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
Applicant’s remarks and amendments filed 10/7/2025 and the replacement amendment to the drawings filed 10/22/2025, in response to the non-final rejection mailed 5/7/2025, are acknowledged and have been fully considered.
Any previous rejection or objection not mentioned herein is withdrawn.
Applicant’s amendment to the claims is acknowledged. This listing of the claims replaces all prior versions and listings of the claims. Claims 1-20 are pending, of which claims 11-20 remain withdrawn as being drawn to a non-election invention.
Claims 1-10 have been examined on the merits herein.
Drawings
Replacement drawings were received on 10/22/2025. These drawings are acceptable.
Response to Arguments
Applicant’s amendments and remarks, on pgs. 8-9 of the remarks filed 10/7/2025, with respect to the objections to the specification have been fully considered. The previous objections to the specification have been withdrawn in response to the amendments.
Applicant’s arguments, see pages 9-11 of the remarks filed 10/7/2025, with respect to the rejections of claims 1 and 3-8 under 35 U.S.C. § 102(a)(1)/(a)(2) as being anticipated by Pongracz et al. (US PGPub No. 20190128870, of record) and of claims 1 and 4-9 as being anticipated by Shuford et al. (Scientific Reports, 2019, of record) have been fully considered and are persuasive in light of the claim amendments. The previously cited art does not disclose explicitly a patent-derived microtumor (e.g. a 3D cell culture) having a maturation time of 2-5 days, nor that the cells are treated for a period of 7 to 14 days, as required in the amended claims. The rejections under 35 U.S.C. § 102 have been withdrawn.
Applicant’s arguments, on pages 11-13 of the remarks filed 10/7/2025, with respect to the rejections of claims 1-10 under 35 U.S.C. § 103 have been fully considered and are also persuasive in light of the amendments to claim 1. Therefore, the rejection has been withdrawn.
However, upon further consideration, new and/or modified grounds of rejection are presented below, in view of applicant’s amendments to the claims, prompting additional searching of the art and further consideration of the amended limitations.
Claim Interpretation
The term “patient-derived microtumor (PMT)”, as recited in the amended claims, 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 that comprises structures of patient-tumor derived cancer cells. Such structures are also known as microtumors, spheroids, and microtissues in the art. The specification, at [11], states that “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”.
Claim Rejections - 35 USC § 103
(Modified as necessitated by Applicant’s amendments)
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 3-8 are rejected under 35 U.S.C. 103 as being unpatentable over Pongracz et al. (US PGPub No. 20190128870) in view of Benton et al. (“In Vitro Microtumors Provide a Physiologically Predictive Tool for Breast Cancer Therapeutic Screening”, Plos One, April 9, 2015, of record).
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 teaches 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]). Thus, Pongracz pertains to methods for generating and testing patient-derived microtumors, as it teaches using cells from neoplastic tissue, e.g. a tumor.
Pongracz teaches 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 teaches next 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]: “Pipette 200 μl/well mixed suspension into a sterile 96-well, U-bottom cell culture plate with Ultra-low attachment surface” and [0167]).
Pongracz teaches 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 teaches next 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.”).
Regarding claim 3, Pongracz teaches: that lymphoid CD45+ cells are removed from the aggregates, i.e. thus removing immune cells ([0054-0056]; [0112]); 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.
In regards to claim 4, Pongracz teaches 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).
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 patient-derived microtumor, determination of the intracellular ATP content in the microtumor, and determination of pre-selected biomarkers in the microtumor. Pongracz teaches assessing cell viability 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 teaches that following treatment, cell surface markers are assayed to determine the presence of neoplastic stem cells ([0073]; [0135]-[0138]), thus teaching determination of pre-selected biomarkers in the 3D cultured patient-derived tissue.
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 teaches, in one embodiment, 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 teaches that a 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 teaches and suggests means for histochemical analysis. Pongracz 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]).
However, Pongracz does not explicitly teach a microtumor culture having a maturation time of 2-5 days, nor that the cells are treated with drugs for a period of 7 to 14 days.
