formed by printing a third bio-ink comprising a cell-free hydrogel”), as stated above, these are product-by process limitations. Lee in view of Shepard makes obvious the instantly claimed organoid for the reasons stated above because Lee in view of Shepard make obvious the structural requirements of the instant organoid. Further, regarding the recited limitations of claim 1 that “the inner cavity being formed by printing a third bio-ink comprising a cell-free hydrogel,” the hydrogel suggested by Lee is cell-free prior to use, and Shepard suggests printing with a bio ink comprising a cell-free hydrogel (Figures 9-12, para. [0022-0025] ; see also para. [0118, 0121, 0124, 0132, 0168, 0198] and Examples 4-5). Additionally, the transitional phrase comprising is open ended, and therefore does not preclude cells from being present in addition to a cell-free hydrogel (see MPEP 2111.03).
Regarding claim 2, further to the discussion of claim 1 above, Lee teaches the outer cavity and the inner cavity each comprise a hydrogel (“hydrogel layers” pg. 5339 col. 1; “hepatocyte-containing hydrogel layers” Figure 2; “hydrogel matrix” pg. 5341; Experimental Section “Construction of Three-Dimensional Engineered Tissues” pg. 5342 col-2 - pg. 5343 col 2), and the cell aggregate comprises hepatocytes embedded in the hydrogel (“hepatocyte-containing hydrogel layers” Figure 2), where the hydrogel is polyethylene glycol (poly(ethylene glycol) (PEG)-based hydrogels (pg. 5342 col. 2 “Experimental Section”).
Regarding claim 3, further to the discussion of claims 1-2 above, although Lee teaches hydrogel (“(PEG)-based hydrogels” Experimental Section “Construction of Three-Dimensional Engineered Tissues” pg. 5342 col-2 - pg. 5343 col 2), Lee is silent to a hydrogel comprising gelatin and alginate.
Nevertheless, regarding claim 3, Shepard discloses a 3D-pritned liver organoid which is printed using a 4% gelatin and 2% alginate hydrogel (Figures 9-12, para. [0022-0025] ; see also para. [0118, 0121, 0124, 0132, 0168, 0198] and Examples 4-5). Shepard teaches the gelatin and alginate hydrogels as know alternative options to polyethylene glycol hydrogels (para. [0198] lists gelatin, alginate, and PEG hydrogels as suitable hydrogels.
Therefore, regarding claim 3, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the liver organoid fabricated by three-dimensional printing as suggested by Lee in view of Shepard, and simply substitute the know prior art element of the 4% gelatin and 2% alginate hydrogel of Shepard for the (PEG)-based hydrogel of Lee to obtain the predictable result of a Liver organoid. One of ordinary skill would have been motivated to do so as taught by Shepard because gelatin and alginate hydrogels were know suitable alternative options to polyethylene glycol hydrogels (para. [0198] lists gelatin, alginate, and PEG hydrogels as suitable hydrogels. Regarding the reasonable expectation of success, Shepard evidences preparation of a 3D-pritned liver organoid which is printed using a 4% gelatin and 2% alginate hydrogel (Figures 9-12, para. [0022-0025] ; see also para. [0118, 0121, 0124, 0132, 0168, 0198] and Examples 4-5).
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
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.
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.
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, Peter Paras can be reached at (571) 272-4517. 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.
/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
Prosecution Insights