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 .
Election/Restrictions
Applicant’s election of Group I in the reply filed on 1/29/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-20 are pending of which claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Pending claims 1-10 have been examined on the merits.
Priority
This application is a National Stage entry of PCT/EP2020/084383, filed December 3, 2020. Applicant’s claim for the benefit of a prior-filed application, German Patent Application DE 10 2019 132 865.9, filed December 3, 2019, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/10/2022; 8/12/2024; and 4/1/2025 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, the references in the specification have not been considered.
Specification
The disclosure is objected to because of the following informalities:
Throughout the disclosure, chemical compounds are used with improper capitalization (see for example [28], [92], [102]-[103], [141]). There is no special convention for capitalizing chemical compounds (unless appearing at the beginning of a sentence), especially not those in reference to chemical names or generic drugs (i.e. chloramphenicol, estradiol, testosterone, oestrogen, et. cetera), nor is this necessary for common terms (such as “coal tar containing products”, “Interferon containing products”), as used in [28] on page 7, cited herein for exemplary purposes only. Careful consideration of the proper use of capitalization throughout the specification is recommended.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (in paragraph [6] of the specification). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The term “peg- interferon” as used in [28] should instead be either “pegylated interferon” or “PEG- interferon”.
The abbreviation “Bcg”, as used in [28] of the specification, is improper. One skilled in the art may be able to determine that this means Bacillus Calmette–Guérin (BCG)” therapy, which is used to treat bladder cancer, or to a “Bacillus Calmette–Guérin (BCG) vaccine, historically used to inoculate against tuberculosis infection. However, additional clarification or removal of the term is required.
TRADE NAMES, TRADEMARKS, AND OTHER MARKS USED IN COMMERCE:
The use of the terms DISPASE ([14], [92]); SYNTOCINON ([28]); SYNTOMETRINE ([28]); ABRAXANE ([0102]); KUKA LBR MED ([0118]); and Liberase™ ([0129]) which are each a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks 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 (see MPEP 608.01(v) and 608.01(u)).
ABRAXANE appears in Figures 11 and 12 and is recited without any generic identifying information in paragraph 102 on page 29 of the specification. In order to properly provide clarification of the disclosed composition, without introducing new matter, the following proposed phrasing is suggested for consideration: --Two single drugs (gemcitabine and the drug sold under the trade name ABRAXANE) and two combinations of drugs (gemcitabine in combination with erlotinib and gemcitabine in combination with the drug sold under the trade name ABRAXANE) were tested.--
Drawings
The drawings are objected to because the term ABRAXANE appears in Figures 11 and 12. The anti-cancer drug ABRAXANE is a registered trademark and therefore the use of the term, without any information regarding its chemical composition is objected to. The specification, as presented, does not clarify the composition of the trademarked product.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(4) because:
The reference character “(1)” has been used to designate “a tumor tissue sample” in Figure 1; “a loading port” in Figures 2-4; and a “top of the device” in Figure 6. The same reference character may not be used for different parts of an invention. See 37 C.F.R. 1.84(p).
The same objection applies to (2) - [“a single cell solution”, a “4°C zone”, and a “middle sector”], (3) - [a “non-adherent multi-well plate”, “an incubator”, and a “bottom of the device”], (4) - [“the resulting effects on microtumor growth observed by appropriate non-disruptive technologies over time”; “a detection device”, and an “automated robotic arm”], (5) - [“a central drug response database” and “a centralized automated liquid handling system”], and (6) - [“the test results” and a “37°C zone”].
