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 .
Election/Restrictions
Applicant's election with traverse of Group II in the reply filed on 06/24/2026 is acknowledged. The traversal is on the ground(s) that the claims are directed to a product and a process and as such have unity of invention. This is not found persuasive because in order to establish unity of invention between the combination of a product and process specially adapted for the manufacture of said product, the combination must also be linked by a special technical feature. As cited in the Office Action 03/27/2026, “Where a group of inventions is claimed in a national stage application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.” See PCT Rule 13.1 and 13.2
The requirement is still deemed proper and is therefore made FINAL.
Applicant's election with traverse of (a) interleukin-10 (IL-10); (b) genetic modification; (c) a combination of methylprednisolone, cyclosporin and azathioprine; (d) SEQ ID NO: 36; and (e) VP64 from herpes simplex virus, p65 from human NF-KB, Rta from Epstein-Barr virus, or a combination thereof in the reply filed on 06/24/2026 is acknowledged. The traversal is on the ground(s) that the Office has not provided any explanation for why there would be a serious search and/or examination burden. This is not found persuasive because search and examination burden is not a consideration for the species elections under requirement of unity of invention.
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
Claims 1, 4-5, 8, 12-13, 15-17, 21-22, 26, 28-29, 61-62, and 73-76 are pending. Claims 1, 4-5, 8, 12-13, and 76 are withdrawn for being directed to a non-elected invention.
Claims 15-17, 21-22, 26, 28-29, 61-62, and 73-75 are under examination.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Embedded hyperlinks are found on Pgs. 20-21 and 28-29 of the Specification.
The use of the terms Perfade™ (Pg. 22) and Primaxin™ (Pg. 22) which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Examples of appropriately used tradenames in the specification of a disclosure are Steen Solution™ (Pg. 22) and Solumedrol™ (Pg. 22) which are defined using generic terminology.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 15 and 21 are objected to because of the following informalities:
Claim 15 is objected to because of subsection (ii) which states: “modifying at least one endogenous inflammation-regulating and/or immune- regulating gene in the organ” which does not provide an additional active step to the method. The “modifying” of the gene is accomplished as a result of step (i) with the introduction of the polynucleotide encoding at least one gRNA and Cas protein.
Claim 21 is objected to for not defining the subject that is receiving the step of immunosuppression. To illustrate, this objection is resolved in claim 22 with the statement “the step of immunosuppression comprises administering an agent to a recipient of the organ” (emphasis added).
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 26 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 26 recites the limitation "polypeptide" in Line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 15-17, 29, and 73-75 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mesaki (The Journal of Heart and Lung Transplantation, Volume 39, Issue 4, Supplement, 2020, Page S70, ISSN 1053-2498, Available online 30 March 2020, cited in filed IDS 05/06/2025, new copy of publication attached herewith) as evidenced by Chavez (Nat Methods. 2015 Apr;12(4):326-8, cited in IDS filed 05/06/2025).
The disclosure of Mesaki is directed to gene therapy for donor lungs to improve the outcomes of lung transplantation (Left column, Purpose). Their preclinical proof-of-concept study was performed in rats.
Regarding claim 15, pertaining to a method of preparing an organ for transplantation into an animal, said method comprising the steps of (i) introducing into the organ (a) a polynucleotide encoding a guide RNA (gRNA) that binds to a regulatory region of elected species IL-10; and (b) a polynucleotide encoding a CRISPR-associated protein; and (ii) modifying at least one endogenous inflammation-regulating and/or immune-regulating gene in the organ, Mesaki discloses administration of adenoviral vectors expressing a Cas9 activator (Cas9-VPR) with a gRNA designed to target the promoter region of the rat IL-10 gene, administered to Lewis rats via the airway (Left column, Methods, Lines 1-4). The Cas9-VPR was detected in the lung tissue of the animals and the gRNA group showed increased IL-10 (Left column, Results, Lines 1-3).
Regarding claims 16 and 17, wherein the method of modifying the gene in the organ comprises CRISPR/Cas-mediated modification (claim 16) and wherein the CRISPR/Cas-mediated modification comprises genetic modification (claim 17), Mesaki teaches the gene therapy of the instant disclosure is CRISPR/Cas9 genetic modification (Left column, Purpose, Lines 1-5).
