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 .
Claims 1, 3-6, 8-13, 15-16, 18-20, 22-23 and 27-28 of the instant application are pending and are examined herein.
Priority
Acknowledgement is made of applicant’s claim for foreign priority under 35 U.S.C 119 (a)-(d). The certified copy has been filed in the instant application. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The instant claims herein are examined utilizing the accepted effective filing date of 10/26/2019 for the basis of any prior art rejections.
Claim Objections
Claim 11 and 13 are objected to because of the following informalities:
Claim 11 repeats the phrase “of all” twice in a row in the claim.
Claim 13 repeats the phrase “from a” twice in a row in the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-6, 8-13, 15-16, 18-20, 22-23 and 27-28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "measuring the immune-mediated effect" in the preamble. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any “immune-mediated effect” in the claim. Thus, the claim is indefinite.
The term “size-normalized” in claim 1 is a relative term which renders the claim indefinite. The term “size-normalized” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, the claim is indefinite.
The term “multitude of replicates” in claim 1 is a relative term which renders the claim indefinite. The term “multitude of replicates” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, the claim is indefinite.
The term “pre-defined time period” in claim 1 is a relative term which renders the claim indefinite. The term “pre-defined time period” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, the claim is indefinite.
Claim 1 recites the limitation "tumor cell aggregates" in step (d). There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any tumor cell aggregates in the claim.
Claim 1 recites the limitation "the total area of objects in the culture" in step (d). There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any total area in the claim.
Claim 1 and 5 recites multiple instances of “objects” in the claim. It is unclear what the objects Applicant is referring to are (could be cells, metabolites, dust, etc.). Thus, the claim is indefinite. The examiner is interpreting that the “objects” are cells.
Claim 1 recites the limitation "the patient" in step (e). There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any patient (other than “patient-derived” cell cultures).
Furthermore, claim 1 recites “identifying the patient that responds to one or more immunotherapeutic agents.” It is unclear if this step requires comparison between different patients as the claim only requires preparing a tumor culture from a patient-derived sample.
It is unclear if the immunotherapeutic of step (e) is the same as the immunotherapeutic recited in step (b) and (d). Thus, the claim is indefinite. The examiner suggests amending the claim to recite “the one or more immunotherapeutic agents.”
Claim 3 recites the limitation "the multitude of samples". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any multitude of samples in the claim. Thus, the claim is indefinite.
Claim 3 recites the limitation "the tissue or fluid sample". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any tissue or fluid sample in the claim or claim 1. Thus the claim is indefinite.
Regarding claim 3, 13, 16, and 22, the multiple recitations of the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The multiple instances of the term “suitable amount/volume” in claim 3 is a relative term which renders the claim indefinite. The term “suitable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, the claim is indefinite.
Regarding claim 4, the recitation of the phrase "may be directly employed after sampling" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. It is unclear whether it is an actual requirement of the claim or is merely an optional result. See Application of Collier, 397 F.2d 1003 (C.C.P.A. 1968), which states claims are considered indefinite when “things which may be done are not required to be done". Thus, the claim is indefinite.
Claim 4 recites “according to a standard protocol for preserving viability of human cells present in the sample.” It is unclear what this limitation intends to encompass and is undefined by the specification. Thus, the claim is indefinite.
Claim 4 recites “wherein the sample is split into a fresh sample and a cryopreserved sample for correlation of the data at a later point in time.” It is unclear whether the “correlation at a later point in time” is an actual requirement of the claim or is merely an optional result. See Application of Collier, 397 F.2d 1003 (C.C.P.A. 1968), which states claims are considered indefinite when “things which may be done are not required to be done". Thus, the claim is indefinite.
Claim 4 recites the limitation "the data". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any data in claim 4 or claim 1. Thus, the claim is indefinite.
Claim 5 recites the limitation "measuring the fluorescence intensity". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any fluorescence intensity in the claim or in claim 1.
Claim 5 recites the limitation "the object intensity". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any object intensity in the claim or in claim 1.
Claim 5 recites the limitation "(iii) . . . the luminescent surface areas". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any luminescent surface areas in the claim.
Claim 5 recites “determining the luminescent surface areas.” It is unclear what this limitation intends to claim. It is unclear what Applicant means by determining the surface areas and the specification does not reasonably define what this means. Thus, the claim is indefinite. For the purpose of compact prosecution, the examiner is interpreting that this recitation is a result of the active method steps of (i), (ii), and (iii).
Claim 6 and 8 recites the limitation "the sum of area of all tumor aggregates”. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any sum in the claim or in claim 5 or 1 of which this claim ultimately depends.
Claim 6 and 8 recites the limitation "the sum of all immune cells". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any immune cells in the claim or in claims of which claim 6 depends.
Claim 6 and 8 recites “the same components.” It is unclear what “same components” the claim is referring to.
Claim 6 and 8 recites the limitation "the negative control". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any negative control in the claim or in the claims of which the claim depends.
Claim 8 recites the limitation "the percentage decrease". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any percentage decrease in the claim or in claims which this claim ultimately depends.
Claim 9 recites the limitation "the luminescence images of the layers". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any luminescence images in the claim or in claim 1.
Claim 9 recites the limitation "the image contrast". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any image contrast in the claim or in claim 1.