The drawings are also objected to as failing to comply with 37 CFR 1.84(p)(4) because reference characters "(7)" (in Figs. 2-4) and "(4)" (in Fig. 6) have both been used to designate a robotic arm.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
The term “3D microtissue”, as recited in line 6 of claim 1, is being interpreted according to the broadest reasonable interpretation (B.R.I.) of the language in view of the specification. In this case the term is being interpreted as encompassing any artificially grown (in vitro) three-dimensional tissue models, including aggregates and/or structures of cancer cells. Such structures are also known as microtumors, spheroids, and microtissues in the art. The specification, at [11], states that “a 3D microtissue shall designate an in vitro generated cell aggregate comprising cells as desired. Consequently, a microtumor shall mean a 3D microtissue generated from, at least in part, selected cancer cells derived from a cell line or a neoplastic sample, such as a tumor”.
The specification describes an "array" as “a set of separate 3D microtissues that tested/analyzed, such as, for example, 3D microtumors in a multi-well plate. An array are at least 2 or more, or 3, 4, 5, 6, 7, 8, 9, 10 or more, 12, 48, 96, 128, 384 or more, or even 200, 300, 400, or more 3D microtumors/microtissues”. Thus, the term “array”, as used in line 6 of claim 1, is being interpreted according to the B.R.I in light of the specification as encompassing a plurality of multiple of 3D microtissues (spheroids, microtumors, or arrays), including those found in separate wells of a multi-well cell culture plate.
Claim Objections
Claim 2 is objected to because of the following informalities:
In claim 2, “step (ii)” appears twice, and it is presumed that “step (ii)” in line 9 is a typographical error and should be corrected to “step (iii)”.
Further, claim 2 line 11 recites “wherein steps (ii) and (iii) are repeated at least once”. Step (iii) is not explicitly mentioned in claim 2, however, one of ordinary skill in the art would understand that the referenced step is the third step, which is incorrectly labeled as a repeated “step (ii)”. Claim 2 has been examined under all statutes with this interpretation.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 3-8 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Pongracz et al. (US PGPub No. 20190128870).
Pongracz is drawn to a 3-Dimensional (3D) tissue culture aggregate of cells derived from a neoplastic tissue sample and a method for assessing the effectiveness of an anti-neoplasm treatment by measuring the effect of said treatment on the viability of a three dimensional (3D) neoplasm tissue culture aggregate (Abstract). Pongracz states that “The method of the present invention uses patient-derived cells so the aggregate formed can be used to select the most effective treatment. Anti-neoplasm compounds or treatments, such as chemotherapeutic agents, or combinations thereof can be tested, and those which reduce the tumour cell viability can be used to treat the patient.” ([0026]).
Pongracz discloses dissociating the cells of a patient-derived tissue sample in order to obtain dissociated cells ([0050]: “Solid tumour samples can be reduced in size and undergo mechanical dissociation by cutting or mincing, for example using sterile scalpels. The cells in the tissue sample are dislocated according to known tumour dissociation methods”)
Pongracz discloses generating a 3D aggregate, i.e., a 3D microtissue according to the claim interpretation described above, using dissociated tumor cells ([0047]; [0059]-[0060]), and generating an array of the 3D aggregates or microtissues which comprises using a multi-well plate containing a number of 3D aggregates ([0109]: “Pipette 200 μl/well mixed suspension into a sterile 96-well, U bottom cell culture plate with Ultra-low attachment surface” and [0167]).
Pongracz discloses contacting the array of said 3D microtissues with at least two drugs and/or combinations thereof and determining an effect of said drugs and/or combinations on the 3D microtissues ([0063]-[0067]; and see specific embodiments of FIGs. 3-4 and FIGs. 7-8)
Pongracz also discloses identifying a patient-specific drug or drug combination based on the effect as determined ([0064]: “Anti-neoplasm treatments identified as reducing cell viability can then be used to treat the patient.”).
Claim 3 recites that the method further comprises at least one of the following, because the language “and/or” is used:
step b) comprises adding or removing stroma cells, stromal fibroblasts, endothelial cells and immune cells to said dissociated cells;
in step b) for each 3D microtissue a predetermined number of cells is provided;
in step b) said 3D microtissues are generated in at least one system selected from a hanging drop system; and a multiwell system.
