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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 20 April 2026 has been entered.
Status of the Claims
Applicant’s submission filed 20 April 2026 has been entered. Claims 1, 3, 5, 8-18, and 20-21 are pending. Claims 1, 3, 5, and 13 have been amended. Therefore, prosecution on the merits continues for claims 1, 3, 5, 8-18, and 20-21. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Objection to the Specification
The substitute Specification filed 20 April 2026 is acknowledged and entered into the application file. However, the substitute Specification failed to remove the reference to the color “white” within Page 4 in reference to Figure 2J.
Therefore, the rejection is maintained.
RE: Rejection of claims 1 and 12-13 under 35 USC 102(a)(1) over Chan et al
Applicant has submitted an affidavit filed under 37 CFR 1.130 by co-inventor Andrew Ewald in order to disqualify the Chan et al reference under 35 USC 102(b)(1)(A). The affidavit filed 20 April 2026 addresses all requirements presented in MPEP § 717.01(a)(1), and is sufficient to disqualify the Chan et al reference under 35 USC 102(b)(1)(A).
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1, 3, 5, 8-18, and 20 under 35 USC 103 over Kretzschmar et al in view of Zhang et al
Applicant’s amendments to independent claims 1, 3, and 5 requiring the NK cells to have KLRG1 and TIGIT present on their surface obviate the rejection of record.
Therefore, the rejection is withdrawn.
It is of note that Applicant has not provided any specific arguments against the disclosures of Kretzschmar et al or Zhang et al.
RE: Rejection of claims 1, 3, 5, 8-18, and 20-21 under 35 USC 103 over Kretzschmar et al in view of Zhang et al and Zhou et al
Applicant’s amendments to independent claims 1, 3, and 5 requiring the NK cells to have KLRG1 and TIGIT present on their surface obviate the rejection of record.
Therefore, the rejection is withdrawn.
It is of note that Applicant has not provided any specific arguments against the disclosures of Kretzschmar et al, Zhang et al, or Zhou et al.
New/Maintained Grounds of Rejection
Specification
The instant Specification remains objected to for referencing colors within the figures, when colored drawings have not submitted in the application. More specifically, the Specification references colors at least within Page 4 in reference to Figures 2J. Applicant is requested to review the Specification to identify any additional references to colors within the drawings and delete as appropriate since black and white drawings are submitted. The Specification must be amended to delete reference to specific colors within the text of the Specification.
Appropriate correction is required.
Claim Objections
Claim 21 is objected to because of the following informalities:
Regarding claim 21: The instant claim is objected to for reciting “the drug” instead of “the drug candidate” in Line 9.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 3, 5, 8-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Kretzschmar et al (US 2021/0208131 A1, of record) in view of Zhang et al (Nat Immunol, 2018, of record) and Paul et al (Oncoimmunology, 2014).
Kretzschmar et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 21 December 2018. Zhang et al is considered prior art under 35 USC 102(a)(1). Paul et al is considered prior art under 35 USC 102(a)(1).
Regarding claim 1: Kretzschmar et al disclose co-cultures of organoids and immune cells, wherein the organoid/immune cell co-culture is embedded within a collagen extracellular matrix and submerged in co-culture medium (Abstract; Paragraphs [0045], [0072], [0197], [0205], [0235], [0237]-[0248]).
As such, Kretzschmar et al disclose that the organoids are tumoroids, or tumor organoids (Paragraphs [0007], [0045], [0056], [0058], [0060], [0063], [0124], [0133], [0176]-[0177]; Figures 1-2).
Kretzschmar et al further disclose that the immune cells are NK cells (Paragraph [0178]).
Kretzschmar et al do not disclose that the NK cells comprised within the embedded tumoroid co-culture have KLRG1 and TIGIT present on their surface, as required by instant claim 1.
Zhang et al, however, disclose that intratumoral NK cells, or tumor-infiltrating NK cells, have an increased expression of TIGIT on their surface (Pages 723-725).
With that, Paul et al disclose that a percentage of intratumoral NK cells express KLRG1 on their surface (Page 4; Figure 2).