Claim 11 recites “wherein normalizing the average size of the sample contents by subjecting the sample to mild shear and filtration to yield a homogenized sample.” It is unclear which step in claim 1 this particular limitation is further limiting. Thus, the claim is indefinite. For the purpose of compact prosecution, the examiner is interpreting this to be limiting the sample preparation step.
Claim 11 recites the limitation "the average size of the sample". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any average size in the claim or in claim 1.
Claim 11 recites the limitation "the growth medium". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any growth medium in the claim or in claim 1.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13 recites the broad recitation “preferably”, and the claim also recites “more preferably” and “even more preferably,” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 16, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The multiple instances of the term “suitable mesh” in claim 16 is a relative term which renders the claim indefinite. The term “suitable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, the claim is indefinite.
Regarding claim 18, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear if the culturing of about 1 to 7 days is part of the claimed invention.
Regarding claim 20, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The term “suitable” in claim 22 is a relative term which renders the claim indefinite. The term “suitable fluorescence marker” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what this claim means to encompass.
Claim 22 recites the limitation "the viability". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any viability of any cells in the claim or in claim 1.
Claim 22 recites the limitation "the anti-proliferation agent". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any anti-proliferation agent in the claim or in claim 1.
Claim 22 recites the limitation "the primary cell population". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any primary cell population in the claim or in claim 1.
Claim 22 recites the limitation "the automated computer-controlled multifocal microscope" in step (I). There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any automated computer-controlled multifocal microscope in the claim or in claim 1.
The term “sufficient” in claim 23 is a relative term which renders the claim indefinite. The term “sufficient number of cells” and “conditions sufficient” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, the claim is indefinite.
Claim 27 recites “A 3-dimensionl cell culture obtainable according to claim 1. However, claim 1 is a method of measuring immune mediated effects of one or more immunotherapeutics and not a method of making a 3D cell culture. Thus, there is no nexus between the product being claimed in claim 27 and the method of claim 1. Thus, the claim is indefinite. For the purpose of compact prosecution, the examiner is interpreting claim 27 to be a product-by-process limitation. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (see MPEP 2113).
Claim 28 recites “a kit comprising the cell culture obtained according to claim 1 and an imaging analyzing apparatus”. However, claim 1 is a method of measuring immune mediated effects of one or more immunotherapeutics and not a method of making a 3D cell culture. Thus, there is no nexus between the product being claimed in claim 28 and the method of claim 1. Thus, the claim is indefinite. For the purpose of compact prosecution, the examiner is interpreting claim 28 to be a product-by-process limitation. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (see MPEP 2113).
Please note that claims 3-6, 8-13, 15-16, 18-20, 22-23 and 27-28 are also included in this rejection for being dependent on indefinite claims.
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to rejections made based on said interpretations. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3-6, 8-13, 15-16, 18-20, and 22-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions (natural correlation and abstract ideas) without significantly more. These judicial exceptions are not integrated into a practical application and do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below:
Step 1 (Statutory Category): This part of the eligibility analysis evaluates whether the claim falls within any statutory category. Here, the claims recite “A method for measuring the immune-mediated effect of one or more immunotherapeutic agents on ex vivo three-dimensional (3D) patient derived tumor cultures.” This is a process; therefore, the claims fall within a statutory category. [Step 1: YES]
Step 2A (Judicial Exceptions), Prong 1: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. A claim “recites” a judicial exception when the exception is “set forth” or “described” in the claim (see MPEP 2106.04(II)).
Natural Phenomena/Correlation
The law of nature and natural phenomenon exceptions reflect the Supreme Court's view that the basic tools of scientific and technological work are not patentable, because the "manifestations of laws of nature" are "part of the storehouse of knowledge," "free to all men and reserved exclusively to none." Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948). Examples of natural phenomena include the correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017); and the natural relationship between a patient’s CYP2D6 metabolizer genotype and the risk that the patient will suffer QTc prolongation after administration of a medication called iloperidone, Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals, 887 F.3d 1117, 1135-36, 126 USPQ2d 1266, 1281 (Fed. Cir. 2018). Instant claim 1 recites the natural correlation between the administration of a particular immunotherapy and the effect on patient-derived cell cultures (i.e., correlation between immunotherapy and its anti-cancer activity). This also requires a mental step because evaluation requires drawing a conclusion from the comparison of the immunotherapy during the data gathering step (see below).
Abstract Idea: Mental Processes
Claims recite a mental process when they contain limitations that can practically be performed in the human mind, including for example, observations, evaluations, judgments, and opinions. Examples of claims that recite mental processes include a claim to "collecting information, analyzing it, and displaying certain results of the collection and analysis," where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016); claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014); and a claim to collecting and comparing known information (claim 1), which are steps that can be practically performed in the human mind, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011) (see MPEP 2106.04(a)(2)(III)(a)).
Instant claim 1 recites a judicial exception of “(d) determining the effect that the one or more immunotherapeutic agents has on the tumor cell aggregates by measuring the total area of objects in the culture that are above about 420 um2 and the total area of objects that are below about 160 using three-dimensional imaging of the cell culture, and (e) identifying the patient that responds to one or more immunotherapeutic agents.” The language of “determining” and “identifying” are directed to a judicial exception because it is an abstract idea that falls under mental processes (i.e., concepts performed in the human mind, including an observation, evaluation, judgment, opinion, etc.). The determination step, which is an act of evaluating information, can be practically performed in the human mind. Although the claim recites the utilization of 3D imaging, claims that encompass performing a mental process with or without physical aid (such as pen and paper) or a computer (used as a mere tool) still recite a mental process. Furthermore, the act of identifying a responsive patient is an observation and judgment that can be practically performed in the human mind.
