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 Amendment
Claims 2-3, 14-55, and 57 have been cancelled. Claims 1, 4-5, and 56 have been amended as requested in the amendment filed on 18 July 2025. Following the amendment, Claims 1, 4-13, 56 and 58-59 are pending in the instant application, and are under examination in the instant office action. Applicant has elected the following species: T-cells (claim 6), Olaparib (claim 11), and PD-1 (claim 58).
It should be noted that Claims 3 and 4 previously recited “the ratio of the tumor cells to the immune cells” is within the range of 1:0.05 to 1:100 (claim 3) and “is 1:10” (claim 4). However, now claims 1 and 4 have been amended to recite the inverse ratio and an added step of prior to co-culture. Claim 1 recites a ratio of immune cells to tumor cells is 1:0.05 to 1:100 prior to the step of co-culture recited within claim 1. Claim 4 states the ratio of immune cells to tumor cells is 1:10. These are entirely new limitations and not just a rolling up of a previously stated limitation, as argued by Applicant in Remarks filed 18 July 2025. Therefore, these new limitations warrant new grounds of rejection.
Withdrawn Rejections:
Claim 15 has been cancelled, therefore the rejection 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn.
Claim 16 has been cancelled, therefore the rejection under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement, is withdrawn.
Priority (New, Necessitated by Amendment)
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119 as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
As amended, Claim 1 recites a range of ratios (immune to tumor cells) of “1 : 0.05 to 1:100”. There is no support for this recitation within US Provisional Application No. 62/933,339 filed on 8 November 2019. That document provides only support of the following:
[0081] “the ratio of tumor cells to immune cells may range anywhere from 1:0.05 to 1:20. The ratio may be 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, 1:10.5, 1:11, 1:11.5, 1:12, 1:12.5, 1:13, 1:13.5, 1:14, 1:14.5, 1:15, 1:15.5, 1:16, 1:16.5, 1:17, 1:17.5, 1:18, 1:18.5, 1:19, 1:19.5, 1:20, or anywhere in between”.
Therefore, there is no support for the range up to 1:100. The first mention of ratios above 1:20 occurs in the PCT/US20/59667 application.
Since the disclosure of the prior-filed application, Application No. 62/933,339, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for Claim 1 of this application, then Claims 1, 4-13, 56 and 58-59 no longer have the benefit of this earlier filed application.
Claims 1, 4-13, 56 and 58-59 now have an earliest effective US filing date of PCT/US2020/059667 filed on 11/09/2020.
Claim Rejections - 35 USC § 112(b) (Maintained)
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.
As currently amended, Claims 1, 4-13, 56 and 58-59 stand as rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for reasons of record in the prior Office action.
On page 5 of Remarks filed 18 July 2025, Applicant traverses the rejection on the grounds that Claim 1 has been amended to provide antecedent basis. Applicant further argues that the specification does not need to provide a definition for responsiveness.
While this has been considered in full, it is not persuasive. Claim 1 recites “measuring a responsiveness of the tumor cells” and the specification merely provides exemplary responses (see paragraphs [0012], [0040], [0098], [0143], [0167], and [0187]) but these do not set forth the processes that are encompassed by the claim. Therefore, the metes and bounds of the invention are indefinite since it is unclear what process steps fall within the scope of “measuring a responsiveness”. Lastly, as currently amended, the claim recites a ratio of one cell type to another (immune cells to tumor cells) of “1: 0.05 to 1:100”, which claims the invention in units that are less than one whole cell. When expressed as a whole number, since cells can only be whole numbers, “1 : 0.05” is equivalent to a ratio of 20:1. However, this renders the claimed range 20:1 to 1:100, which renders the claim unclear because there is a question as to whether the lower limit of immune cells is 20 or 1. These issues affect the scope of all depending claims, Claims 4-13, 56 and 58-59.
On page 6 of Remarks, Applicant traverses the rejection of Claim 13 set forth in the previous action by asserting the specification does more than what is required to teach how to measure a decrease in viability.
This is not persuasive because the term “decrease” in claim 13 is a relative term and relative terms render claims indefinite. See MPEP 2175. The indefiniteness arises because there is nothing within the claim itself that defines what the decrease is in relation to; nor does the specification provide the standard for ascertaining the requisite degree of decrease. Therefore, one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. Additionally, there are no positively stated active steps whereby viability is even assessed. Thus, it is unclear if viability is even required for infringement of this claim, let alone what degree of a decrease may be required.