Pongracz discloses that lymphoid CD45+ cells are removed from the aggregates, i.e. thus removing immune cells ([0054-0056]; [0112]); that fibroblasts may be added to the cells in order to form an aggregate ([0057]; [0118]); that the number of cells in the cell population are counted and controlled and a set amount is determined for the aggregates ([0058]; [0116]-[0117]); and that the 3D microtissues are generated with a hanging drop system ([0059]), and using multi-well plates (e.g. in [0121]: “96-well, U-bottom cell culture plate with Ultra-low attachment surface”)
Thus Pongracz discloses, in specific embodiments, one or more of the claimed alternatives encompassed in claim 3.
Claim 4 recites that the method further comprises at least one of the following, because the language “and/or” is used:
the generation of said 3D microtissues does not require the use of a solubilized basement membrane preparation;
wherein the generation of said 3D microtissues comprises self-assembly of said cells comprised in said dissociated cells;
wherein the generation of said 3D microtissues comprises a maturation time of about 6 hours to 7 days.
Pongracz discloses that the method therein does not use a scaffold or artificial extracellular matrix ([0024]-[0027]; [0061]: “it is preferred that the aggregates are formed and cultured in the absence of an artificial scaffold or matrix”. One skilled in the art would recognize that this would exclude the use of a solubilized basement membrane preparation (evidenced from [0011] of Pongracz). Pongracz discloses in one embodiment that the cultured cell aggregates are incubated, initially, for 24 hours prior to treatment ([0124]), thus having a maturation time of between 6 hours to 7 days. Therefore Pongracz discloses, in specific embodiments, one or more of the claimed alternatives encompassed in claim 4.
In regards to claim 5, Pongracz discloses a continuous exposure to at least two drugs, and to combinations thereof ([0063]-[0067] and [0167], as an example: “aggregates were cultured for 24, 48 or 72 h respectively, at 37° C. using the drugs”, i.e. a continuous exposure). Pongracz also discloses that “following treatment with a antineoplastic treatment, any residual cells can be tested for sensitivity to a second antineoplastic treatment”, which one of skill in the art would understand to encompass removing the drug and then applied a different drug ([0068]-[0072]).
Claim 6 recites that the determining of the effect on the microtissues is selected from one of: size determination, quantification of internal reporter gene expression in the 3D microtissue, determination of the intracellular ATP content in the 3D microtissue, and determination of pre-selected biomarkers in the 3D microtissue. Pongracz discloses that cell viability is assessed following the drug treatment, including the determination of intracellular ATP content ([0064]; [0067]: “Methods of assessing cell viability are well known to the person skilled in the art. For example, ATP production can be measured, or the incorporation of propidium iodide”; and [0131]-[0133]). Pongracz also discloses that following treatment, cell surface markers are assayed to determine the presence of neoplastic stem cells ([0073]; [0135]-[0138]), thus disclosing determination of pre-selected biomarkers in the 3D microtissue.
In regards to claim 7, Pongracz discloses that the methods may include steps of cryopreserving the suspension culture and thawing the cryopreserved culture ([0045]-[0046]; [0062]). Pongracz also discloses that the cells are obtained from a patient-derived tissue sample and may be derived from a primary tissue sample, a solid tumor sample, or a metastatic tissue sample (i.e. from lymph nodes or other organs) ([0033]-[0034]). Pongracz discloses that the cells may split into additional samples (i.e. thus a sub-sample of a tissue sample, see [0159]-[0161]).
In regards to claim 8, Pongracz discloses in one embodiment, the processing and culturing of cells from a patient-derived glioblastoma sample (thus a primary tissue sample), including steps of collecting of additional samples for DNA and RNA isolation (which were collected and stored at −80° C), and used for additional sequencing or comparative gene expression studies ([0159]-[0161]), thus disclosing molecular profiling of a subsample.