Regarding claim 29, pertaining to an expression cassette comprising (i) a polynucleotide encoding at least one gRNA that binds to a regulatory region of IL-10, and (ii) a polynucleotide encoding a CRISPR-associated (Cas) protein, the specification teaches expression cassettes comprise polynucleotides encoding Cas protein(s), CRISPR gRNA and or cDNA transgenes (Specification, Pg. 30, [0159]. These limitations are fully provided for in the disclosure of Mesaki, specifically in the adenoviral vector expressing a Cas9-VPR and IL-10 gRNA (Left column, Methods, Lines 1-3).
Regarding claims 73 and 74, wherein the organ is selected from the listed group (claim 73), and wherein the organ is a lung (claim 74), Mesaki teaches the CRISPR/Cas9 gene therapy was performed in the lungs of a rat model (Left column, Purpose, Lines 1-4).
Regarding claim 75, wherein the method of claim 15 further comprises introducing into the organ a polynucleotide encoding a transcriptional activator, the transcription activator comprising a combination of VP64 from herpes simplex virus, p65 from human NF-KB, Rta from Epstein-Barr
Virus, Mesaki teaches the use of Cas9 activator, Cas9-VPR. As evidenced by Chavez, as Cas9-VPR comprises the “VPR” tripartite activator fusion protein comprising VP64-p65-Rta (Pg. 326, Right column, Full paragraph 2, Lines 8-11). The VPR fusion increases the transcriptional activity of the Cas9 protein.
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.
Claims 15-17, 21-22, 29, 61-62, and 73-75 are rejected under 35 U.S.C. 103 as being unpatentable over Mesaki (The Journal of Heart and Lung Transplantation, Volume 39, Issue 4, Supplement, 2020, Page S70, ISSN 1053-2498, Available online 30 March 2020.) as applied to claims 15-17, 29, and 73-75 above, and further in view of Machuca (Hum Gene Ther. 2017 Sep;28(9):757-765, cited in IDS filed 05/06/2025) and Knoop (Eur Respir J. 2004 Jan;23(1):159-71).
The disclosure of Mesaki teaches a method of preparing an organ for transplantation into an animal comprising introducing into the organ a polynucleotide encoding a gRNA that binds a regulatory region of IL-10 and a Cas protein.
The disclosure of Mesaki does not teach: (1) the method further comprises the step of immunosuppression, wherein the immunosuppression comprises the combination of methylprednisolone, cyclosporin, and azathioprine or (2) a kit comprising the expression cassette of claim 29.
These deficiencies are taught by Machuca and Knoop.
Machuca:
The disclosure of Machuca is directed to investigating the effects of ex vivo adenoviral human IL-10 gene delivery to prevent the development of primary graft dysfunction in a large animal survival model (Abstract, Lines 1-5).
Regarding claims 21 and claim 22, wherein the method further comprises the step of immunosuppression before, during, and/or after the transplantation (claim 21), and wherein the step of immunosuppression comprises administering to the organ recipient the elected species combination of methylprednisolone, cyclosporin, and azathioprine (claim 22), Machuca teaches organ recipient mice were treated with an oral three-drug immunosuppressive regimen consisting of cyclosporine, azathioprine, and prednisone Pg. 759, Left column, Full paragraph, Lines 13-16.
Regarding claim 61, pertaining to a kit comprising the expression cassette and instructions for using the same, Machuca teaches the adenoviral vector comprising the IL-10 cassette was provided to them by a third party, the University of Iowa College of Medicine Gene Transfer Vector Core (Pg. 758-759). This limitation wherein the researchers received the expression cassette from a third party, reads on a “kit” comprising the expression cassette. The instant specification teaches: “Provided herein are kits comprising the expression cassettes and/or delivery vectors comprising polynucleotides encoding Cas protein(s), CRISPR guide RNAs (gRNAs) and/or cDNA transgenes [0159].” The instructions for use have not been given patentable weight (see MPEP 2112.01 (III) Product Claims – Nonfunction printed matter does not distinguish claimed product from otherwise identical prior art product).
