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, 25-27, and 31 are currently pending in this application.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10, in the reply filed on Dec. 23, 2024 is acknowledged. Claims 11-13, 18-19, 22-23, and 25-27 are withdrawn for being directed to non-elected subject matter, there being no allowable generic or linking claim. Claims 1-2, 5-10, and 31 have been considered on the merits and all arguments have been fully considered.
Specification
The disclosure is objected to because of the following informalities:
Although the use of trademarks 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.
The use in the specification of the terms “Matrigel” or “Matrigel,” which is a trademark used in commerce, has been noted in this application e.g., at [0049] and [0196]. 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. Appropriate correction at numerous instances in the specification is required because the proprietary nature of trademarks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
The system of claim 1 is interpreted as a product-by-process regarding the term “fused to form a single tumor.” Firstly, a claim to a “system” is by default considered a product (e.g., an article of manufacture) which is defined by its physical and/or functional components and how the components interact rather than the any series of steps used to operate or create it (e.g., a fusing step).
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]). As the fertilized avian egg of the claims is not limited to being entirely whole, the term “egg” is interpreted as encompassing eggs modified to lack some or all of their eggshell, albumen, vitellus, and/or embryo/zygote so long as a suitable CAM is present as a surface for said hydrogels (see instant [0004]; [0096]-[0100]). Furthermore, the “egg” is also 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 (id).
Claim Rejections - 35 USC § 112(a), Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5-10, and 31 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite “wherein said separate hydrogels are fused to form a single tumor comprising a partition between said mammalian cancerous cell and said mammalian immune cell.”
Claims must be given their broadest reasonable interpretation in light of the specification as it would be interpreted by one of ordinary skill in the art without impermissible importation of subject matter from the specification into the claims (MPEP 2111).
Claim 1 is interpreted as encompassing systems wherein the separate hydrogels are either (1) physically in contact (e.g., creating said partition as an interface created by their fusing (see instant [0120])) or (2) the separate hydrogels are as much as 5 mm apart (e.g., the gap constituting said partition).
It is not possible to have separate hydrogels that are both “fused” and physically apart (e.g., 5 mm or less apart) based on the claim interpretation herein.
The instant specification is silent as to any representative species of a system comprising 5 mm apart separate hydrogels which are fused to form a single tumor. The application ([0018]) does describe whereby two hydrogels grafted separately to a CAM over time become cojoined or fused into a single mass or single gel entity, but it is not clear how this is accomplished, e.g., “drawn close to each other” due to movement of a hydrogel(s), cells, and/or cell growth and ECM secretion by the cells (Examples 2-7; [0041], [0156])).
The instant specification describes embodiments wherein separate hydrogels placed apart on a CAM can over time subsequently fuse to form a “single tumor” comprising both cell types and allowing for the cell types to subsequently interact with each other (implying cell communication/movement between the separate hydrogels) ([0057]). The specification further explains, a method of making such a system may comprise co-engrafting two different matrix pellets within 5 mm of each other on the same CAM and allow for fusing to form a single tumor ([0156]-[0157]). In some embodiments, the calls are described as infiltrating or migrating across the partition ([0118]-[0120]); however the instantly claimed system seems to preclude this arrangement with the phrase “single tumor comprising a partition between said mammalian cancerous cell and said mammalian immune cell” (Fig. 7 and 11; [0172]-[0173], [0179], Table 4).
The instant specification is silent as to any representative species of a partition other than a visible interphase boundary between two hydrogels that are in physical contact; however applicant is invited to furnish evidence to the contrary. Further, the claims are unclear as to whether the fused hydrogels are separated by a partition at a position/location of physical contact (e.g., due to separate hydrogel fusion) or does the “single” tumor have a partition between cells due to something unrelated (e.g., a separate mesh/filter component)? If the former, what is the nature of the partition regarding structure and function, is the partition permissible/porous to some components but not others (e.g., certain cell types).
Furthermore if the separate hydrogels are made predominantly of the same substance (e.g., Matrigel®), once fused and time allows for cell migration, the two separate hydrogels may not be distinguishable by the cell type present but rather the quantity/quality of extracellular secretions (unique microenvironment) previously left by the cells prior to migration ([0057], [0123]). Moreover, the mere appearance of a visible interphase within a composition comprising a hydrogel (in ovo hydrogel-tumor mass) does not necessarily denote a partition having the claimed function (i.e., related to how the hydrogel-cell mass was made by a fusing event/step).
Thus, the skilled artisan cannot envision the scope of “single tumors” encompassed by the claims: (1) fused hydrogels that are at a distance of 5 mm or less apart from one another (i.e., not in direct physical contact) and (2) partitions other than ones formed at the interphase contact point between two “separate” hydrogels in physical contact. Therefore, there is a lack of evidence in the instant specification as filed that the inventors were in possession of the system as claimed.
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.
Claims 1-2, 5-10, and 31 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.
Claim 1 recites separate hydrogels “fused to form a single tumor comprising a partition” between cell types, which is ambiguous, incoherent and unclear as to the meaning of the terms “single tumor,” “fused” and “partition.” Firstly, claim 1 also recites the separate but fused hydrogels may be at a distance of 5 mm from one another on the CAM, and yet are “fused.” This wording simultaneously implies the “fused” hydrogels may either be physically touching or as much as 5 mm apart. Fused ordinarily means the mixing, blending or uniting of separate things, yet here there is a “partition” that at least partitions the cancerous cells from the immune cells in the single tumor.
