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 .
Response to Arguments
Applicant's arguments filed 02/26/26 have been fully considered but they are not persuasive.
On pages 7-11 regarding drawing objections, 101 and 112 rejections Applicant argues amendments overcome the objections and rejections of record.
The Examiner respectfully withdraws drawing objections, 101 and 112 rejections of record.
On pages 11-12 regarding 102 rejections Applicant argues amendments overcome the rejections of record.
The Examiner respectfully refers to the rejection below regarding amended claims.
On page 14 regarding 103 rejections Applicant argues the prior art of Fu and Liu differ from the instant invention. On page 15 Applicant points out more differences between the prior art and the instant invention.
The Examiner respectfully notes this argument is not a sufficient reason to overcome the rejection of record. See MPEP 2144.
On pages 14-15 Applicant argues further that crosslinking in a whole-organ vascular structure includes significant technical risks and so a person of ordinary skill would not have expected success in crosslinking for reinforcement.
The Examiner respectfully notes that the arguments of counsel cannot take the place of evidence in the record. See MPEP 716.01(c). There is no evidence in the record to support this statement. Further, the Examiner notes the requirement for the instant invention to be a “whole-organ” system is considered new matter, as there is no support for this in the originally filed disclosure. See 112a rejections below.
On pages 15-16 Applicant argues further that Fu and Liu are not in the same technical field as the instant invention since they have different technical problems, and argues they have no applicability to the liver. Applicant points out elements lacking in Fu and Liu.
The Examiner respectfully disagrees and maintains a person of ordinary skill in the tissue engineering art would consider Fu and Liu as relevant in the art. The Examiner also notes it appears Applicant as arguing only against Fu and Liu while neglecting Bai, who was referenced to teach elements relating to the organ being a liver.
On pages 16-18 Applicant presents more arguments which fail to take into account the entire rejection of record which relies upon Bai in addition to Fu and Liu, and also include statements which are unsupported by evidence in the record. These statements are accordingly unpersuasive.
On pages 18-22 Applicant argues Fu and Bai are not in the same field of endeavor as Applicant’s invention, since Applicant’s invention utilizes a whole organ and Fu and Bai are involved in tissue scaffolds.
The Examiner respectfully notes these are considered the same field of endeavor, and also notes a lack of discussion of the instant invention requiring a whole organ. The Examiner maintains that the prior art is in the same field of endeavor.
Claim Objections
Claims 26, 28-30, 32, 34-37 and 39 are objected to because of the following informalities:
Claim 26 is objected to for referring to “a whole liver” and “a non-human mammal” with improper antecedent basis.
Claim 28 is objected to for referring to “a decellularized whole-liver scaffold” and “a non-human mammal” multiple times with improper antecedent basis.
Claim 29 is objected to for referring to “the graphene nanostructure” when it is unclear if this is referring back to the “graphene oxide nanostructure” or whether this is something different.
The claim is further unclear for claiming the graphene nanostructure is “a nano-sized graphene oxide” when it is unclear how (if at all) this is different from the previously claimed “graphene oxide nanostructure”.
Claim 30 is objected to for referring to “the graphene nanostructure” when it is unclear if this is referring back to the “graphene oxide nanostructure” or whether this is something different.
Claim 32 is objected to for referring to “the graphene nanostructure” when it is unclear if this is referring back to the “graphene oxide nanostructure” or whether this is something different.
The claim is further objected to for referring to “the physical properties” and “a decellularized whole-liver scaffold” with improper antecedent basis.
The claim is further objected to for apparently missing a word between “combination thereof” and “the physical properties”.
Claim 34 is objected to for referring to “the graphene nanostructure” when it is unclear if this is referring back to the “graphene oxide nanostructure” or whether this is something different.
Claim 35 is objected to for referring to “the graphene nanostructure” when it is unclear if this is referring back to the “graphene oxide nanostructure” or whether this is something different.
The claim is further unclear for referring to “a decellularized whole-liver scaffold” with improper antecedent basis.
Claim 36 is objected to for referring to “the graphene nanostructure” when it is unclear if this is referring back to the “graphene oxide nanostructure” or whether this is something different.
The claim is further unclear for referring to “a non-human mammal” with improper antecedent basis.
Claim 37 is objected to for including the phrase “parenchymal cells may be” which appears to be extraneous.
The claim is also objected to for referring to “a non-human mammal” with improper antecedent basis.
Claim 39 is objected to for referring to “a non-human mammal” with improper antecedent basis.
Appropriate correction is required.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: “whole-liver scaffold”, “vascular structure”.