Benton teaches in vitro microtumor models 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), in order to provide a model system that has more authentic responses to anti-cancer treatments (pg. 2, last ¶).
Benton teaches that cancer cells can be directed to adopt an appropriate tumor morphology as multicellular tumor spheroids (MCTS) (pg. 2, 2nd ¶). Benton teaches a method of producing tumor microtumors (see pg. 7, under “In Vitro Microtumors”), comprising providing human breast cancer cells (from cell lines originally derived from human tumor samples) and human mesenchymal stem/stroma cells (hMSCs) which are incubated for 72 hour at 37°C (see also S2 Fig. “The stepwise process for the in vitro microtumor model for evaluating breast cancer progression.”). Benton teaches that using “preformed spheroids containing both breast cancer cells and hMSCs to endothelial tubules composed of both HUVECS and hMSCs provided an improved cell environment, promoting physiological architecture and activity for each microtumor model” (pg 10, 4th ¶).
Benton teaches applying varying doses of the anti-tumor drugs fluorouracil or paclitaxel and measuring the effect on proliferation in MCF-7 and MDA-MB-231 microtumors, for at least 7 days and up to 10 days (see Figure 6), and teaches that the microtumors exhibit near physiological responses regarding cell proliferation to paclitaxel or fluorouracil treatment.
Therefore, before the effective filing date of the instant invention, to one of ordinary skill in the art, it would have been prima facie obvious to modify the method taught in Pongracz for assaying the effectiveness of an anti-neoplasm treatment, such that the patient-derived 3D spheroids (e.g. patient-derived microtumors) are produced according to the teachings of Benton, wherein the culturing of the spheroids is performed for 72 hours, and it would have been obvious over the combined teachings of Pongracz and Benton to apply the combination of drugs for at least 7 days, in order to better assay the effects of cancer drugs on cell proliferation.
One would have been motivated to improve upon the 3D aggregate cultures used in Pongracz for predicting the effect of a particular patients response to at least two drugs or combinations thereof and determining an effect of said drugs and/or combinations on the 3D microtissue by incorporating knowledge known in the art, including the microtumor structures disclosed in Benton. Benton teaches that such microtumors (comprised of cancer cells originally derived from human patient tumor samples) can be used to better model the tumor micro-environment, and that treatment of such microtumor structures with anti-cancer drugs leads to predictably improved assay behavior, better mimicking the effects of the drugs on cell proliferation of an in-vivo tumor. Thus, one would have been motivated to apply the methods for optimizing a 3D microtumor culture taught in Benton to the individualized medicine assays, using patient-derived tumor cells, as taught in Pongracz to select the most effective treatment. In doing so, one would have arrived at the instantly claimed methods, wherein microtumors are produced by “self-assembling” cancer cells, the microtumors mature for 72 hours (as taught in Benton), and the drugs used for testing are applied to the microtumor culture for 7-10 days, because Benton teaches such application, and the microtumors are viable for at least that long.
Regarding claims 3-8, these additional limitations are taught in either Pongracz or Benton, as described above, and represent obvious variations and matter of judicious selection to one having ordinary skill in the art.
From the teachings of the cited references, it is apparent that there would have been a reasonable expectation of success in combining the teachings therein to arrive at the claimed invention because both Pongracz and Benton pertain to 3D tumor culture models with cancer cells, Pongracz teaches culturing primary dissociated tumor cells, and Benton teaches means for improving a 3D microtumor culture, such that drugs can be applied for over 7 days. Therefore, one would reasonably expect to yield a culture system for patient-derived microtumors, wherein drugs can be applied for an extended period of time.
Therefore, the invention of claims 1 and 3-8 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the cited references, especially in the absence of evidence to the contrary.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Pongracz et al. (US PGPub No. 20190128870) and Benton et al. (“In Vitro Microtumors Provide a Physiologically Predictive Tool for Breast Cancer Therapeutic Screening”, Plos One, April 9, 2015, of record), as applied to claims 1 and 3-8 above, and further in view of Macleod et al. (2004. “Essential Techniques of Cancer Cell Culture” Methods Mol Med.; 88:17-29, of record) (to include the rejection of claim 2).
