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 .
Claim Status
Claims 1-2, 5-13, 18-19, 22-23, and 25-27 are currently pending in this application.
Election/Restrictions
Applicant’s election of Group I, claims 1-10, in the reply filed on Dec. 23, 2024 is acknowledged. Because applicant did not distinctly and specifically point out any supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). Claims 11-13, 18-19, 22-23, and 25-27 are withdrawn for being directed to non-elected subject matter, there being no allowable generic or linking claim, and claims 1-2 and 5-10 have been considered on the merits.
Previous Rejections
Status of the rejections: the previous claim rejections under sections 112(b) and 103 are withdrawn in view of applicant’s claim amendments and arguments.
Claim Interpretation
The term “egg” in claim 1 is interpreted as being limited to an egg having a chorioallantoic membrane which has been modified to comprise within in it a first and second hydrogel and respective first and second types of living mammalian cells as expressly recited in claim 1. Also, the “egg” is interpreted as being living in view of the term “mammalian-avian chimeric model system” implying an in vivo system, also referred to as in ovo, as described by the instant application (see instant [0004]; [0096]-[0100]). As the egg is not limited to being entirely whole, the term “egg” is interpreted as encompassing eggs modified to lack some or all of their eggshell and/or embryo/zygote (id).
In claim 1, the term “chorioallantoic membrane (CAM)” is interpreted as being a vascular membrane comprising a chorionic epithelium, mesenchyme and allantoic epithelium naturally present in fertilized eggs (instant [0097]).
In claim 1, the term “cancerous cell” is interpreted as encompassing primary cancer cells as well as immortalized cancer or nonmetastatic tumor cells grown in vitro and derivatives thereof.
In claim 1, the phrases “separate hydrogels positioned side by side” and “at a distance of not more than 5 mm from one another” is interpreted as encompassing two or more hydrogels in direct contact with each other wherein the only distinguish feature making them “separate” is the type of cell dispersed therein.
Claim Rejections - 35 USC § 103 (new)
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 6-10 are rejected under 35 U.S.C. 103 as being unpatentable over Pathak (US20190029235A1; published 2019-01-31) in view of Rodenhizer (Rodenhizer et al., Adv Healthc Mater 7: e1701174 (2018)).
The claims are interpreted as explained in a previous section.
Pathak teaches a mammalian-avian chimeric tissue comprising a fertilized avian egg comprising a CAM and mammalian cancer cells (e.g., a human cancer tissue, or cells thereof, or human-mouse xenograft tumor tissue) dispersed in a first hydrogel ([0042]; [0065]; [0045]; [0061]), and then later adding putative therapeutic mammalian immune cells, e.g., human T cells, ([0144]), on top of or next to the growing tumor CAM graft (i.e., less than 5 mm from one another), wherein the CAM serves as a nutrient multilayer membrane surface supporting the growth of the cells and mimicking the in vivo environment ([0003]), such as to create a model to study cancer biology (e.g., metastasis and invasion) and/or for screening therapeutic T cells ([0003], [0006]; FIG. 1). Pathak teaches culturing a tumor graft on the CAM improves graft survival, sustains unique characteristics of a 3-D tumor and is reproducible, provides easy access to the tumor graft/plaque, e.g., for drug administration, and provides a renewable, scalable and cost-effective in ovo approach for personalized cancer therapeutic screening ([0003]; [0042]; [0087]; [0092]; [0118]).
Regarding claim 1, Pathak does not teach first dispersing the immune cells in a second hydrogel positioned on the CAM less than 5 mm from the first hydrogel.