Pongracz also discloses that the cellular composition of the tissue culture aggregate may be identified using surface cell marker analysis, and that surface cell markers can be identified using antibodies such as CD31-APC Cy7, CD44-FITC, CD45-PerCp, CD90-BV421, EpCam-APC. Thus Pongracz discloses means for histochemical analysis. Pongracz also teaches that when the glioblastoma sample was acquired, samples of it were analyzed by a pathologist, thus intrinsically disclosing a step for histological analysis in that embodiment ([0161]).
Thus, claims 1 and 3-8 are rejected under 35 U.S.C. § 102 as being anticipated either explicitly or inherently by the methods and embodiments of Pongracz.
Claims 1 and 4-9 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Shuford et al. ("Prospective Validation of an Ex Vivo, Patient-Derived 3D Spheroid Model for Response Predictions in Newly Diagnosed Ovarian Cancer”, Scientific Reports, Vol.9:11153, published online August 1, 2019, on IDS submitted 11/10/2022).
Shuford et al. describes a method that utilizes primary patient tissue in 3D cell culture to make patient-specific response predictions prior to initiation of treatment in the clinic (Abstract).
Shuford et al. discloses that biopsy samples of primary tumor sites were obtained from patients, the tumor tissue was enzymatically dissociated into single cells, and the cells were formed as 3D spheroids in 384-well spheroid microplates, i.e. an array of 3D microtissues (pg. 11, ¶ “Assay performance”, entire paragraph). Shuford discloses that the array of cells were exposed to standard of care chemotherapies as single agents, and at least two drugs were tested on different wells of the array so that cell viability could be calculated for each treatment, thus disclosing determining an effect of the drugs (pg. 11, ¶ “Assay performance”, lines 4-7).
In regards to claims 1 and 9, Shuford discloses that using the ex vivo assay results, patients were categorized as either test Responders or Non-Responders to individual chemotherapeutics (see Figure 3 and pg. 11, ¶ “Test response determination”), thus disclosing identifying patient-specific drug or drug combination based on the determined effect, i.e. prediction of patient-specific response before treatment (see Abstract), and performing a stratification of the patient based on the assay results (e.g. the patients are stratified as responder or non-responder), as recited in claim 9.
Shuford discloses that the 3D spheroids were formed in 384-well spheroid microplates (Corning Inc., Corning, NY), i.e. a multiwell system, and that the spheroids were cultured for 24 hours (pg. 11, ¶ “Assay Performance”), thus disclosing generating the 3D microtissues within the range of 6hrs to 7 days, as required in claim 4.
Shuford discloses a continuous exposure to at least two drugs for 72 hours, as recited in claim 5 (see Figure 1 and pg. 11, ¶ “Assay Performance”; and page 3: “All 83 successfully assayed tissues were tested for categorical response to carboplatin, paclitaxel, and cell numbers permitting, approved second- and third-line agents, including doxorubicin, topotecan, gemcitabine, and Olaparib”).
Regarding claim 6, Shuford discloses that the tumor model responses to the drugs were measured via CellTiter-Glo 3D (pg. 11, ¶ “Assay performance”, lines 4-5; Figure 1B), thus disclosing determination of the intracellular ATP content.
Regarding claims 7 and 8, Shuford discloses that the samples were obtained from primary tissue samples, including from tumor samples obtained from ovarian cancer patients (see pg. 11, ¶ “Assay Performance”; and pgs. 3-5). Shuford discloses that subsamples of the primary tissue samples were used for histological analysis, as recited in claim 8 (Figs. 4 and 8 and pg. 5: “histology of the primary tumor samples received revealed pan-cytokeratin positive cells indicating the presence of epithelial cells and these samples were verified to be ovarian cancer through pathology”; see also the “Histology” section on pg. 11).
Thus, claims 1 and 4-9 are rejected under 35 U.S.C. § 102 as being anticipated either explicitly or inherently by Shuford.
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 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Pongracz et al. (US PGPub No. 20190128870) in view of Macleod et al. (2004. “Essential Techniques of Cancer Cell Culture” Methods Mol Med.; 88:17-29).