Pongracz et al., modified according to the teachings of Benton 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) microtumor cultures (Abstract; [0026]), including the limitations of claims 1 and 3-8, for all the reasons set forth above.
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]). Modified Pongracz teaches contacting the array of microtumors 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). Modified Pongracz also teaches identifying a patient-specific drug or drug combination based on the effect as determined ([0064]).
However, the combination of Pongracz and Benton does not teach a tissue sample 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” (pg. 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 (pg. 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 (pg. 22, step 6).
Thus, 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 made obvious by Pongracz and Benton for assaying the effectiveness of an anti-neoplasm treatment, by incorporating 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 and Benton because Pongracz teaches 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. 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 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 the cited references, 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.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Pongracz et al. (US PGPub No. 20190128870) and Benton et al. (“In Vitro Microtumors Provide a Physiologically Predictive Tool for Breast Cancer Therapeutic Screening”, Plos One, April 9, 2015, of record), as applied to claim 1 above, and further in view of Shuford et al. ("Prospective Validation of an Ex Vivo, Patient-Derived 3D Spheroid Model for Response Predictions in Newly Diagnosed Ovarian Cancer”, Scientific Reports, of record).
The combined teachings of Pongracz and Benton make obvious a method for assessing the effectiveness of an anti-cancer treatment by measuring the effect of said treatment on the viability of three dimensional (3D) microtumor cultures, including the particular limitations of the amended claim 1, as discussed above (Abstract; [0026]). The relevant teachings of Pongracz and Benton include all those discussed above.
However, Pongracz and Benton do not explicitly teach producing a stratification of patients based on a patient-specific drug or drug combination, as recited in claim 9.
Shuford et al. teaches 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 discusses 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).
Shuford teaches patients were categorized using the ex vivo assay results as either test Responders or Non-Responders to individual chemotherapeutics (see Figure 3 and pg. 11, ¶ “Test response determination”), thus teaching 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).
Thus, before the effective filing date of the claimed invention, to one of ordinary skill in the art it would have been obvious when performing the method taught in the combination of Pongracz and Benton for predicting a patient’s response to a drug treatment using 3D microtumor cultures to further analyze the data as taught in Shuford by performing a stratification of the patient based on the assay results such that the patients are stratified as responder or non-responder.
One would have been motived by the teachings of Shuford to do so, as an analogous ex vivo assay is taught therein, and the stratification or classification of patients is taught to be useful for making patient-specific response predictions prior to initiation of treatment. The analysis of data and stratification of patients amounts to nothing more than gathering and processing of data 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. To one having ordinary skill in the art, with knowledge of the cited references wherein cell culture chemotherapy data is useful for predicting patient responses, the categorizing of patients as responders or non-responders would have been a normal and routine analysis method.
From the teachings of the cited references, particularly the stratification taught in Shuford, it is apparent that there would have been a reasonable expectation of success in combining the teachings therein to arrive at the claimed invention because all of the reference pertain to methods for personalized chemotherapy medicine, using 3D tissue cultures.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the cited references, especially in the absence of evidence to the contrary.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Pongracz et al. (US PGPub No. 20190128870) and Benton et al. (“In Vitro Microtumors Provide a Physiologically Predictive Tool for Breast Cancer Therapeutic Screening”, PLOS One, April 9, 2015, of record), as applied to claim 1 above, and further 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, of record).
The combination of Pongracz et al. (hereafter “Pongracz ‘870”) and Benton 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) microtumor cultures, including the particular limitations of the amended claim 1, as discussed above (Abstract; [0026]). The relevant teachings of Pongracz ‘870 and Benton include all those discussed above.
Claim 10 recites identifying adverse effects associated with a treatment with a patient-specific drug or drug combination in a patient, comprising performing the method according to 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, the combination of Pongracz ‘870 and Benton et al. does not 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, 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 (pg. 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 (pg. 1, right hand col). Moen teaches the art recognizes genetic markers associated with response to chemotherapy (see pg. 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 made obvious by the combination of Pongracz ‘870 and Benton for predicting a patient’s response to a drug treatment using 3D microtumor cultures and evaluating tumor cell viability with exposure to chemotherapeutics, to further assay the patient-derived cells as taught in Pongracz ‘744 and 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 made obvious by the combined teachings of Benton and Pongracz ‘870, to a patient would have been a clearly obvious step to perform in view of the combined teachings of the cited art. 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.