However Rodenhizer teaches a 3-D mammalian cell culture platform using two different types of cells dispersed in separate hydrogels positioned side-by-side and wherein said separate hydrogels are physically touching and representing a tumor region (red) comprising cancerous cells and a stromal region (green), such as wherein the stromal region comprises immune cells (Fig. 6, compartmentalization; pg. 13, left col., last para., to right col., last para.). Rodenhizer teaches using such platforms for, inter alia, imaging of cell behaviors in engineered environments, e.g., regarding microstructure and/or complex architectures along with drug or growth factor gradients, such as specifically modeling a tumor–stromal interface (pg. 13, right col., last para. to pg. 14, left col., last para.; Fig. 6).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to construct a mammalian-avian chimeric tissue as taught by Pathak wherein both the cancer cells (e.g., in the graft) and the immune cells (e.g., putative therapeutic immune cells) are encapsulated in their own adjacent hydrogels arranged less than 5 mm from each other as in Rodenhizer, such as using a stromal-type second hydrogel comprising stromal cells and their secretions. One of ordinary skill in the art would be motivated to evaluate the cells in such 3-D tumor-stromal microenvironments mimicking a tumor-stromal interface (i.e., the boundary between the first and second hydrogels) to research how the immune cells behave in the second hydrogel (e.g., regarding activation, chemotaxis, and migration across the tumor-stromal interface) and infiltrate into the first hydrogel and tumor graft, e.g., to specifically research the behaviors of engineered anti-cancer immune cells (CAR-targeted T cells) as taught by Pathak ([0144]), e.g., using real-time or end-point microscopic imaging. Additionally, one of ordinary skill in the art would be motivated to test how engineered immune cells behave if the tumor cells invade across the tumor-stromal interface and encounter the immune cells in the stromal-type hydrogel, as a model of a metastasizing tumor.
Regarding claims 6-7, Pathak teaches wherein the immune cell is a tumor infiltrating lymphocyte, e.g., an engineered, chimeric antigen receptor (CAR) expressing T lymphocyte ([0144]; [0067]).
Regarding claim 8, Pathak teaches including a drug in the system for testing wherein the drug is a therapeutic agent that is a chemical or molecule (chemotherapeutic), a polypeptide (protein or hormone therapy), a cell (immunotherapy), or a virus ([0067]; [0144]).
Regarding claim 9, Pathak teaches including in the hydrogel stimulatory agents affecting proliferation, growth, and survival, such as including epidermal growth factor (EGF), fibroblast growth factor (e.g., bFGF), NGF, PDGF, insulin like growth factor (IGF-1), TGF-β, and other agents in ECM compounds like Matrigel (e.g., laminin, collagen and entactin) ([0130]; Table 2; [0003]; [0045]).
Regarding claim 10, Pathak teaches the mammalian cancerous cell in the form of a tumor, e.g., a human or mouse tumor graft or tumor xenograft ([0042]; [0065]).
Thus, the claimed invention as a whole is prima facie obvious before the effective filing date in the absence of evidence to the contrary.
Claims 1-2 and 6-10 are rejected under 35 U.S.C. 103 as being unpatentable over Pathak and Rodenhizer as applied above, and further in view of Atik (Atik et al., J Clin Neurosci 56: 163-8 (2018)).
Regarding claim 2, the combination of Pathak and Rodenhizer does not expressly teach wherein either hydrogel comprises 50,000-1,000,000 cells. However Atik teaches a hydrogel preparation of CAR-T cells (LVHydrogel) comprising 600,000 cells (6 x 105) and that the CAR-T cells can migrate toward CXCL10 and kill tumor cells, at least in solution (pg. 165, right col., 3rd para., to pg. 166, right col., 1st para.; pg. 164, right col., para. 5-6; Fig. 2, 4; Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to construct a mammalian-avian chimeric cell culture platform comprising CAR-T immune cells and target cancer cells (e.g., a tumor graft) in separate hydrogels positioned side-by-side as taught by Rodenhizer and Pathak to test CAR-T cell migration out of the hydrogel preparation and toward cancer cells or even into a tumor, wherein the hydrogel preparation comprising the immune cells is initially seeded with 50,000-1,00,000 CAR-T cells (e.g., 600,000) in order to test the effectiveness and dose dependence of the CAR-T cell hydrogel taught by Atik to kill cancer cells in a tumor-graft CAM hydrogel model taught by Pathak ([0067]; [0144]) using the spatial arrangement taught by Rodenhizer, such as to model whereby the hydrogel preparation is to be administered locally to a tumor site (e.g., injected within about 5 mm from a tumor).
Claims 1 and 5-10 are rejected under 35 U.S.C. 103 as being unpatentable over Pathak and Rodenhizer as applied above, and further in view of Zakrzewski (Zakrzewski et al., Nat Biotechnol 26: 453-61 (2008)).
