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 .
Status of the Claims
Applicant’s submission filed 29 July 2026 has been entered. Claims 1, 3, 5, 8-18, and 20-22 are pending. Claims 1, 3, 5, 9, and 21 have been amended, while claim 22 has been newly added. Therefore, prosecution on the merits continues for claims 1, 3, 5, 8-18, and 20-22. 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
Applicant’s arguments regarding the reference to the color “white” within Figure 2J have been fully considered and are found persuasive.
Therefore, the objection is withdrawn.
RE: Objection to claim 21
Applicant’s amendments to instant claim 21 correct the minor informality, thus obviating the objection of record.
Therefore, the objection is withdrawn.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 and Paul et al
Applicant's arguments filed 29 July 2026 have been fully considered but they are not found persuasive.
Applicant has traversed the rejection, asserting in Pages 7-9 of the Remarks filed 29 July 2026 that Kretzschmar et al fail to teach that the natural killer cells are splenic or peripheral blood mononuclear natural killer cells. In response, the Examiner respectfully submits that Kretzschmar et al disclose that the natural killer cells comprised within the co-culture can be peripheral blood mononuclear natural killer cells. See, for example, Paragraphs [0063], [0115], [0178], [0180], [0191], and [0292] of Kretzschmar et al. It is also of note that Applicant has amended independent claim 1 to only require the alternate splenic natural killer cells to express Klrg1 and TIGIT on their surface.
Applicant has further traversed the rejection, asserting in Pages 9-10 of the Remarks filed 29 July 2026 that the cited prior art fails to teach measuring one or more metastatic properties of the embedded organoid in the co-culture, wherein the one or more metastatic properties measured are metabolic activity, apoptosis, cancer invasion, or molecular or cellular correlates of metastatic ability. In response, the Examiner respectfully submits that Kretzschmar et al 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 an increase in cell death of the tumoroid. See, for example, Paragraphs [0009], [0011]-[0017], [0032]-[0038], [0135]-[0159], [0170]-[0173], [0199], [0348] of Kretzschmar et al and Page 7 of the Office action filed 26 May 2026.
Therefore, the rejection is maintained for claims 3, 5, 8-11, 14-18, and 20 and amended to encompass the claims as currently written. The rejection is withdrawn for claims 1 and 12-13 because Applicant has broadened the scope of independent claim 1.
It is also of note that, contrary to what Applicant has stated in Page 8 of the Remarks filed 29 July 2026, independent claims 3 and 5 – and their corresponding dependent claims thereof – are not dependent upon independent claim 1.
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 Paul et al, and further in view of Zhou et al
Applicant's arguments filed 29 July 2026 have been fully considered but they are not found persuasive.
Applicant has traversed the rejection, citing the same assertions in Pages 10-13 in the Remarks filed 29 July 2026 with regards to the 35 USC 103 rejection over Kretzschmar et al in view of Zhang et al and Paul et al, as was previously discussed above.
Therefore, the rejection is maintained for claims 3, 5, 8-11, 14-18, and 20-21 and amended to encompass the claims as currently written. The rejection is withdrawn for claims 1 and 12-13 because Applicant has broadened the scope of independent claim 1.
New/Maintained Grounds of Rejection
Information Disclosure Statement
The information disclosure statement filed 25 August 2026 fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Claim Interpretation
Applicant has amended independent claim 1 to require the organoid/NK cell co-culture to comprise “one or more splenic or peripheral blood mononuclear NK cells embedded in an extracellular matrix, wherein the one or more splenic NK cells have Klrg1 and TIGIT present on its surface”. Therefore, the instant claim is being interpreted as only requiring the alternate splenic natural killer cells to express Klrg1 and TIGIT on their surface, and not the peripheral blood mononuclear NK cells.
Claim Rejections - 35 USC § 112
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 10-11 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 10: The instant claim recites the limitation "the tumor-promoting potential" in Line 1. There is insufficient antecedent basis for this limitation in the claim, as there is no prior recitation of “tumor-promoting potential" within the instant claim or parent claim 3. Therefore, the ordinary artisan cannot readily determine the metes and bounds of the claim.
Instant claim 11 is included within the rejection because it depends from instant claim 10 and fails to correct the deficiencies of the parent claim.
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 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Kretzschmar et al (US 2021/0208131 A1, of record).
Kretzschmar et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 21 December 2018.
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 derived from peripheral blood, wherein the immune cells are NK cells (Paragraphs [0063], [0115], [0178], [0180], [0191], [0292]).