Pongracz et al. teaches a method for assessing the effectiveness of an anti-neoplasm treatment by measuring the effect of said treatment on the viability of three dimensional (3D) neoplasm tissue culture aggregates (Abstract; [0026]), including the limitations of claims 1 and 3-8, for all the reasons set forth above.
Briefly, Pongracz teaches dissociating the cells of a patient-derived tissue sample in order to obtain dissociated cells ([0050]), generating a 3D aggregate (i.e. a 3D microtissue), using dissociated tumor cells ([0047]; [0059]-[0060]), and generating an array of the 3D aggregates or microtissues which comprises using a multi-well plate containing a number of 3D aggregates ([0109]; [0167]). Pongracz teaches contacting the array of 3D microtissues with at least two drugs and/or combinations thereof and determining an effect on the 3D microtissues ([0063]-[0067]; FIGs. 3-4 and FIGs. 7-8). Pongracz also teaches identifying a patient-specific drug or drug combination based on the effect as determined ([0064]).
However, Pongracz does not teach explicitly that the tissue sample is treated with an enzyme capable of dissociating cells, producing a supernatant comprising dissociated cells, and removing the supernatant comprising the dissociated cells, wherein the steps of enzymatic treatment and cell collection are repeated at least once, as recited in claim 2.
Macleod teaches methods for obtaining cancerous cells from primary tissue samples, including solid primary tumors (3.1. Primary Culture, section: 3.1.1. Initial Establishment from Solid Primary Tumor or Solid Metastasis). Regarding dissociating the tumor sample, Macleod states that “Two options are then available for tumor disaggregation—mechanical or enzymatic dispersion” (page 22, step 3). In the enzymatic method, Macleod teaches that cells in the sample may be disaggregated (broadly, broken up or dissociated) by the use of proteolytic enzymes, which include trypsin, collagenase, hyaluronidase, elastase, dispase, and papain (page 22, step 5). Macleod then states that “the supernatant is collected and centrifuged at 600g for 5 min to collect a cell pellet. This cell pellet is resuspended in full culture medium (containing serum which will inactivate the trypsin).” Macleod teaches that the fragments will not necessarily disaggregate fully after a single 30-min step and thus the process may be repeated until most cells have become suspended in the supernatant (page 22, step 6).
To one of ordinary skill in the art before the effective filing date of the instant invention, it would have been prima facie obvious to modify the method taught in Pongracz for assaying the effectiveness of an anti-neoplasm treatment, by applying the teachings of Macleod such that the dissociating of the primary tissue or tumor sample comprises steps of applying a solution containing a proteolytic enzyme, collecting a supernatant that contains dissociated cells, and repeating the process at least once in order to fully disaggregate the collected sample cells.
One would have been motivated to use the proteolytic enzyme dissociating method of Macleod in combination with the methods taught in Pongracz because Pongracz states that “the cells in the tissue sample are dislocated according to known tumour dissociation methods, known in the art (see Langdon and Macleod (2004)” Essential Techniques of Cancer Cell Culture” Methods Mol Med.; 88:17-29.)”, citing to Macleod. Thus, one of ordinary skill in the art would have been motivated to select the dissociation method using an enzyme, such as trypsin, as this was one of two finite method choices presented in Macleod, and generally known in the art. Further, Macleod explicitly teaches that repeating the enzymatic digestion steps is advantageous because the repetition will increase the amount of dissociated cells in the supernatant.
From the teachings of Macleod and of Pongracz, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention, and Macleod teaches that the use of proteolytic enzymes is commonly and successfully used to disaggregate or dissociate tumor samples.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Pongracz et al. (US PGPub No. 20190128870), in view of Pongracz et al. (US Patent No. 9151744 B2, referred to hereafter as “Pongracz ‘744”) and Moen et al. (2012. “Pharmacogenomics of chemotherapeutic susceptibility and toxicity.” Genome medicine vol. 4,11 90, doi:10.1186/gm391).