Claim Rejections - 35 USC § 112
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 26, 28-30, 32, 34-39 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 26 is rejected for having new matter for claiming the artificial organ is an artificial liver that is “based on a whole liver derived from a non-human mammal”. There is no support for this in the originally filed disclosure, since it does not discuss how the method of producing an artificial organ is an artificial liver based on a whole liver derived from a non-human mammal.
The claim also has new matter for claiming a “whole liver” derived from a non-human mammal is provided, as there is no support for a “whole liver” being provided.
The claim further has new matter for claiming the decellularizing of the whole liver occurs by perfusion through a “vascular structure”, which is not mentioned anywhere in the originally filed disclosure, and also for claiming a “decellularized whole-liver scaffold” is prepared.
The claim further has new matter for claiming “a composition comprising graphene oxide nanostructure” is perfused through the vascular structure to cross-link the graphene oxide nanostructure to the decellularized whole-liver scaffold. There is no whole-liver scaffold mentioned anywhere in the originally filed disclosure, no discussion of graphene oxide nanostructure composition perfusing through a vascular structure, or that perfusion of graphene oxide nanostructure resulting in crosslinking the graphene oxide nanostructure to a decellularized whole-liver scaffold.
The claim is further rejected for having new matter for claiming the crosslinking of the graphene oxide nanostructure to the decellularized whole-liver scaffold (which is not supported by the disclosure) comprises covalent crosslinking bones between the graphene oxide nanostructure and the extracellular matrix (ECM) proteins of the decellularized whole-liver scaffold. There is no discussion of any of the EC proteins of a whole-liver scaffold that has been decellularized let alone their crosslinking with covalent bonds to a graphene oxide nanostructure.
Claim 28 is rejected for having new matter for referencing a “decellularized whole-liver scaffold” which is not supported by the originally filed disclosure.
Claim 32 is rejected for having new matter for claiming the graphene nanostructure strengthens, improves, “or a combination thereof” since no combination of improving and strengthening is present in the originally filed disclosure.
Further, the claim is rejected for having new matter for referring to physical properties of a “decellularized whole-liver scaffold”, when a whole-liver scaffold is not supported by the originally filed disclosure.
Claim 35 is rejected for having new matter for claiming the graphene nanostructure ameliorates, suppresses, “or a combination thereof” since no combination of ameliorating or suppressing is present in the originally filed disclosure.
The claim is additionally rejected for having new matter for referencing induction of inflammatory response of a “decellularized whole-liver scaffold” when there is no reference to a whole-liver scaffold in the originally filed disclosure.
Remaining claims are rejected for depending on a claim with new matter.
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 26, 28-30, 32, 34-39 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 pre-AIA the applicant regards as the invention.
Claim 26 is indefinite for claiming the whole liver is decellularized by perfusion through “a vascular structure”, and then for claiming a composition of graphene oxide nanostructure is perfused “through the vascular structure of the decellularized whole-liver scaffold” when the “vascular structure” does not appear to belong to the whole-liver scaffold based on the claims. It is accordingly unclear whether or not the “vascular structure” mentioned twice is actually two different elements or not.
Further, the claim is unclear for claiming “a method for producing an artificial organ, wherein the artificial organ is an artificial liver based on a whole liver derived from a non-human mammal” since it is unclear whether the artificial organ is intended to be based on “a whole liver derived from a non-human mammal” (e.g. as opposed to being based on a liver of a human), or whether this is intended to be an artificial organ which is an artificial liver based on a whole liver, the whole liver being derived from a non-human mammal. The specification does not support either interpretation, as whole livers, and particularly whole livers derived from non-human mammals is not present or described anywhere in the specification.
Claim 29 is indefinite for claiming the “graphene nanostructure is…graphene quantum dot” when claim 26, from which this depends has referenced a “graphene oxide nanostructure”. It is unclear how the graphene oxide nanostructure can be a graphene quantum dot, as the claim requires.
Claim 32 is indefinite for claiming the graphene nanostructure strengths, improves, or a combination there of the physical properties consisting of suppression of weight loss due to degrading enzymes of the decellularized whole-liver scaffold. It is unclear to the Examiner how suppression of weight loss due to degrading enzymes constitutes a physical property of the whole-liver scaffold, and especially how it constitutes a “strengthening”, “improving”, or a combination there of the scaffold.
Claim 38 is indefinite for claiming the parenchymal cells are stem cell-derived parenchymal cells, when the claim from which this depends has stated the parenchymal cells are already selected from a specific group of parenchymal cells. The specification does not indicate anywhere that the parenchymal cells can be both stem cell-derived AND from one of the specific locations listed in claim 37, making it unclear if the limitations from claim 38 and 37 can be met at the same time or not, and unclear whether the two, if met at the same time, is supported by the originally filed disclosure. Further, the originally examined invention already examined the parenchymal cells as being stem cell-derived, making it unclear whether or not claim 37 should be withdrawn as being drawn towards a non-originally-presented embodiment.