Instant 5 recites a judicial exception of an abstract idea (mental process) in the recitation of “determining the luminescent surface areas.” The language of “determining” is directed to a judicial exception because it is an abstract idea that falls under mental processes (i.e., concepts performed in the human mind, including an observation, evaluation, judgment, opinion, etc.). The determination step of claim 5, which is an act of observation/evaluation, can be practically performed in the human mind.
Instant claim 6 recites a judicial exception of an abstract idea (mental process) in the recitation of “wherein it is determined if the sum of all areas is statistically significantly lower across the replicates comprising the same components; and/or . . . wherein it is determined if the sum of all areas is statistically significantly higher across the replicates comprising the same components compared to the negative control.” The language of “wherein it is determined if the sum of all areas is statistically significantly lower/higher and “compared to a negative control” is directed to a judicial exception because it is an abstract idea that falls under mental processes (i.e., concepts performed in the human mind, including an observation, evaluation, judgment, opinion, etc.). These steps, which are acts of observation and evaluation, can be practically performed in the human mind.
Instant claim 8 recites a judicial exception of an abstract idea (mental step) in the recitation of “wherein it is determined if the sum of all areas is statistically significantly lower across the replicates comprising the same components and . . . wherein it is determined if the sum of all areas is statistically significantly higher across the replicates comprising the same components compared to the negative control.” The language of “wherein it is determined if the sum of all areas is statistically significantly lower/higher” and “compared to a negative control” are directed to a judicial exception because it is an abstract idea that falls under mental processes (i.e., concepts performed in the human mind, including an observation, evaluation, judgment, opinion, etc.). These steps are acts of observation and evaluation that can be practically performed in the human mind.
Instant claim 22 recites a judicial exception of an abstract idea (mental step) in the recitation of “assessing the viability and/or size of the tumor cell aggregates of a surface area of more than 420 um in the presence or absence of the immunotherapeutic and/or anti-proliferation agent tested to create comparative data on viability and/or size of the cell aggregates in presence or in absence of the immunotherapeutic and or anti-proliferation agent, and relating the data obtained to values indicative of immunotherapeutic and/or anti-proliferation agent activity for reducing/increasing viability and/or size of the primary cell population.” The language of “assessing the viability and/or size of the tumor cell aggregates” and “relating the data obtained to [known] values of immunotherapeutic activity” is an abstract idea that falls under mental processes (i.e., concepts performed in the human mind, including an observation, evaluation, judgment, opinion, etc.). These steps are acts of observation and evaluation that can be practically performed in the human mind.
Thus, claims 1, 5, 6, 8, and 22 recite an abstract idea judicial exception (mental processes).
Abstract Idea: Mathematical Concepts and Calculations
The enumerated groupings of abstract ideas includes mathematical concepts (i.e., mathematical relationships, mathematical formulas or equations, and mathematical calculations). A claim that recites a numerical formula or equation will be considered as falling within the “mathematical concepts” grouping (see MPEP 2106.04(a)(2)(B)). A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the “mathematical concepts” grouping as well. A mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number, e.g., performing an arithmetic operation such as exponentiation. There is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word "calculating" in order to be considered a mathematical calculation.
Instant claim 6 recites a judicial exception of a mathematical concept (mathematical calculation) in the recitation of “wherein the sum of area of all tumour aggregates with an area of above about 420 um2 in each sample is calculated, . . . and/or wherein the sum of area of all immune cells with an area smaller than about 160 um2 in each sample is calculated.” Instant claim 8 recites a judicial exception of a mathematical concept (mathematical formula/equation) in the recitation of “wherein the sum of area of all tumor aggregates with an area of above about 420 um2 in each sample is calculated and . . . wherein the sum of area of all immune cells with an area smaller than about 160 um2 in each sample is calculated . . . and wherein the effect on tumor aggregates is derived by calculating the percentage decrease of tumor aggregate area as a median of multitude of parallel tests within each replicate, and the median as calculated across the replicates, wherein the tumor aggregates are distinguished by an area threshold of 40 um2 and immune cells are distinguished by having their area smaller than 160 um2 according to formula I: I) Wilcoxon test: Does total area of large objects decrease in treatment condition compared to the negative control? – No -> Selection factor = 0; (II) Wilcoxon test: Does the total area of small objects increase in treatment condition compared to the negative control? – No -> Selection factor = 0; If (i) & (II) are met [Wingdings font/0xE0]
Selection factor = 100*(
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wherein a selection factor below -30% indicates an effective treatment, and a patient responsive to the treatment.” These claims recite both mathematical calculations (“sum of area” and “calculation of percentage decrease” is a mathematical operation) and mathematical formula.
Thus, claims 6 and 8 recite an abstract idea judicial exception (mathematical concept/calculation).
Accordingly, the claims recite abstract idea judicial exceptions in the forms of natural correlation, mental processes, and mathematical concepts/calculations. [Step 2A, Prong 1: YES] Therefore, the analysis proceeds to Step 2A Prong 2.
Step 2A (Judicial Exceptions), Prong 2: This part of the eligibility analysis evaluates whether the claims as a whole integrate the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claims beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claims as a whole integrate the exception into a practical application.