Therefore, it would have been prima facie obvious to have modified the co-culture composition of Kretzschmar et al such that the NK cells express TIGIT and KLRG1 on their surface, as detailed in Zhang et al and Paul et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to produce a tumoroid/NK co-culture model that recapitulates the cancer disease state within subjects, and would have had a reasonable expectation of success given that Kretzschmar et al disclose that the immune cells comprised within the co-culture can be tumor-infiltrating lymphocytes, or tumor-infiltrating NK cells (Paragraph [0178]). See MPEP § 2143(I)(G).
Consequently, Kretzschmar et al as modified by Zhang et al and Paul et al render obvious a composition comprising a tumoroid/NK cell co-culture that has been embedded within a collagen extracellular matrix, wherein the NK cells express TIGIT and KLRG1 on their surface. This therefore renders obvious the composition of the instant claim.
Regarding claims 3, 5, 9, and 15: As aforementioned in the discussion of claim 1, Kretzschmar et al as modified by Zhang et al and Paul et al render obvious a composition comprising a tumoroid/NK cell co-culture that has been embedded within a collagen extracellular matrix, wherein the NK cells express TIGIT and KLRG1 on their surface.
Kretzschmar et al further disclose methods for screening candidate agents utilizing the embedded tumoroid/immune cell co-culture, wherein the co-culture is contacted with a candidate agent and then assessed for changes due to the candidate agent, which include a reduction in cell viability, a reduction in cell proliferation (claim 9), an increase in cell death, or a change in the cell or organoid size (Paragraphs [0009], [0011]-[0017], [0032]-[0038], [0135]-[0159], [0170]-[0173], [0199], [0348]).
Kretzschmar et al further disclose that assessment of the tumoroid/immune cell co-culture following the contacting of a candidate agent includes the comparison of the tumoroid/immune cell co-culture to a reference tumoroid co-culture (Paragraphs [0022], [0153]-[0157], [0190]-[0191], [0347]).
Kretzschmar et al further disclose that the candidate agent is an antibody (claim 15), including tumor-specific antibodies (Paragraphs [0161], [0163], [0209], [0340]-[0343], [0348]).
This therefore renders obvious the methods of instant claim 3 and instant claim 5 for the same reasons as discussed in the rejection of instant claim 1.
Regarding claim 8: Following the discussion of claim 3, Kretzschmar et al further disclose that the embedded tumoroid/immune cell co-culture is first generated via the culturing of the tumoroid with the immune cells, and then embedding the tumoroid/immune cell co-culture in a collagen extracellular matrix (Paragraphs [0045]-[0050], [0072], [0235]). This therefore reads on the method of the instant claim.
Regarding claims 10-11: Following the discussion of claim 3, Kretzschmar et al further disclose that the potential of the immune cells to kill the tumoroid – which inversely also simultaneously assesses the potential of the immune cells to promote the tumoroid – is assessed using quantitative real-time polymerase chain reaction (claim 11) (Paragraphs [0102], [0345]-[0347], [0363]-[0364]; Figure 9). This therefore reads on the method of instant claim 10.
Regarding claims 12 and 17-18: Following the discussion of claims 1 and 3, Kretzschmar et al further disclose that the tumoroid is derived from primary human epithelial cells of a breast tumor (claim 18) (Paragraphs [0175]-[0176], [0183]-[0185]). This therefore reads on the composition (claim 12) and method (claim 17) of the instant claims.
Regarding claims 13 and 16: Following the discussion of claims 1 and 3, Zhang et al further disclose that TIGIT+ NK cells also express LAG3 on their surface (Page 725; Figure 1). This therefore renders obvious instant claims 13 and 16 for the same reasons as discussed in the rejection of instant claim 1.
Regarding claim 14: Following the discussion of claim 3, Kretzschmar et al further disclose that the candidate agent is an immunotherapeutic, which is an agent that induces, suppresses or enhances the immune system of a patient for the treatment of a disease (Paragraphs [0122], [0144], [0161]-[0163], [0348]). This therefore reads on the method of the instant claim, as the immunotherapeutic will either be an immune receptor inhibitor or an immune receptor activator.