Regarding claim 62, wherein the kit further comprises a perfusate, Machuca teaches the adenoviral vector was diluted in 10mL saline for bronchial delivery, which reads on the limitation of a “perfusate”.
Knoop:
The disclosure of Knoop is directed to reviewing different strategies of immunosuppressive therapy after human lung transplantation. Knoop teaches most clinical lung transplant programs rely on triple-agent immunosuppression comprising steroids. Knoop teaches most physicians have adopted the use of a moderate dose of intravenous methylprednisolone before initiating oral prednisone (Pg. 165, Right column, Steroids, Lines 1-7).
Regarding the limitation of claim 21 wherein the immunosuppression combination comprises the steroid methylprednisolone, Knoop teaches the standard protocol for lung transplant involves intravenous methylprednisolone (Pg. 165, Right column, Steroids, Lines 1-7).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the method of Mesaki by: (1) adding a step of immunosuppression wherein the immunosuppression comprises the three-drug regimen of Machuca comprising a steroid, cyclosporin and azathioprine and specifically methylprednisolone as taught by Knoop and (2) to formulate a kit comprising the expression cassette of Mesaki. One would have been motivated to do so because (1) Machuca and Mesaki are directed to analogous method of preparing lungs for transplantation and Machuca provides a standard triple drug immunosuppressive regimen, with Knoop teaching the triple drug regimen comprises methylprednisone and (2) Machuca teaches the adenoviral vector provided from a third party could be shipped and used for lung transplant gene therapy, which reads on a “kit” comprising the adenoviral vector. There would be an expectation of success in using the immunosuppressive regimen in the method of Mesaki because Machuca demonstrates an effective method of preparing lungs with IL-10 genetic modification and the use of a standard immunosuppressive method that could readily be incorporated into Mesaki’s method of transplantation. There would be an expectation of success of packaging the polynucleotide components of Mesaki as a kit for use because Machuca teaches use of a third party product comprising the polynucleotide components.
Claims 15-17, 26, 28-29, and 73-75 are rejected under 35 U.S.C. 103 as being unpatentable over Mesaki (The Journal of Heart and Lung Transplantation, Volume 39, Issue 4, Supplement, 2020, Page S70, ISSN 1053-2498, Available online 30 March 2020.) as applied to claims 15-17, 29, and 73-75 above, and further in view of Udalova (US2017/0030218A1, published 01/30/2014).
The disclosure of Udalova is directed to methods of regulating the immune system to treat autoimmune disease ([0001], Lines 1-3). The disclosure provides methods for identifying transcripts of cytokines such as IL-10 using qPCR ([0386], Lines 4-7).
Regarding claim 26, wherein the method comprises subjecting the organ to a perfusate comprising a polynucleotide encoding at least one gRNA wherein the polynucleotide comprises a nucleotide sequence set forth in SEQ ID NO: 36, Udalova discloses IL-10 locus primer SEQ ID NO: 28 which comprises the IL-10 gRNA sequence of instant SEQ ID NO: 36. The alignment is shown below:
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Regarding claim 28, wherein the organ is a lung and the step of subjecting the organ to a perfusate comprises ex vivo lung perfusion (EVLP) or in vivo lung perfusion (IVLP), Mesaki teaches the adenoviral vectors comprising the Cas9-VPR and gRNA administered via airway and that the adenovector is administered in a buffer (Left column, Methods, entire section). This limitation reads on IVLP with the buffer being the “perfusate”.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to use a gRNA comprising the IL-10 sequence disclosed in Udalova. It would have been obvious to do so because gRNA sequences are complementary to endogenous sequences; for this reason, the IL-10 primer and the IL-10 gRNA are analogous products as they both rely on specific base-pair complementarity to recognize a target. Primers and gRNA can bind the same genomic region. There would be an expectation of success in using the IL-10 sequence of Udalova in the gRNA of Mesaki because Udalova provides a nucleotide sequence with proven binding to endogenous IL-10.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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