Remaining claims are rejected for depending on an indefinite claim.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The claims as listed below are rejected as they are best understood, and based on the Examiner’s best ability to understand the subject matter in the originally filed disclosure (see 112a and 112b rejections above).
Claims 26, 28-30, 32, 34-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over JinPin Fu, et al. “Reduced graphene oxide incorporated acellular dermal composite scaffolds enables efficient local delivery of mesenchymal stem cels for accelerating diabetic wound healing”, ACS Biomaterials Science & Engineering, (20190812), vol. 5, no. 8, pages 4054-4066.), hereinafter known as Fu in view of Bai et al. “Graphene-based 3d scaffolds in tissue engineering; fabrication, applications, and future scope in liver tissue engineering.”, International Journal of Nanomedicine, Vol. 14 (2019), pages 5733-5783, hereinafter known as Bai, and further in view of Liu et al. (CN 107519534 A) hereinafter known as Liu, and further in view of Applicant’s Admitted Prior Art (page 27 line24 – page 28 line 10 of Applicant’s specification), hereinafter known as AAPA.
Regarding claim 26 Fu discloses a method for producing an artificial organ (Abstract: skin) based on a whole organ (skin is a whole organ) derived from a non-human mammal (page B, left column paragraph 2 mice) comprising:
providing a tissue derived from the non-human mammal (Abstract: acellular dermal matrix (ADM)),
decellularizing the tissue (Abstract: the matrix is acellular) and
the graphene oxide nanostructure being incorporated into the decellularized scaffold (Abstract: there is an ADM scaffold; page B paragraph 2.3 describes the incorporation.),
but is silent with regards to the organ being the liver,
and is silent with regards to how the organ is decellularized and with regards to the graphene nanostructure being perfused to be crosslinked into the scaffold via covalent bonds.
However, regarding claim 26 Bai teaches that graphene nanostructures can be useful in liver tissue healing (page 5766, left column. paragraph 3: graphene-based 3d scaffolds are used for tissue engineering of the liver; see also paragraph 5773 left column paragraph 3 liver-derived scaffold). Fu and Bai are involved in the same field of endeavor, namely tissue scaffolding. It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of Fu by utilizing it within the context taught by Bai, to help the liver, in order to apply the novel tissue healing techniques to a different part of the body, thus broadening the scope of use of the method to help more people.
Further, regarding claim 26 Liu teaches graphene can be cross-linked to its scaffold (abstract; page 2 paragraph 2) by perfusion through a vascular structure of the scaffold (Liu claim 5) to result in covalent crosslinking bonds between the graphene oxide nanostructure and extracellular matrix proteins of the scaffold (this is considered inherent within the method of Liu). Fu and Liu are involved in the same field of endeavor, namely tissue engineering. It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of the Fu Bai Combination by cross-linking the graphene nanostructure to the scaffold of the Fu Bai Combination as is taught by Liu in order to strengthen the scaffold as a whole, stabilizing the scaffold, and increasing its longevity.
Further, regarding claim 26 AAPA teaches decellularization can occur via perfusion through a vascular structure to prepare a decellularized tissue scaffold (AAPA Applicant’s specification page 27 line 24 – page 28 line10). It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of Combination so that the decellularization occurred via perfusion as is taught by AAPA since the courts have held that choosing from a finite number of identified, predictable solutions with a reasonable expectation of success results in a prima facie case of obviousness. See MPEP 2143 (I)(E).
Regarding claim 28 the Fu Bai Liu AAPA Combination teaches the method of claim 27 substantially as is claimed,
wherein Fu further discloses re-cellularizing a decellularized organ into non-parenchymal cells derived from the non-human mammal (page C “cell culture on the scaffold and cytotoxicity assay” bone marrow mesenchymal stem cells were cultured onto the RGO-ADM combination).
Regarding claim 29 the Fu Bai Liu AAPA Combination teaches the method of claim 26 substantially as is claimed,
wherein Fu further discloses the graphene nanostructure is a nano-sized graphene oxide OR graphene quantum dot (page B, left column, RGO nanosheets indicate a nanometer sized thickness sheet, considered to be made of particles of graphene oxide with at least one dimension measurable in nanometers).
Regarding claim 30 the Fu Bai Liu AAPA Combination teaches the method of claim 29 substantially as is claimed,
wherein Fu further discloses the nano-sized graphene oxide has a thickness of 20 nm or less OR an average diameter of 15-50 nm (page E left column, 4.53 +- 2.31 nm).