Claim 1 does not have additional elements that would integrate the judicial exception into a practical application. Claim 1 utilizes the judicial exceptions recited in step (d) to inform the judicial exceptions recited in step (e). A judicial exception cannot form the basis for integration, so it cannot be considered to integrate the natural correlation and mental processes into a practical application. “Because a judicial exception alone is not eligible subject matter, if there are no additional claim elements besides the judicial exception, or if the additional elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application” (see MPEP 2106.04(d)(III)).
The claims do not recite additional elements that apply or use the recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition that would elevate the claim to another stand-alone consideration in the Step 2A Prong Two analysis. Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117, 126 USPQ2d 1266 (Fed. Cir. 2018). The instant claims are similar to the claims recited in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 101 USPQ2d 1961 (2012), where Mayo’s step of administering a drug to a patient was performed in order to gather data about the recited laws of nature, and this step was thus ancillary to the overall diagnostic focus of the claims. 887 F.3d at 1134-35, 126 USPQ2d at 1280. Here, the administration of the immunotherapeutic to the patient-derived cell culture is performed to gather relevant data about the effect of the therapeutic remedies being tested to create a correlation between the observed effects and treatment efficacy. As such, the claim reciting a mental analysis that informed by an administration to identify if a patient responds to a particular treatment (by way of patient-derived tumor cell cultures) falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a) without integration into a practical application (such as recitation of a particular administration step that is not merely instructions to “apply” the exception in a generic way).
In addition to the judicial exceptions, the claims also recites steps for: preparing the 3D patient-derived tumor cultures, adding immunotherapeutics to the culture (administration) and culturing for a pre-defined period of time (see instant claim 1); staining cell culture, capturing fluorescent images, and measuring object intensity (see instant claim 5); providing sample in a vessel, determining imaging parameters, lighting the sample in a region of interest, scanning flurorescent response, imaging layers of the sample, sectioning the sample, scanning light across another region, imaging the second layer of the sample, and processing the first and second image data (see instant claim 22). These steps are data acquisition that does not integrate the judicial exception into practical application. They are considered to be insignificant extra-solution activity because the preparation, addition, and culturing steps are all performed in order to gather data for the mental processes and correlation analysis and is a necessary precursor for all uses of the recited exception. Thus, they are extra-solution activity and do not integrate the judicial exceptions into practical application (see MPEP 2106.05(g)). Dependent claims 3-4, 9-13, 15-16, 18-20, and 23 also fail to integrate the judicial exception into a practical application. [Step 2A, Prong 2: NO]
Step 2B (Significantly More): This part of the eligibility analysis evaluates whether the claims as a whole amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (MPEP 2106.05). This is based on an additional consideration of whether the elements in addition to the judicial exception add beyond what was well-understood, routine, and conventional to the claims. Testing immunotherapies in tumor cultures was well-understood, routine, and conventional in the art.
Fessas et al (Semin Oncol, 4 Jul 2017; 44(2):136-140; hereinafter “Fessas”) evidences that two anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, should be considered clinically interchangeable based on clinical data for targeted cancer therapy (p. 136, “Introduction” para 1). Both antibodies were, when tested, were able to stimulate IFN-gamma responses in cancer patients (p. 139, col 1 para 2). The reference also evidences the assessment of both antibodies in murine tumor models and showed similar effectiveness in colon adenocarcinoma, with nivolumab showing 76% growth inhibition at day 20 and pembrolizumab showing tumor growth inhibition of 92.5% at day 20 (p. 139, col 1, para 3).The art demonstrates that screening the effects of immunotherapeutics against cancer and identifying patient response to a known immunotherapeutic would have been routine and conventional in the art. The claims recite use of the immunotherapies to see if they affect tumor aggregates at a high level of generality. Thus, Applicant is relying on the conventional and well-understood preparation of patient-derived tumor cultures, use of immunotherapies, culturing steps as instantly claimed that are directly informed by the judicial exception, and therefore are not evidence of additional features over the judicial exception itself.
As such, none of these limitations impose a practical use or application of the claimed natural correlation, mental processes, and mathematical concepts/calculations as stated in Step 2A2, and thus do not add significantly more to the exception. [Step 2B: NO]
The claims fail to recite additional elements that are sufficient to amount to significantly more than the judicial exception. Therefore, the claims do not qualify as eligible subject matter under 35 USC 101.
Claim Interpretation
Claim 1 recites “determining the effect that the one or more immunotherapeutic agents has on the tumor cell aggregates by measuring the total area of objects in the culture that are above 420 and below 160 um2 using three-dimensional imaging of the cell culture.” Based on BRI, the examiner is interpreting that “measuring the total area” encompasses measuring the change in size of the tumor cell population (“objects above 420 um2”; decrease in size in the culture) and immune cell populations (objects below 160 um2; increase in size in the culture).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 27-28 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Nair et al (US 20190128871 A1, 30 Oct 2018; Published 2 May 2019).
Nair teaches a method of testing proliferative responses of a drug on patient-derived tumor cells, the method comprising obtaining cells from biopsy or tumor resection material; culturing the cells on a 3D extracellular matrix (ECM), treating the cells in ECM with a drug, subjecting the treated cells to high-content (HC) imaging; and evaluating the HC imaging of the treated cells; thereby testing the proliferative responses of the drug on the patient-derived tumor cells (see claim 1 of Nair). The patient-derived tumor cells are selected from the group consisting of breast cancer cells, prostate cancer cells, non-small cell lung cancer cells, ovarian cancer cells, melanoma cells, and pancreatic cancer cells (see claim 5 of Nair). This reads on “a 3-dimensional cell culture” as recited in instant claim 27. Furthermore, the cell culture and high-content imaging reads on “a kit comprising the cell culture obtained according to claim 1 and an imaging analyzing apparatus” as in instant claim 28.