On page 7 of Remarks, Applicant argues that Claims 58 and 59 are not indefinite because methods of assessing PD-1 expression were already well-known in the art.
This is not persuasive. Applicant appears to be conflating the issue of written description (where one need not describe known methods) with the issue of clarity of the claims, separate requirements under 35 USC 112. Claim 58 is unclear because it recites “the immune cells express an immune checkpoint protein …[the instantly-elected] PD-1”; and Claim 59 limits the expression to PD-1. Yet, neither of these claims set forth any method steps whereby expression of PD-1 is assessed. Absent active steps, the scope of this claim is materially and manipulatively identical to the scope of the parent claim, claim 1. It is unclear if expression of PD-1 is even required for infringement of this invention. For purposes of applying prior art, this claim will be interpreted as merely reciting an inherent property of the immune cells of Claim 1, and not as imposing any further limitations upon the scope of that claim.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
As currently amended, Claims 1 and 4 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception mathematical calculation without significantly more.
On page 8, Applicant asserts that since “claims 2 and 3 have been amended to claim 1”, and the wording of “determining a ratio” has been removed, then the rejection has been overcome.
This is not persuasive for the following reasons. The claims still recite a ratio and MPEP 2106.04(a)(2)(A) explicitly states: A mathematical relationship may be expressed in words or using mathematical symbols. And defines ratios as mathematical relationships that are abstract idea judicial exceptions. Therefore, the claims still recite at least one judicial exception (STEP 2A, Prong One: YES)
The examiner maintains the position that this mathematical relationship judicial exception is not integrated into a practical application because the steps/elements recited, in addition to the judicial exception (co-culturing immune cells and tumor cells isolated from a subject under conditions that allow the immune cells and the tumor cells to form a cell mass, exposing the cell mass to at least one therapeutic agent, and measuring a responsiveness of the tumor cells in the cell mass to the at least one therapeutic agent), fail to provide any of the considerations pertaining to integration set forth in MPEP 2106.05(a-c), (e), and (h). There are no additional elements that reflect any improvement within the technical field. There are no additional elements that apply the judicial exception to a particular treatment/prophylaxis, or which utilize a particular machine. There is no transformation of the mathematical relationship into a practical application. (STEP 2A, Prong Two: NO). Since the claims recite a judicial exception but there is no integration, then the claim is “directed to” the judicial exception itself.
The examiner has provided evidence that the additional steps/element set forth what was well-understood, routine and conventional activity before the effective filing date of the application. The specification itself states that methodology was known (see [0106], [0119], [0135], [0163] and [0250]). Therefore, in in accordance with MPEP 2106.07(a)(III)(A), the examiner has cited express statements in the specification indicating that the additional steps/elements were sufficiently well-known that the specification does not need to describe the particulars thereof. In other words, the disclosure describes no new technology, but merely refers to techniques and elements that were known in the art at the time of filing.
Lastly, in accordance with MPEP 2106.07(a)(III)(C), the examiner has cited publications that demonstrate the well-understood, routine, conventional nature of the additional element(s). See citation of Nwani et al., 2018 set forth in the previous action.
For all of these reasons, Claims 1 and 4 are directed to the judicial exception without significantly more, and are rejected.
Claim Rejections - 35 USC § 103 (New, Necessitated by Amendment)
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.
(1) As currently amended, Claims 1, 5-7, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Gottfried et al., 2006 (cited in the previous action) and further in view of Dangles et al., Int J Cancer, 98: 51-56, 2002.
As stated above, it should be noted that Claims 3 and 4 previously recited “the ratio of the tumor cells to the immune cells” is within the range of 1:0.05 to 1:100 (claim 3) and “is 1:10” (claim 4). However, now claims 1 and 4 have been amended to recite the inverse ratio and an added step of “prior to co-culture”. Claim 1 recites a ratio of immune cells to tumor cells is 1:0.05 to 1:100 prior to the step of co-culture recited within claim 1. Claim 4 states the ratio of immune cells to tumor cells is 1:10. These are entirely new limitations and not just a rolling up of a previously stated limitation(s).
On page 9 of Remarks, Applicant argues that the claims now recite a ratio of immune cells to tumor cells, prior to co-culture, 1:0.05 to 1:100, which is absent from the Gottfried prior art. A new reference (Dangles) has been cited to teach this new limitation.