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 useful information regarding potential normal tissue toxicity and thus adverse effects of drugs using microtissue models.
Moen and Pongracz ‘744 are relied upon for the reasons discussed above. If not expressly taught by the cited art, based upon the overall beneficial teaching provided by the references 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 ‘870 in view of Benton would have 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.
Response to Arguments
The applicants arguments regarding the obviousness of the claimed methods have been fully considered, however as indicated above, the additional reference Benton et al. has been applied in view of the amendments to the claims.
Regarding the arguments towards the relevant portions of Pongracz et al. (on pages 11-13 of the remarks), the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, when taking into account all of the teachings of Pongracz and Benton et al. regarding the production of ex vivo patient-derived 3D cultures or microtumors, the instantly claimed invention would have been a matter of routine optimization and judicious selection to one of ordinary skill.
The applicant argues that the PMTs of the instant invention are ready for drug testing within 4 days after taking tumor samples, however Benton addresses this shortcoming, as the microtumors comprised of cancer cells therein are generated in 72 hours. Further, the microtumors cultured in Benton et al. were tested for at least 7 days, and up to 10 days based off of the data in Figure 6. Thus, the results of the extended testing period, as claimed (7-14 days), is within the reasonable expectations of the art, and cannot be considered an unpredictable result.
Generally, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
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 7 of the reference application recites that the incubation time is between 7 to 28 days, thus fully encompassing the claimed range of 7-14 days.
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 ¶ [0084] of the reference specification which defines an array of separated 3D microtissue cultures.
Further, the specification of the ‘740 application, referenced herein to determine the full breadth and scope of the claimed element “3D microtissues”, describes that the generation of the 3D microtissues comprises a maturation time of about 6 hours to 7 days, thus fully encompassing the claimed time of 2-5 days. MPEP §804.II.B.1. establishes that "The Patent and Trademark Office (‘PTO’) determines the scope of the claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction ‘in light of the specification as it would be interpreted by one of ordinary skill in the art.’ " Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) (en banc) (quoting In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364, 70 USPQ2d 1827, 1830 (Fed. Cir. 2004);” and also describes that “the portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02.” Further, MPEP §804.II.B.1. also states that “If the reference patent discloses several species within the scope of the reference genus claim, that portion of the disclosure should be analyzed to properly construe the reference patent claim and determine whether it anticipates or renders obvious the claim in the application being examined”.
Therefore, the instantly claimed method, as recited in claim 1, is found prima facie obvious over, if not anticipated by, the subject matter of the claims of 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”.
Further, claim 7 recites that the treatment is for at least 7 days and up to 28 days, therefore 7-14 days would be clearly anticipated by these claims. Regarding the generation of the microtumor, the maturation time of 2-5 days, as recited in the amended claim 1, is well within the times given of the preferred embodiments in the reference application. In order to produce and use the microtissue cultures of the reference application claims, one would turn to the specification for determining the metes and bounds of the incubating step, such that an optimal time of culturing can be found. This amounts to optimization of routine steps in the art.
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.
Response to Arguments
Applicant’s argument to the previously presented Provisional Double Patenting rejection amounts to nothing more than a request that the rejections be held in abeyance. See MPEP § 804 Subsection I.B.1. which states “A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action. Such a response is required even when the nonstatutory double patenting rejection is provisional”
The rejections of record are maintained as stated in the section above, and updated to reflect any amendments to the claims.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW TERRY MOEHLMAN whose telephone number is (571)270-0990. The examiner can normally be reached M-F 9am-5pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Terry McKelvey can be reached at (571)272-0775. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
ANDREW T MOEHLMANExaminer, Art Unit 1655
/AARON J KOSAR/Primary Examiner, Art Unit 1655
Prosecution Insights