Accordingly, Nair anticipates the invention of instant claim 27 and 28.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 3-4, 9-10, 12-13, 15, 18-20, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nair et al (US 20190128871 A1, 30 Oct 2018; Published 2 May 2019) in view of Daszkiewicz et al (Cancer Res, 1 July 2017; 77(13_Supplement):4611; Ref. 2 of Non-patent literature in IDS filed 10/27/2022).
Nair teaches a method of testing proliferative responses of a drug on patient-derived tumor cells, the method comprising obtaining cells from biopsy or tumor resection material; culturing the cells on a 3D extracellular matrix (ECM), treating the cells in ECM with a drug, subjecting the treated cells to high-content (HC) imaging; and evaluating the HC imaging of the treated cells; thereby testing the proliferative responses of the drug on the patient-derived tumor cells (see claim 1 of Nair) (“wherein the culturing period in step (b) is between about 1, preferably and 7 days” as in instant claim 18). The starting material is from a high quality source of quantified tumor biobank samples or tumor biopsy samples (para 0005 and 0008) (“wherein the tissue sample may be directly employed after sampling or as a cryopreserved sample according to a standard protocol for preserving viability of human cells present in the sample” as in instant claim 4). The patient-derived tumor cells are selected from the group consisting of breast cancer cells, prostate cancer cells, non-small cell lung cancer cells, ovarian cancer cells, melanoma cells, and pancreatic cancer cells (see claim 5 of Nair) (“wherein the samples comprising tumor cells are derived from a patient with metastatic or non-metastatic cancer . . . lung cancer, pancreatic cancer, melanoma, . . . ovarian cancer, . . . breast cancer, . . . prostate cancer” as in instant claim 13). he drug is selected from the group consisting of small molecule drugs, kinase inhibitors, macromolecules, and combinations thereof (see claim 6 of Nair). The kinase inhibitors include ipilimumab (para 51) (“wherein the one or more immunotherapeutic agents comprises ipilimumab” as in instant claim 12; “wherein the immunotherapeutic agent is ipilimumab . . . as a monotherapy” as in instant claim 20). By combining EdU incorporation assay with staining for tumor specific markers, the effect of drug candidates in specific cell populations can be assessed (para 42). Fluorescent images of spheroids are analyzed using image cytometry algorithms to look at the proliferation in subsets of cells and analyzed for drug effects on the cell populations of interest (same para) (“wherein prior to the 3D imaging the cell culture is stained with suitable fluorescence marker” as in instant claim 22). The reference also teaches that the method can be used to enrich for patients that selectively respond to a targeted therapeutic and exclude patients that do not benefit from treatment with a targeted therapeutic (para 48) (“preparing a three-dimensional size-normalized tumour culture from a patient derived tumour sample in a multitude of replicates; (b) adding one or more immunotherapeutic agents to the culture, and (c) culturing for a pre-defined time period; and (d) determining the effect that the one or more immunotherapeutic agents has on the tumour cell aggregates . . . using three-dimensional imaging of the cell culture, and (e) identifying the patient that responds to one or more immunotherapeutic agents” as in instant claim 1 in-part).
The difference between Nair and the instant invention is that it does not teach measuring the total area of cells in the culture that are above 420 um2 and 160 um2 (see claim interpretation above).
Daszkiewicz teaches a 3D in vitro culture-based method to visualize and quantify effects of immune-modulatory drugs (title). Cancer cells of different sources were grown in a hydrogel using functional read-outs in a high-throughput format (384 well plate) to form tumoroids and HLA-matched PBMCs preconditioned via different protocols to achieve activated or exhausted T-cells we added in the presence or absence of immune-modulatory drugs (abstract) (“wherein the multitude of samples are prepared from the tissue or fluid sample in parallel, wherein each sample is placed in a well of a microtiter plate, and wherein each sample comprises a suitable amount of cell aggregates in a suitable volume of a suitable growth matrix, preferably a hydrogel, and a suitable amount of growth medium” as in instant claim 3). T cell infiltration and subsequent tumor killing was quantified using 3D high content imaging (same para). After optical-sectioning, 3D image stacks were reconstituted and morphometric analysis was performed with Ominer software (“wherein step (d) further segmenting the 3-dimensional culture into layers, capturing images of each layer, and deconvoluting the luminescence images of the layers to enhance the image contrast and create segmentation masks for individual cells and cell aggregates in the culture” as in instant claim 9). The addition of immune checkpoint inhibitors pembrolizumab and ipilimumab led to enhanced T cell infiltration and cytotoxicity of exhausted T cells (“wherein the one or more immunotherapeutic agents comprises ipilimumab . . .pembrolizumab” as in instant claim 12; “wherein the immunotherapeutic agent is ipilimumab, . . . pembrolizumab . . . as a monotherapy” as in instant claim 20). The automated 3D imaging and data analysis enabled discrimination of immune-tumor cell interactions depending on the activity status of T cells and allowed visualization of T cell re-gain of function in the presence of immune checkpoint inhibitors (“wherein the three-dimensional culture comprises tumor cells and immune cells” as in instant claim 15). The 3D environment allowed for different cell types to engage in a more realistic environment and enabled quantification