This phrasing is also ambiguous as to the scope of the “partition” as it is defined as comprised within the single tumor and functioning only regarding the cells but not expressly limited as having any relationship regarding the fused hydrogels, such as by position or separation of hydrogel components. Are the fused hydrogels separated by a partition at a position/location of their physical contact or does the “single” tumor have a partition between cells due to something unrelated (e.g., a separate mesh/filter component)? The term “single” tumor implies the presence of cancerous cells throughout the tumor and thus across both sides of the partition yet the partition limitation describes a “single” tumor comprising a compartment lacking cancerous cells due to the functioning of the partition. This wording is ambiguous as to whether the separate hydrogels must be physically touching with a physical demarcation between them represented by said partition (i.e., both fused and partitioned) or instead may be comingled and sharing a structure(s) (e.g., allowing for the flow of a solution or solute therein) and the partition between the cells within the single tumor is unrelated to the separate hydrogels. Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). Claims 2, 5-10, and 31 are included in this rejection for depending on indefinite claim 1.
Claim 6 recites a “cytokine-mediated remote killing” or “cell-cycle arresting” immune cell, both terms of which are ambiguous, incoherent, and unclear. Neither term is defined the specification or by the claim beyond this generic functional language. The term “cytokine-mediated remote killing” immune cell appears to refer to two types of lymphocyte: cytotoxic T cells and natural killer cells, and possibly other immune cells such as B cells. The term “cell-cycle arresting” immune cell may refer to any immune cell as the all possess the function ability of cell-cycle arrest, e.g., in response to DNA damage or other stresses (starvation). Furthermore, does this refer to the immune cell’s status in the mammalian-avian chimeric model system or prior to being included into the system in a specific context? Thus, one of ordinary skill in the art would not be reasonably apprised of the scope of these terms.
Claim 31 recites the trademark/trade name “Matrigel®.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademarks/trade name Matrigel® is used to identify/describe a specific component(s) of a hydrogel.
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.
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 1-2 and 6-10 are rejected under 35 U.S.C. 103 as being unpatentable over Pathak (US20190029235A1; published 2019-01-31) in view of Engel (Engel et al., Adv Healthc Mater 4: 1664-74 (2015)).
The claims are interpreted as explained in a previous section. Further, as noted above regarding indefiniteness, the limitation of forming a “single tumor” is not clear for paradoxically implying the presence of cancerous cells throughout the fused separate hydrogels while expressly requiring a partition seemingly preventing cancerous cells from being present throughout the single fused entity, i.e., not where the immune cells are. Thus, this ambiguous limitation was interpreted below as non-limiting awaiting clarification.
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 wherein the two hydrogels are fused and comprise a partition between the cancer cells and immune cells.
However Engel teaches a multilayered hydrogel 3-D cell co-culture platform for cancer cells and stromal cells dispersed in separate hydrogels positioned side-by-side (at distances as small as 6 microns) and fused permitting paracrine signaling between spatial localized cell types, such as for screening drug effects in vitro (Fig. 1; pg. 1664, right col., last para., to pg. 1665, left col., 1st para.; pg. 1670, left col., last para.). Engel describes the presence of a partition in the form of beads between the cell type layers and imaging such platforms made with transparent hydrogels with confocal microscopy (Fig. 1; pg. 1665, left col., para. 2). Engel teaches the cancer cells in the cancer cell hydrogel layer over culture time can form a spheroid or be initially seeded as such, i.e., a tumor-like cell mass (pg. 1667, left col., last para., to right col., 1st para.).
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 Engel, such as using a stromal-type second hydrogel comprising stromal cells in addition to immune cells. One of ordinary skill in the art would be motivated to evaluate the cells in such 3-D tumor-stromal microenvironments mimicking a tumor architecture to research how the immune cells behave in the second hydrogel (e.g., regarding activation, chemotaxis, and migration toward the partition/cancer cells). A layered construct taught by Engel also comprising immune cells in view of Pathak could either be positioned/built vertically or horizontally, and when there are limited, predictable solutions, then there is likely a high expectation of success at arriving at the configuration in the claimed invention.
Regarding claim 2, Pathak does not expressly teach wherein either hydrogel comprises 50,000-1,000,000 cells; however Engel teaches performing the co-culture for 7 days while starting with 2500-5000 cells (e.g., C4-2B or Ishikawa) (pg. 1666, right col., 1st para.; pg. 1672, High Throughput Dispensing). Thus, Engel teaches platforms comprising over 50,000 cells (e.g., > 100,000) when considering a doubling time of about 36 hours for the cancerous cells (e.g., Ishikawa)).
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]).
Claims 1-2 and 5-10 are rejected under 35 U.S.C. 103 as being unpatentable over Pathak and Engel 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 Engel 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 Engel 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.).
Claims 1-2, 6-10 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Pathak and Engel as applied above, and further in view of Rodenhizer (Rodenhizer et al., Adv Healthc Mater 7: e1701174 (2018)).
Regarding claim 31, the combination of Pathak and Engel does not teach wherein each hydrogel comprises Matrigel®. However Rodenhizer teaches Matrigel® is a commonly used component of hydrogels used for 3-D in vitro tumor models (pg. 10, right col., pg. 12). Further, Rodenhizer teaches 3-D tumor culture platforms 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., for 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 the hydrogels comprises Matrigel® in view of Rodenhizer. One of ordinary skill in the art would be motivated to use a prior art taught component with a well-known predictable effect of supporting cell growth within a hydrogel by providing ECM components generally beneficial to mammalian cells in in vitro 3-D hydrogel culture.
Thus, the claimed invention as a whole is prima facie obvious before the effective filing date in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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
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