Pongracz et al. teaches a method for assessing the effectiveness of an anti-neoplasm treatment by measuring the effect of said treatment on the viability of three dimensional (3D) neoplasm tissue culture aggregates (Abstract; [0026]), including all of the limitations of claim 1 as set forth above. The relevant teachings of Pongracz ‘870 include all those discussed above.
Claim 10 recites a method for identifying adverse effects associated with a treatment with a patient-specific drug or drug combination in a patient, comprising performing the method according to any one of claim 1, and further comprising the step of testing and analyzing said patient-specific drug or drug combination for adverse effects in said patient.
However, Pongracz does not explicitly teach a step of testing and analyzing said patient-specific drug or drug combination for adverse effects in said patient, as required in claim 10.
Pongracz ‘744 teaches an engineered three dimensional (3D) pulmonary model tissue culture which is free of any artificial scaffold (Abstract), and wherein the model tissue is a pulmonary disease model tissue culture (Col. 9, lines 13-36). Particularly, Pongracz ‘744 teaches that the disease model is a tumor model, such as a non-small cell lung carcinoma (Col 9, lines 32-45), and that the models may comprise cells obtained from a patient and may be used for establishing personalized therapy (Col 10, lines 6-9). Pongracz ‘744 teaches using a model to test an adverse effect of a drug, wherein alteration or modification which is detrimental to the cells of test sample is considered as a toxic or adverse effect of said drug (Col 11, lines 46-50).
Moen et al. is a review article that teaches that a goal of personalized medicine is to tailor a patient’s treatment strategy on the basis of his or her unique genetic make-up (Abstract).
Moen states that the goal of pharmacogenomics is to use a patient’s genotype to inform clinical decision making regarding treatment strategies, with the ultimate goal of avoiding adverse drug reactions while achieving the best drug response (page 7, left col). Moen teaches that Genome-wide association studies (GWAS) can be utilized to identify genetic markers that will facilitate physician decision-making regarding optimal drug selection, dose and treatment duration on a patient-by-patient basis, with consequent improvement in drug efficacy and decreased toxicity (Page 1, right hand col). Moen teaches the art recognizes genetic markers associated with response to chemotherapy (see page 2, left hand col). Moen discusses the use of genomics to associate toxicity with particular drug responses (Table 1: “The top half of the table shows tumor genome mutations associated with drug response and the bottom half shows germline mutations associated with drug toxicity.”).
Thus, to one of ordinary skill in the art before the effective filing date of the claimed invention, it would have been prima facie obvious after performing the method taught in Pongracz ‘870 for predicting a patient’s response to a drug treatment using an array of 3D microtissues and evaluating of tumor cell viability after exposure to chemotherapeutics, to further assay the patient-derived cells as taught in Pongracz ‘744 and/or to monitor the patient’s response to the drug as taught in Moen, for the expected purpose of identifying any possible adverse effects in said patient, as suggested by the teachings of Moen.
Moen teaches that many chemotherapy drugs are known for their cytotoxicity and possibility of inducing adverse events, and thus one would have been adequately motivated to monitor patients for any adverse effects. The administering of the identified drug, identified by the method anticipated or made obvious by the teachings of Pongracz ‘870, to a patient would have been an obvious step to perform in view of the combined teachings of Pongracz ‘870 and Moen. Further, the monitoring and assaying of the patients encompasses steps that amount to nothing more than gathering and processing of data, steps which may be performed by the mind of an observer. These steps do not result in any patentable distinct over those methods and knowledge of the cited prior art.
Finally, although the steps do not absolutely require monitoring the 3D microtissue model for adverse effects, such a step is not outside the breadth of the disclosure, and Pongracz ‘744 establishes that in vitro cellular models may be used to obtain information regarding potential normal tissue toxicity and thus adverse effects of drugs using microtissue models.