of spatially resolved information. Finally the reference teaches that the platform is a powerful tool to evaluate drug performance. This reads on “determining the effect that the one or more immunotherapeutic agents has on the tumor cell aggregates by measuring the total area of objects in the culture that are above 420 and below 160 um2 using three-dimensional imaging of the cell culture” as in instant claim 1 in part; “wherein a decrease in the total area of objects that are above about 420 um and an increase in the total area of objects that are less than about 160 um compared to a control indicates efficacy of one or more immunotherapeutic agents on the tumor cells” as in instant claim 10; and “wherein the objects that have a surface area of above about 420 um are tumor cell aggregates or tumoroids and the object that are below 160 um are considered immune cells” as in instant claim 19.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to measure the effect of immunotherapeutics on patient-derived tumor cultures as taught by Nair, where 3D imaging is used to measure changes in tumor size and immune cell infiltration as taught by Daszkiewicz, to arrive at the instantly claimed invention. As Daszkiewicz shows 3D imaging can be used to successfully visualize and quantify the effects of immune-modulatory drugs, one of ordinary skill would have been motivated to use the 3D imaging protocol of Daszkiewicz in the method taught by Nair with a reasonable expectation of advantageously quantify immune cell infiltration and tumor killing when particular drugs are tested as taught by the prior art.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nair et al (US 20190128871 A1, 30 Oct 2018; Published 2 May 2019) in view of Daszkiewicz et al (Cancer Res, 1 July 2017; 77(13_Supplement):4611; Ref. 2 of Non-patent literature in IDS filed 10/27/2022) as applied to claims 1, 3-4, 9-10, 12-13, 15, 18-20, and 22 above, and further in view of Booij et al ( J Biomol Screen. 7 July 2016; 21(9):912-22).
The teachings of Nair and Daszkiewicz in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 1 of which claim 5 depends.
Daszkiewicz teaches that after optical-sectioning, 3D image stacks were reconstituted and morphometric analysis was performed with Ominer software (see above 103 rejection) (“capturing a layered . . .image of the . . . sample” as in instant claim 5 in-part).
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the measuring is by staining the cell culture, measuring the object intensity of the luminescent surface areas in the sample and determining the luminescent surface areas.
Booij teaches the development of a 3D tissue culture-based high-content screening platform that uses invasive human prostate cancer cells cultured in 3D in standard 384-well assay plates and phenotypic profiling to study the activity of potential therapeutic small molecules and antibody biologics (abstract). Image analysis tools were developed to process 3D image data to measure over 800 phenotypic parameters (same para). 3D invasion assays were performed on human prostate adenocarcinoma cell lines (p. 913, Materials and Methods). The cells were stained with 0.25 μM rhodamine-phalloidin and 0.1% Hoechst 33258 in PBS (p. 913, 3D invasion assay para 1). A BD Pathway 855 automated inverted fluorescence microscope was used for automated imaging of 384-well plates (wide-field epifluorescence) (p. 913, Imaging para 1). This microscope was used to image both Hoechst 33258 and rhodamine-phalloidin staining (same para). Ominer image analysis software and KNIME were used to extract in focus information from the Z-stacks generated by the BD Pathway 855 (BD Biosciences) for both Hoechst 33258 (nuclei) and rhodamine-phalloidin (F-actin) using maximum intensity projections (Data analysis, para 1). For image processing, a monochrome mask was created for both channels to define the regions of interest (ROIs) (same para). The in-focus images were used to quantify staining intensities and a set of Hu moments and Gabor wavelet-based features describing image intensity and texture (same para). The reference teaches that the ultra-high-content multiparametric analysis allowed a clear discrimination of the phenotypes associated with active and inactive c-Met and EGFR, which could be quantified using a single PCA measurement (p. 920, left column). The use of 3D imaging and high-content analysis can maximize the information that can be extracted from the more complex phenotypes obtained in 3D cell culture (p. 920, right column). This reads on “wherein step (d) comprises measuring the effect of the one or more immunotherapeutic agents on ex vivo patient derived 3D tumour cultures, by: i) staining of the cell culture with a fluorescence marker and measuring the fluorescence intensity to determine the total area of stained objects in the culture that are above about 420 pm2 and below 160 pm2, and ii) capturing a layered fluorescent image of the stained sample; iii) and measuring the object intensity of the luminescent surface areas in the sample; and iv) determining the luminescent surface areas” as in instant claim 5 in-part.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to measure the effect of immunotherapeutics on patient-derived tumor cultures as taught by Nair and Daszkiewicz in combination, where 3D imaging and staining is used to measure the effect of immunotherapeutics as taught by Booij, to arrive at the instantly claimed invention. As Booij shows 3D imaging and staining can be used to measure immunotherapeutics, one of ordinary skill would have been motivated to modify the method of Nair and Daszkiewicz to include the staining and imaging protocol of Booij with a reasonable expectation of advantageously maximize the information that can be extracted from the more complex phenotypes obtained in 3D cell culture as taught by the prior art.