Regarding claim 32 the Fu Bai Liu AAPA Combination teaches the method of claim 26 substantially as is claimed,
wherein Fu further discloses the graphene nanostructure strengthens OR improves or a combination thereof the physical properties of a decellularized whole organ scaffold (pages E-F, paragraph 3.3; the Young’s modulus, ultimate tensile stress, and strain and failure improved),
wherein the physical properties are either:
an elastic modulus of the decellularized scaffold OR weight loss due to degrading enzymes of the decellularized scaffold OR tensile strength of the decellularized scaffold (pages E-F, paragraph 3.3; the Young’s modulus, ultimate tensile stress, and strain and failure improved).
Regarding claim 34 the Fu Bai Liu AAPA Combination teaches the method of claim 26 substantially as is claimed,
wherein Fu further discloses the graphene nanostructure suppresses in vivo degradation of the decellularized scaffold (page K left column: the scaffold has multiple porous delayed enzymatic biodegradation), via the direct suppression of matrix metalloproteinase (MMP) activity (the direct suppression of MMP is understood to be an inherent result of graphene or its derivatives interacting with MMP).
Regarding claim 35 the Fu Bai Liu AAPA Combination teaches the method of claim 26 substantially as is claimed,
wherein Fu further discloses the graphene nanostructure ameliorates OR suppresses or a combination thereof induction of inflammatory response of a decellularized scaffold following transplantation into a non-human mammal (page H right column; less inflammation is present; right column: diabetic mice).
Regarding claim 36 the Fu Bai Liu AAPA Combination teaches the method of claim 26 substantially as is claimed,
wherein Fu further discloses the graphene nanostructure alleviates post-transplantation inflammatory responses following transplantation into a non-human mammal (page H right column; less inflammation is present; right column: diabetic mice),
and wherein Bai further teaches that graphene-based scaffolds include pro-regenerative macrophages (page 5770, left column, paragraph 2: RCO scaffolds displayed pro-regenerative macrophages (understood to be polarized m2 macrophages)). It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of the Fu Bai Combination to ensure that the graphene-based scaffolds of the Combination also promote polarization to M2 macrophages (e.g. to pro-generative macrophages) as is taught by Bai, since Bai suggests that RGO-based scaffolds used in wound healing naturally perform in this manner.
Regarding claim 37 the Fu Bai Liu AAPA Combination teaches the method of claim 26 substantially as is claimed,
but is silent with regards to the composition comprising parenchymal cells.
However, regarding claim 37 Bai teaches that graphene can be used for liver-tissue scaffolds (page 5766, left column. paragraph 3: graphene-based 3d scaffolds are used for tissue engineering of the liver) and that this desirably includes hepatic parenchymal cells (page 5772, left column, paragraph 3: stem cells which differentiate into hepatocytes (see page 5772 left column paragraph 2: the main parenchymal cells are liver hepatocytes)). Fu and Bai are involved in the same field of endeavor, namely tissue scaffolding. It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of Fu by utilizing it within a liver engineering application as is taught by Bai which includes the inclusion of parenchymal cells (being the main cells of the liver), in order to apply the novel tissue healing techniques to a different part of the body, thus broadening the scope of use of the method to help more people.
Further, regarding claim 37 Bai teaches parenchymal cells can originate from a non-human mammal (page 5773 left column paragraph 3 rat hepatocytes). It would have been obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of the Combination so that the parenchymal cells originate from a non-human mammal as a known alternative in the art to originating from a human. The courts have held that choosing from a finite number of identified, predictable solutions with a reasonable expectation of success results in a prima facie case of obviousness. See MPEP 2143 (I)(E).
Regarding claim 38 the Fu Bai Liu AAPA Combination teaches the method of claim 37 substantially as is claimed,
wherein Bai further teaches the parenchymal cells are stem cell-derived parenchymal cells (page 5772, left column, paragraph 3: stem cells which differentiate into hepatocytes).
Regarding claim 39 the Fu Bai Liu AAPA Combination teaches the method of claim 38 substantially as is claimed,
wherein Bai further teaches the stem cells are marrow-derived stem cells (page 5770 last paragraph – page 5771 first paragraph; stem cells which differentiate in the scaffold can include those from bone marrow).
Conclusion
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 extension fee 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 Jacqueline Woznicki whose telephone number is (571)270-5603. The examiner can normally be reached M-Th 10am-6pm EST.
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/Jacqueline Woznicki/Primary Examiner, Art Unit 3774 03/10/26