Moen is relied upon for the reasons discussed above. If not expressly taught by Moen, based upon the overall beneficial teaching provided by this reference with respect to the knowledge in the art of adverse effects and cytotoxicity of chemotherapeutics, it is deemed obvious that further clinical or in-vivo testing of a drug or drug combination identified by the method according to Pongracz would lead one to determine if there are any adverse effects.
Therefore, from the teachings of the cited references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success and adequate motivation in performing the method as claimed before the effective filing date of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-8, 10-12, 14-19, and 22 of copending Application No. 18726740 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed subject matter of the conflicting application anticipate or make obvious each and every of the features of the instant claims.
The claims of the reference application are drawn to a method for determining the effectivity of at least one drug or drug combination for the treatment of a patient, the method comprising at least the following steps, as recited in claim 1:
providing at least one culture of a 3D microtissue comprising a microtumor based on dissociated cells of a tissue sample derived from a patient;
providing at least one drug or a combination of drugs or a panel of drugs to be tested;
contacting the at least one 3D microtissue culture with the drug or combination of drugs or panel of drugs identified to have a longest t½ time period(s);
incubating said at least one 3D microtissue culture with the drug or combination of drugs or panel of drugs with the longest t½ time period;
determining an effect of said drug or combination of drugs or panel of drugs thereof on at least one physiological parameter of the at least one 3D microtissue culture; and
selecting at least one of the drug or combination of drugs or panel of drugs… based on the determined effect as specific to the patient.
Claim 22 recites that the method is performed via a testing system, wherein the testing system comprises a unit for culturing an array of the 3D microtissues based on dissociated cells of a tissue sample derived from the patient. See also paragraph [0084] of the reference specification which defines an array of separated 3D microtissue cultures.
Therefore, the instantly claimed method, as recited in claim 1, is prima facie obvious over, if not anticipated by, the subject matter of the method claimed in the ‘740 application. The conflicting claims of the reference application share overlapping subject matter with that of the instant application. The instant claims are comprising type claims and thus do not exclude the additional subject matter recited in the reference application claims such as “identifying a t½ period for each of said drug or combination of drugs or panel of drugs of drugs”.
Claim 12 of the ‘740 application recites that “the tissue sample is derived by physically dissecting said tissue sample into smaller pieces comprising cells, by treating said tissue sample with a solution comprising at least one enzyme capable of dissociating cells in said tissue sample, wherein the enzyme is selected from a protease, a collagenase, trypsin, elastase, hyaluronidase, papain, chymotrypsin, deoxyribonuclease I, and neutral protease, as recited in claim 2 of the instant application. Repeating any one or more of the dissociating steps to obtain fully separated cells would have been obvious to one of ordinary skill in the art. Mere repetition of the enzyme treatment and cell collection steps does not result in a patentable distinction from the method of the reference claims.
In regards to the instant claim 3, claim 14 of the reference application recites adding or removing stroma cells, stromal fibroblasts, endothelial cells and immune cells to the dissociated cells, wherein for each 3D microtissue a predetermined number of cells is provided.
Regarding claim 4, the claims 1 and 22 of the reference application recite providing at least one culture of a 3D microtissue comprising a microtumor based on dissociated cells of a tissue sample derived from a patient, however specific methods for generating the 3D microtissues are not explicitly recited in the reference claims. However, the specification of the ‘740 application, referenced herein to determine the full breadth and scope of the claimed element “3D microtissues”, describes that the production of the 3D microtissues of the claimed invention does not require the use of a solubilized basement membrane preparation; that the generation of said 3D microtissues comprises self-assembly of said cells comprised in said dissociated cell, that the generation of the 3D microtissues comprises a maturation time of about 6 hours to 7 days, and that the 3D microtissues as generated have a size of about 350 μm +/−100 μm ([0086]-[0087]). Thus, it is determined from the full disclosure of the application that the claimed 3D microtissues of the reference application claims encompasses those having one or more of the properties recited in the instant claim 4.