Regarding claim 20: Following the discussion of claim 3, Kretzschmar et al further disclose that the candidate agent is any biological, chemical, physical, or other agent, wherein the candidate agent can be selected from one or more of the following therapeutic classes: immunotherapeutic, tumor-specific peptides, checkpoint inhibitors, alkylating agent, antimetabolite, metabolic agonist, metabolic antagonist, plant alkaloid, mitotic inhibitor, antitumor antibiotic, topoisomerase inhibitor, radiotherapeutics, chemotherapeutics, antibodies, photosensitizing agent, stem cell transplant, vaccine, cytotoxic agent, cytostatic agent, tyrosine kinase inhibitor, proteasome inhibitor, cytokine, interferon, interleukin, intercalating agent, targeted therapy agent, small-molecule drug, hormone, steroid, cellular therapeutic, viral vector, and nucleic acid therapeutic (Paragraphs [0160]-[0161]).
Therefore, it would have been prima facie obvious to have selected any of these candidate agents from a library. One of ordinary skill in the art would have been motivated to select agents that are known in the art and well-indexed, as is done for cells (Paragraph [0179]), and would have had a reasonable expectation of success due to the disclosure of Kretzschmar et al reasonably suggesting all of the therapeutic classes of candidate agents. See MPEP § 2143(I)(G).
Consequently, Kretzschmar et al as modified by Zhang et al and Paul et al render obvious the method of the instant claim, wherein the candidate agent is selected from a library of compounds.
Claims 1, 3, 5, 8-18 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Kretzschmar et al (US 2021/0208131 A1, of record) in view of Zhang et al (Nat Immunol, 2018, of record) and Paul et al (Oncoimmunology, 2014), and further in view of Zhou et al (US 2017/0022273 A1, of record).
The discussion of Kretzschmar et al as modified by Zhang et al and Paul et al regarding claims 3 and 16 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Kretzschmar et al as modified by Zhang et al and Paul et al render obvious claims 1, 3, 5, 8-18, and 20. Zhou et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 21: As aforementioned in the discussion of claims 3 and 16, Kretzschmar et al as modified by Zhang et al and Paul et al render obvious methods for screening candidate agents utilizing the embedded primary tumoroid/NK cell co-culture, wherein the NK cells express KLRG1, TIGIT, and LAG3 on their surface, and wherein the co-culture is contacted with a candidate agent and then assessed for changes due to the candidate agent, which include a reduction in cell viability, a reduction in cell proliferation, an increase in cell death, or a change in the cell or organoid size.
Kretzschmar et al further disclose that the candidate agent is an antibody (Paragraphs [0161], [0163], [0209], [0340]-[0343], [0348]).
The combination of Kretzschmar et al, Zhang et al, and Paul et al fail to teach that the drug candidate inhibits or binds to LAG3 present on the surface of the NK cells, as required by instant claim 21.
Zhou et al, however, disclose that LAG3 is a membrane protein that is expressed on activated NK cells (Paragraph [0004]). Zhou et al further disclose antibodies against LAG3 for the treatment of cancer, including breast cancer (Abstract; Paragraphs [0016], [0025]-[0026], [0158], [0162]).
Therefore, it would have been prima facie obvious to have modified the method of Kretzschmar et al in view of Zhang et al and Paul et al such that the drug candidate is an antibody against LAG3, as detailed in Zhou et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to utilize an antibody against LAG3 as the drug candidate, as it serves as a potential therapeutic for breast cancer, and would have had a reasonable expectation of success given that Kretzschmar et al disclose the antibody testing protocols and suggest that the NK cells within the tumoroid co-culture are activated (Paragraph [0088], [0336], [0345]). Therefore, the ordinary artisan would have recognized that the NK cells within the methods of Zhou et al and Kretzschmar et in view of Zhang et al and Paul et al are functionally comparable and would have required minimal adaptation of the protocols. See MPEP § 2143(I)(G).
Consequently, Kretzschmar et al as modified by Zhang et al, Paul et al, and Zhou et al render obvious a method for screening an anti-LAG3 antibody, wherein the embedded primary tumoroid/NK cell co-culture is contacted with the anti-LAG3 antibody and then assessed for its responsiveness to the anti-LAG3 antibody, which include a reduction in cell viability, a reduction in cell proliferation, an increase in cell death, or a change in the cell or organoid size. This therefore renders obvious the method of the instant claim.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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/ALYSSA G WESTON/Examiner, Art Unit 1633
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