Regarding claim 5, the combination of Pathak and Rodenhizer does not teach wherein the immune cell is a progenitor immune cell.
However Zakrzewski teaches using T-lineage committed lymphoid precursor cells (e.g., engineered with a CAR) in lieu of using mature T cells as tumor immunotherapeutic (Abstract, pg. 453, left col., last para, to right col., 1st para.; Fig. 5-6). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to construct a mammalian-avian chimeric cell culture platform as taught by Rodenhizer and Pathak to test a CAR-expressing lymphoid precursor cell’s behavior toward the tumor graft, e.g. cell morphology, migration, and cytotoxicity toward the cancerous cells in the graft-CAM hydrogel tumor model. One of ordinary skill in the art would be motivated by Zakrzewski touting the benefits of using immune precursor cells include eliminating the need for donor-matching (universal from any allogeneic donor), lack of GVHD from the progeny of these precursors in a transplant recipient, and no risk of contamination with residual malignant cells as compared to using autologous or MHC-matched, mature T cells (pg. 458, left col., last para., to right col.; pg. 460, left col., last para.).
Response to Arguments and Declaration Evidence
Applicants arguments of Sept. 15, 2025 and the Declaration of Goldstein are fully considered and found persuasive regarding the previous rejections; however, the claim amendments necessitated the new ground(s) of rejection set forth above.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicant’s arguments do not make clear what knowledge was purportedly relied upon from the instant application in the rejection when the skilled artisan need not expect the immune cell or cancerous cell actually successfully do anything to be motivated to create the claimed product, e.g., to test the immune cell or monitor the cancerous cell’s behavior.
Applicant argues that the claim to a product comprising hydrogels positioned side-by-side is taught away from by Pathak for teaching a method of making a product having sequentially placed components side-by-side via addition instead of simultaneous arranged; however, both arrive at the same arrangement at a point in time and the claims are not directed to a product-by-process but rather a product. Moreover, "[T]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed. MPEP 2141.01(VI). The arrangement in Pathak does not teach away from or discourage the arrangement taught by Rodenhizer.
Regarding Atik, Atik teaches a specific dose of CAR-T cells of the prior art, which would be obvious to test in vitro using a tumor model for efficacy using such platforms taught by Pathak or Rodenhizer as mentioned therein (e.g., tumor cell sensitivity to therapeutics, T-cell cytotoxicity and immune cell infiltration is routinely assessed in vitro (Pathak at [0060], [0089] and Rodenhizer at pg. 27)). Furthermore, there is no evidence that the precise number of cells is important for the claimed invention. Again, for impermissible hindsight reasoning, applicant must indicate what knowledge was gleaned only from the applicant's disclosure, which cannot be said for placing the two hydrogels physically touching side-by-side because this is taught in the prior art of Rodenhizer as noted above.
The Declaration of Goldstein (para. 4) argues that the prior art was not enabled or does not provide a reasonable expectation of success at providing hydrogel embedded therapeutic immune cell infiltration into a tumor graft in a second hydrogel. However none of these features are required in the claimed product, which is not a method producing any specific result. Instead the prior art merely must provide a motivation to arrange the cells in the hydrogels as claimed, which is provided fully above.
The Declaration of Goldstein (para. 6-9) also provides evidence that the side-by-side arrangement was unexpectedly improved for achieving more cancer cell killing than other arrangements, including the specific distance of not more than 5 mm. However, the prior art teaches wherein the hydrogels are arranged with no intervening distance (hence always less than 5 mm) and the possibility of other arrangements (e.g., sponge groove or piggy back) are irrelevant when the exact arrangement claimed is taught in the prior art and there is no requirement for any level of cancerous cell killing in the claimed product, as this only applies to intended uses of the product in quantifying infiltration and killing. Note, an overlapping range between the prior art and a claim provides a prima facie case of obviousness (see MPEP 2144.05).
All the unexpected effects/results argued are specific to methods of using such a mammalian-avian chimeric model system but are not relevant to the system itself as presently claimed. Furthermore, these effects are only shown with Matrigel and the claims are not so limited. Thus, the claims are not commensurate in scope with any purported unexpected result provided in the arguments and declaration when the claims encompass any use of the product taught in the prior art.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore, can be reached on 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638