Regarding the instant claim 5, claim 1 of the reference application recites that the drugs or the drug combination or the panel of drugs are removed from the sample after exposure (“wherein an end of the longest t½ time period defines the time point for a removal R of the drug, the combination of drugs, or the panel of drugs from the culture”).
Claim 15 of the reference application recites that the measured physiological parameter, i.e. the determined effect of the drug, is selected from size determination of said 3D microtissue, quantification of internal reporter gene expression in said 3D microtissue, determination of intracellular ATP content in said 3D microtissue, and determination of pre-selected biomarkers in said 3D microtissue, as recited as alternatives in claim 6 of the instant application.
Regarding the instant claim 7, claim 11 of the reference application states: “wherein said tissue sample is selected from a sub-sample derived from at least one of a primary tissue sample, a primary tumor sample, and a metastasis sample, and wherein said tissue sample has been obtained by a method comprising one or more of core biopsy, tumor resection, liquid biopsy and/or needle aspiration, and/or wherein said tissue sample is frozen and re-thawed prior to generation of said 3D microtissues”. Thus the reference claims encompasses the same subject matter as the instant claim 7.
Claim 16 of the reference application is drawn to the same subject matter as the instant claim 8, as claim 16 recites that “a fraction of the cells is analyzed, and further comprising: providing a primary tissue, sample as the tissue sample; obtaining a subsample in addition to the tissue sample; and subjecting said subsample to at least one of molecular profiling, histological analysis, and histochemical analysis”.
Claim 18 of the reference application recites stratifying of said patient based on the patient-specific drug or combination of drugs or panel of drugs or the other drug or combination of drugs or panel of drugs, as recited in the instant claim 9.
Claim 17 of the reference application recites testing and analyzing said drug or combination of drugs or panel of drugs for adverse effects in said patient, as recited in the instant claim 10.
Therefore, the claims of the instant application are not patentably distinct from the subject matter encompassed by the claims of the reference ‘740 application. Claims 1-10 are rejected under the grounds of nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Citation of pertinent prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Keselowsky et al. (US Patent No. 9,557,319) is drawn to arrays, systems, and methods analyzing cells, methods of making arrays, and the like (Abstract), and teaches using patient-derived colon cancer stem cells, and measuring the stem cells responses to drug-loaded microarrays for screening chemotherapeutics. (Figure 14; Col 13, line 55- Col 14, line 42).
Sobrino et al. (“3D microtumors in vitro supported by perfused vascular networks”, Scientific Reports, Volume 6, Article number: 31589, 2016, doi.org/10.1038/srep31589) teaches in vitro vascularized microtumors (VMTs), referred to as a “tumor-on-a-chip” platform that incorporates human tumor and stromal cells which grow in a 3D extracellular matrix (Abstract). Sobrino teaches that colorectal and breast cancer cells grow vigorously in the platform and respond to standard-of-care therapies, showing reduced growth and/or regression (Figs. 2 and 3).
Benton et al. (“In Vitro Microtumors Provide a Physiologically Predictive Tool for Breast Cancer Therapeutic Screening”, Plos One, April 9, 2015, doi: 10.1371/journal.pone.0123312) teaches an in vitro microtumor model using a tumor-aligned ECM, a tumor-aligned medium, MCF-7 and MDA-MB-231 breast cancer spheroids, human umbilical vein endothelial cells, and human stromal cells that recapitulates the tissue architecture, chemical environment, and cellular organization of a growing and invading tumor (Abstract). Benton teaches applying varying doses of fluorouracil or paclitaxel and measuring the effect on proliferation in MCF-7 and MDA-MB-231 tumor spheroids (Figs. 5 and 6).
Conclusion
Claims 1-10 are rejected. Claims 11-20 are withdrawn from consideration.
No claims are allowed.
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ANDREW T MOEHLMANExaminer, Art Unit 1655
/AARON J KOSAR/Primary Examiner, Art Unit 1655