Claim(s) 11 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nair et al (US 20190128871 A1, 30 Oct 2018; Published 2 May 2019) in view of Daszkiewicz et al (Cancer Res, 1 July 2017; 77(13_Supplement):4611; Ref. 2 of Non-patent literature in IDS filed 10/27/2022) as applied to claims 1, 3-4, 9-10, 12-13, 15, 18-20, and 22 above, and further in view of Wamhoff et al (US 10,221,394 B2, 10 Apr 2017; Published 5 March 2019).
The teachings of Nair and Daszkiewicz in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 1 of which claim 11 and 16 depends.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach subjecting the sample to mild shear and filtration (claim 11) or preparing the hydrogel by subjecting the tumor sample to shearing and/or filtration (claim 16).
Wamhoff teaches a method for testing a drug or compound for an effect on a tumor comprising (a) mimicking a tumor microenvironment in vitro, wherein mimicking the tumor microenvironment in vitro comprises: (i) adding a culture medium to a cell culture container; (ii) plating at least one tumor cell type on a first surface of a porous membrane within the cell culture container; (iii) indirectly applying a shear stress upon the at least one tumor cell type by applying a shear stress upon a second surface of the porous membrane, the shear stress resulting from flow of the culture medium induced by a flow device, the flow mimicking flow to which the tumor cells are indirectly exposed in vivo in the tumor microenvironment; and (b) adding a drug or a compound to the culture medium; wherein a change in the at least one tumor cell type, in the presence of the drug or the compound, indicates that the drug or the compound has an effect on the tumor (see claim 1 of Wamhoff) (“wherein normalizing the average size of the sample contents by subjecting the ample to mild shear and filtration to yield a homogenized sample with objects of all of all stainable components in the growth medium ranging from 30-100 pm in diameter” as in instant claim 11; “subjecting a tumour sample to shearing and/ or filtration, to yield a cell culture comprising cells and cell aggregates ranging from 30-100 pm in diameter prior to the culture step” as in instant claim 16 in-part). The reference teaches that porous membrane acts analogously to the filtering layer. The reference teaches that the shearing more accurately mimics the tumor environment and improves the accuracy of preclinical screening of anticancer agents for efficacy and safety (Background of the invention, para 2).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to measure the effect of immunotherapeutics on patient-derived tumor cultures as taught by Nair and Daszkiewicz in combination, where the culture is subjected to shear and filtration as taught by Wamhoff, to arrive at the instantly claimed invention. As Wamhoff shows shearing and filtration of a tumor sample in drug testing, one of ordinary skill would have been motivated to modify the method of Nair and Daszkiewicz in combination to include the shearing and filtration steps of Wamhoff with a reasonable expectation of advantageously accurately mimics the tumor environment and improves the accuracy of preclinical screening of anticancer agents as taught by the prior art.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nair et al (US 20190128871 A1, 30 Oct 2018; Published 2 May 2019) in view of Daszkiewicz et al (Cancer Res, 1 July 2017; 77(13_Supplement):4611; Ref. 2 of Non-patent literature in IDS filed 10/27/2022) as applied to claims 1, 3-4, 9-10, 12-13, 15, 18-20, and 22 above, and further in view of Strnadel et al (Bio Protoc. 2018 Jun 5;8(11):e2874).
The teachings of Nair and Daszkiewicz in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 1 of which claim 23 depends.
Both Nair and Daszkiewicz teach that the prepared cancer cell samples are in hydrogel (see above 103 rejection) (“contacting the homogenized cellular material with a growth medium for a period and under conditions sufficient to produce a multitude of three-dimensional cell culture comprising aggregates and (iv) adding an aliquot comprising a sufficient number of cells or cell aggregates to a hydrogel” as in instant claim 23 in-part).
The difference between the combined teachings and the invention as instantly claimed is that they do not teach subjecting the sample to a shear sufficient to break up cell aggregates and filtering the sample.
Strnadel teaches 3D cancer model preparation. The reference teaches a protocol that can be used to isolate 3D cancer cell lines directly from tumor tissues (abstract). The reference teaches that to establish a primary 3D spheroid culture from human tumor tissue, one needs to cut the tumor sample with a surgical blade into small pieces and transfer them into a Falcon tube with ~1 ml of 0.5-1% solution of Collagenase IV (Sigma-Aldrich), add sterile PBS to the Falcon tube with the tissue sample to wash out the collagenase by centrifugation (200-500 × g, 3 min, room temperature), and re-suspend the pellet with sterile PBS and filter cells with 70 µm cell filter (Procedure, section D) (“providing a test sample comprising patient-derived tumour cellular material and immune cells from a mammalian tumour tissue or fluid sample by: (i) subjecting the sample to a shear sufficient to break up cell aggregates to obtain a homogenized cellular material comprising isolated cells and cell aggregates; and (ii) filtrating the sample to yield a homogenized cell culture comprising cells and cell aggregates ranging from 30-100 um in diameter” as in instant claim 23 in-part). The reference teaches that tumorspheres generated from freshly isolated tumor tissue are of special interest in the field because cells from established cell lines typically differ from the primary tumor due to mutations and abnormalities gained during multiple rounds of in vitro passaging (Background para 1). The steps recited above are part of an optimized protocol of 3D culture based primary tumor cell isolation (same para).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to measure the effect of immunotherapeutics on patient-derived tumor cultures as taught by Nair and Daszkiewicz in combination, where the tumor cultures are prepared by shearing and filtering patient samples as taught by Strnadel, to arrive at the instantly claimed invention. As Strnadel shows that 3D cultures can be established from sheared and filtered tumor samples, one of ordinary skill would have been motivated to modify the method of Nair and Daszkiewicz in combination to include the preparation steps of Strnadel with a reasonable expectation of advantageously utilizing optimized protocol of 3D culture based primary tumor cell isolation and establish a primary 3D spheroid culture from human tumor tissue as taught by the prior art.