Regarding Claim 1: Gottfried et al. teaches, “Multicellular tumor spheroids (MCTS) are a well-established 3-D in vitro model system that reflects the pathophysiological in vivo situation in tumor microregions” and are a “tool to systematically study heterologous interactions between tumor and immune cells” (Abstract). Thus, the prior art teaches co-culturing immune cells and tumor cells under conditions that form a spheroid or “cell mass”, as claimed. The reference teaches, “contacting the cell mass to at least one therapeutic agent” wherein it teaches testing the “impact of lactate and pH on immune cells” and exposure to oxamic acid, an LDH inhibitor (pg. 693, second paragraph under section titled IMPACT OF LACTATE AND PH ON IMMUNE CELL; and paragraph bridging pgs. 693-694). Further, the reference teaches measuring “tumor hypoxia” and “metabolite and catabolite gradients” (pg. 692, second paragraph). In this way the reference teaches “measuring a responsiveness” of the tumor cells in the cell mass to treatments.
Regarding Claim 5: The method of Gottfried discloses primary tumor cell cultures; cultures in which cells such as fibroblasts and monocytes may be initiated together with tumor cells to form mixed aggregates; or, preformed MCTS that are later incubated with immune cells (paragraph bridging pgs. 691 and 692). The reference teaches these can be patient-specific myeloid immune cells (pg.692, first paragraph under SUPPRESSION OF MYELOID IMMUNE CELLS IN TUMORTISSUES).
Regarding Claim 6: The Gottfried et al. prior art reference discloses different myeloid immune cells are within these model tumor tissues. Specifically, the reference teaches “tumor-associated macrophages” and T-cells (pg. 692, section titled SUPPRESSION OF MYELOID IMMUNE CELLS IN TUMOR TISSUES, first paragraph); as well as dendritic cells (Id, second paragraph). Therefore, the prior art anticipates the immune cells comprise T cells, dendritic cells, or macrophages, as claimed.
Regarding Claim 7: The Gottfried reference discloses T-cells are part of the heterogenous tumor spheroid (Figure 1).
Regarding Claim 12: The Gottfried reference discloses the co-cultures comprise a Multicellular tumor spheroids (MCTS) (Figure 1).
The Gottfried prior art does not disclose any specific ratio of immune cells to tumor cells prior to co-culturing. Gottfried is silent with respect to an immune to tumor cell ratio in the range of 1:0.05 to 1:100 (new limitation of instant claim 1); and, the specific ratio of immune cells to tumor cells is 1:10 (instant claim 4).
The Dangles et al. 2002 prior art, however, remedies this deficiency by teaching an effector (tumor) to target (immune) ratio of 1:1 prior to co-culture (pg. 52, second to last paragraph). This ratio falls squarely within the claimed range of instant claim 1. Additionally, Dangles and colleagues alter the ratio to 10:1 or 20:1 tumor cells to immune cells (see Table I) and subsequently analyze the influence of spheroid architecture on TNF production (pg. 52, last paragraph). In this way, the prior art teaches the limitations of instant claims 1 and 4 and the specific cell type of instant claim 6.
It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, to use the T cells at the specific ratios of 1:1 or 1:10, as taught by the Dangles reference, in the multicellular coculture methods of Gottfried. Motivation to specifically look at T cells is explicit in Dangles et al. wherein it teaches understanding the molecular mechanisms of tumor associated antigen recognition by cytotoxic T lymphocytes is the basis on which novel immunization strategies are designed for treatment of malignant tumors (first paragraph). Motivation to use the specific ratio of 1:1 is explicit wherein it teaches the importance of investigating tumor infiltrating leukocytes (TIL) into spheroids with equal ratios of each cell types (pg. 52, second to last paragraph). Motivation to use the 1:10 ratio is explicit wherein the reference discloses spheroid architecture (i.e. density) affects cytokine production (pg. 52, last paragraph). The reference teaches TNF release decreased in an inverse ratio to the spheroid volume. Since the Dangles et al. reference is itself drawn to methods of multicellular tumor spheroid formation, a skilled artisan would have been able to combine the elements according to known methods with predictable success.
Thus, the invention is obvious in view of the prior art teachings. For all these reasons, the invention of Claims 1, 4-7, and 12 are rejected.
(2) Claims 8-11 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Gottfried et al. 2006 in view of Dangles et al. 2002, as applied to claims 1, 4-7 and 12 above; and further in view of Nwani et al., 2018; and, Eetezadi et al., 2017 (both cited previously).
The teachings of Gottfried and Dangles as they pertain to claims 1, 4-7 and 12 are outlined in the rejection under 35 U.S.C. 102(a)(1) above.
Applicant has provided no separate traverse of the rejection based on Nwani and Eetezadi, only traverse of the Gottfried reference, as explained above. In answer to the newly added claim amendments, the examiner has added the new Dangles reference.