However, Kretzschmar et al do not exemplify or reduce to practice a composition comprising a co-culture of a tumor organoid with peripheral blood mononuclear NK cells that have been embedded in an extracellular matrix, as required by claim 1.
Therefore, it would have been prima facie obvious to have modified the co-culture composition of Kretzschmar et al such that the embedded tumoroid is co-cultured with peripheral blood mononuclear NK cells. One of ordinary skill in the art before the effective filing date of the invention would have recognized that peripheral blood mononuclear NK cells can be successfully co-cultured with the tumoroid, as Kretzschmar et al disclose that any immune cell that can be incorporated into a co-culture is suitable for use within the disclosed methods (Paragraph [0178]), and would have had a reasonable expectation of success given that Kretzschmar et al exemplify and reduced to practice an embedded tumoroid/T cell co-culture (Paragraphs [0300]-[0307], [0318]-[0322]). See MPEP § 2143(I)(G).
Consequently, Kretzschmar et al render obvious a composition comprising a tumoroid/ peripheral blood mononuclear NK cell co-culture that has been embedded within a collagen extracellular matrix. This therefore renders obvious the composition of the instant claim.
Regarding claim 12: Following the discussion of claim 1, Kretzschmar et al further disclose that the tumoroid is derived from primary human epithelial cells of a breast tumor (Paragraphs [0175]-[0176], [0183]-[0185]). This therefore reads on the composition of the instant claim.
Claims 1 and 12-13 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).
The discussion of Kretzschmar et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Kretzschmar et al render obvious claims 1 and 12. Zhang et al is considered prior art under 35 USC 102(a)(1).
Regarding claim 13: As aforementioned in the discussion of claim 1 above, Kretzschmar et al teach a composition comprising a tumoroid/peripheral blood mononuclear NK cell co-culture that has been embedded within a collagen extracellular matrix.
Kretzschmar et al further disclose that the co-culture can further comprise tumor-infiltrating lymphocytes, or tumor-infiltrating NK cells (Paragraph [0178]).
Kretzschmar et al do not disclose that the NK cells comprised within the embedded tumoroid co-culture have LAG3 present on their surface, as required by instant claim 13.
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). Zhang et al further disclose that TIGIT+ NK cells also express LAG3 on their surface (Page 725; Figure 1).
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 LAG3 on their surface, as detailed in Zhang 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 include tumor-infiltrating NK cells. See MPEP § 2143(I)(G).
Consequently, Kretzschmar et al as modified by Zhang et al render obvious a composition comprising a tumoroid/NK cell co-culture that has been embedded within a collagen extracellular matrix, wherein the tumor-infiltrating NK cells express TIGIT and LAG3 on their surface. This therefore renders obvious the composition of the instant claim.
Claims 3, 5, 8-11, 14-18, 20, and 22 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, of record).
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 claims 3, 5, 9, 15, and 22: 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 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 of the embedded NK cells, an increase in cell death of the tumoroid cells, 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, including tumor-specific antibodies (Paragraphs [0161], [0163], [0209], [0340]-[0343], [0348]).
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 claims 3 and 5.
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 method 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 method wherein a composition comprising a tumoroid/TIGIT+KLRG1+ NK cell co-culture that has been embedded within a collagen extracellular matrix is contacted with a candidate agent – or a tumor-specific antibody (claim 15) – and then assessed for changes due to the candidate agent, which include a reduction in cell viability, a reduction in cell proliferation of the embedded NK cells (claims 9 and 22), an increase in cell death – or apoptosis – of the tumoroid cells (claims 3 and 5), or a change in the cell or organoid size. As the assessment of the tumoroid/ TIGIT+KLRG1+ NK cell co-culture following the contacting of the candidate agent includes the comparison of the tumoroid/ TIGIT+KLRG1+ NK cell co-culture to a reference tumoroid co-culture, this therefore renders obvious the methods of the instant claims.
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 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 16: Following the discussion of claim 3, Zhang et al further disclose that TIGIT+ NK cells also express LAG3 on their surface (Page 725; Figure 1). This therefore renders obvious the instant claim for the same reasons as discussed in the rejection of instant claim 3.
Regarding claims 17-18: Following the discussion of claim 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 method of instant claim 17.
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 3, 5, 8-11, 14-18, and 20-22 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, of record), 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 3, 5, 8-11, 14-18, 20, and 22. 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
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 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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