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.
Claim 1, 4-6, 8, 10, 12-13, and 19-20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 12, and 14 of copending Application No. 17771254 (referenced herein as ‘254). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘254 would anticipate the instant claims if it were available as prior art.
Claim 1 of ‘254 recites “an ex vivo three-dimensional (3D) patient derived tumour culture, the method comprising:(a) preparing a three-dimensional, optionally size-normalized, tumour culture from a patient-derived tumour sample in a multitude of replicates; (b) adding one or more immunotherapeutic agents to the culture, and (c) culturing for a pre-defined time period; and (d) determining the effect that the one or more immunotherapeutic agents has on the tumour cell aggregates by measuring the total area of objects in the culture that are above a threshold area associated with tumour cell aggregates, and the total area of objects that are below a threshold associated with immune cells, using three- dimensional imaging of the cell culture; wherein if following culturing with a composition comprising ipilimumab, the total area of the large objects decreases and/or the total area of the small objects increases relative to a control the patient is treated with ipilimumab.”
Claim 2 of ‘254 recites “wherein the patients have ovarian cancer or mesothelioma”
Claim 3 of ‘254 recites “wherein the Selection Factor is determined according to the following steps: (i) the sum of area of all tumour aggregates with an area of above about 420 pm2 in each sample is calculated, and wherein it is determined if the sum of all areas is statistically significantly lower across the replicates comprising the same components; (ii) the sum of area of all immune cells with an area smaller than about 160 pm2 in each sample is calculated, and wherein it is determined if the sum of all areas is statistically significantly higher across the replicates comprising the same components, compared to the negative control; and (iii) the effect on tumour aggregates is derived by calculating the percentage decrease of tumour aggregate area as a median of multitude of parallel tests within each replicate, and the median as calculated across the replicates, wherein the tumour aggregates are distinguished by an area threshold of 420 pm2 and immune cells are distinguished by having their area smaller than 160 pm2 according to formula I”
Claim 4 of ‘254 recites “wherein the threshold associated with the tumour cell aggregates is above about 420 pm2, and wherein the threshold associated with immune cells is about 160 pm2”
Claim 5 of ‘254 recites “wherein the tissue sample may be directly employed after sampling and optional transport, or as a cryopreserved sample according to a standard protocol for preserving viability of human cells present in the sample, or wherein the sample is split into a fresh sample and a cryopreserved sample for correlation of the data at a later point in time.”
Claims 6 of ‘254 recites “wherein step (d) comprises measuring the effect of the one or more immunotherapeutic agents on ex vivo patient derived 3D tumour cultures, by i) staining of the cell culture with a fluorescence marker and measuring the fluorescence intensity to determine the total area of stained objects in the culture that are above about 420 pm2 and below about 160 pm2, and ii) capturing a layered fluorescent image of the stained sample; iii) and measuring the object intensity of the fluorescent surface areas in the sample; and iv) determining the fluorescent surface areas.”
Claim 7 of ‘254 recites “wherein the sum of area of all tumour aggregates with an area of above about 420 pm2in each sample is calculated, and wherein it is determined if the sum of all areas is statistically significantly lower across the replicates comprising the same components.”
Claim 8 of ‘254 recites “wherein the sum of area of all immune cells with an area smaller than about 160 am2in each sample is calculated, and wherein it is determined if the sum of all areas is statistically significantly higher across the replicates comprising the same components, compared to the negative control.”
Claim 9 of 254 recites “wherein the effect on tumour aggregates is derived by calculating the percentage decrease of tumour aggregate area as a median of multitude of parallel tests within each replicate, and the median as calculated across the replicates, wherein the tumour aggregates are distinguished by an area threshold of 420 pm2 and immune cells are distinguished by having their area smaller than 160 pm2 according to formula I”
Claim 10 of ‘254 recites “wherein step (d) further comprises segmenting the 3-dimensional culture into layers, capturing images of each layer, and deconvoluting the luminescence images of the layers to enhance the image contrast and create segmentation masks for individual cells and cell aggregates in the culture.”
Claim 12 of ‘254 recites “further comprising a synergistic and therapeutically effective amount of nivolumab and/or pembrolizumab and/or ADU-S100.”
Claim 14 of ‘254 recites “metastatic or non-metastatic cancer, preferably lung cancer, peritoneal cancer, gastrointestinal cancer, pancreatic cancer, melanoma, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, mesothelioma, hepatic carcinoma and head and neck cancer, more preferably ovarian cancer, liver cancer or mesothelioma, more preferably ovarian cancer or mesothelioma, wherein the effect on tumour aggregates is derived by calculating the percentage decrease of tumour aggregate area as a median of multitude of parallel tests within each replicate, and the median as calculated across the replicates, wherein the tumour aggregates are distinguished by an area threshold of 420 pm2 and immune cells are distinguished by having their area smaller than 160 pm2 according to formula I.”
If available as prior art, the ‘254 claims would anticipate instant claims 1, 4-6, 8, 10, 12-13, and 19-20.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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