The combination of Gottfried et al. and Dangles et al. teaches methods comprising exposing a multicellular tumor spheroid to therapeutic agents, but are silent with respect to the method wherein the therapeutic agent is a checkpoint inhibitor and one that targets PD-1 (instant claims 8-9). Nor does combination of Gottfried et al. and Dangles et al. teach at least one poly(ADP-ribose) polymerase inhibitor, namely, the instantly-elected Olaparib (instant claims 10-11). Lastly, combination of Gottfried et al. and Dangles et al. is silent with respect to the responsiveness being a decrease in viability of the tumor cells (instant claims 13-14).
The Nwani et al. prior art teaches similar co-cultures of tumor cells and cancer-associated fibroblasts (CAFs), myeloid, immune, endothelial, and mesothelial cells, which the authors call “tumor microenvironment” (TME) cultures (Abstract and Figure 1). Nwani et al. focus on the microenvironment of high-grade serous ovarian cancer and the authors teach testing therapeutics, such as, the TGF-receptor inhibitor LY2109761 and cisplatin (pg. 4/22, section titled: Therapies Targeting Fibroblasts). The cells in the Nwani spheroids includes “The immune reactive cells include primarily cytotoxic T lymphocytes and activated CD4+ T cells” and “immune suppressive cells …known as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs, especially M2 subtype), dendritic cells (DCs) and the lymphocyte subsets of T helper cells (Th2 subtype) and T regulatory cells (Tregs)” (pg. 9/22 at bullet 8). Therefore, the Nwani prior art teaches “wherein the immune cells comprise T cells, natural killer cells, dendritic cells, macrophages, or a combination thereof”, as recited by instant claim 6.
Regarding claim 8: Nwani et al. teach methods comprising the TME cultures and at least one therapeutic agent comprises at least one checkpoint inhibitor (pg. 10/22; at bullet 9).
Regarding claim 9: Nwani et al. teach methods comprising the TME cultures and at least one programmed cell death protein-1 (PD-1) inhibitor (pgs. 10-11; at bullet 9).
Regarding claims 10 and 11: Nwani et al. disclose methods comprising cediranib in combination with olaparib, a poly (ADP-ribose) polymerase PARP inhibitor in women with recurrent OC (pg. 7/22; last sentence of first paragraph).
Regarding claims 13 and 14: Nwani et al. disclose, “Several classes of therapeutics targeting MDSCs or TAMs have been described and were recently reviewed [167]. They include agents which promote MDSCs apoptosis” (third paragraph under bullet 10). Therefore, the prior art teaches responsiveness is a decrease in tumor-associated cell death (a.k.a. “decreased viability” as claimed).
While the Nwani et al. prior art teach tumor and immune cell coculture, the reference is silent with respect to directly measuring the responsiveness of tumor cells in these cell mass co-cultures.
The Eetezadi et al. prior art, however, remedies this deficiency. Eeztezadi et al. disclose the same spheroid models of ovarian cancer tumor microenvironments as disclosed in Nwandi et al. but specifically teach contacting the cultures with Doxorubicin with the PARP inhibitor, Olaparib of instant claim 11, and measuring the responsiveness of the tumor cells to these drugs in order to achieve optimal synergy of both drugs (Abstract). Eetezadi et al. disclose measuring viability following drug treatment (pg. 474, second column, formula for % viability and Figure 3).
It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, to test the therapeutic agents disclosed in Nwandi and/or Eetezadi on the spheroid cultures as disclosed in Gottfried. A skilled artisan would be motivated to combine the prior art elements because combination would result in decreased viability of the spheroid cells with a reasonable expectation of success. Based on the guidance and direction within the prior art, such combination would have been well-within the technical grasp of a skilled artisan. Since each of the elements in combination are merely performing the same function as they did separately, then one of ordinary skill in the art would have been able to predictably combine the elements, according to known methods, with a reasonable expectation of successfully contacting the therapeutic agent with a checkpoint inhibitor that is a PD-1, or at least one poly(ADP-ribose) polymerase inhibitor, specifically Olaparib, and measuring a decrease in viability of the tumor cells. ( See KSR International Co. v. Teleflex, Inc., 127 S. Ct. 1727, 82 USPQ2d 1385, Supreme Court, April 30, 2007). Therefore, the invention as a whole is prima facie obvious, if not actually anticipated by the reference.
Conclusion
No claim is allowed.
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.
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/S.N.M/Examiner, Art Unit 1675
/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675