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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Status of Claims
Claims 1, 4, 5, 7, 26, 27, 32, 34, 36, 38, 41 and 42 are currently pending. Claims 1, 27 and 34 have been amended by Applicants’ amendment filed 02-24-2026. No claims have been added or canceled by Applicants’ amendment filed 02-24-2026.
Applicant's election without traverse of Group I, claims 1, 2, 4, 5, 7-9, 11, 12, 15, 18-20, 22, 25-27, 32, 34, 36, 38, 39, 41-44, 46-52, 56, 59 and 94, directed to a method of assessing a candidate molecule; and
Species (A): wherein the cell sample is cultured in serum-free conditions, at the liquid-air interface, etc. (claim 22);
Species (B): further comprising (d) administering an additional candidate molecule to the cell (claim 4);
Species (C): wherein the response is a viability response comprising measuring a metabolic product (claim 26);
Species (D): wherein the cell sample and the additional cells sample are obtained from the tumor tissue at different times (claim 48); and
Species (E): further comprising step (e) administering the candidate molecule…(i) comparing the response (claim 94), in the reply filed on March 14, 2025 was previously acknowledged.
Claims 34, 36 and 38 are newly withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 2, 8, 9, 11, 12, 15, 18-20, 25, 39, 40, 43, 44, 46, 47-42, 56, 59 and 94 (now canceled) were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
Please Note: instant claim 34 has been amended to recite a new independent claim. In the Response to the Election/Restriction filed March 14, 2025, Applicant elected Group II, where the steps of Group II differ from the steps recited in claim 34. The steps of Group II comprise: administering a candidate molecule to a cell sample of a tumor tissue; culturing the cell sample in the presence of the candidate molecule for at least a day; and assessing a response. The steps of amended claim 34 comprise: obtaining a cell sample of intact tissue; administering the candidate molecule to the cell sample; culturing the cell sample in the presence of the candidate molecule; and assessing a viability response of the cell sample. Thus, claim 34 is withdrawn from further consideration as being drawn to a non-elected invention. Claims 36 and 38 are withdrawn as depending from a withdrawn claim.
The restriction requirement was deemed proper and was made FINAL.
The claims will be examined insofar as they read on the elected species.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Therefore, claims 1, 4, 5, 7, 26, 27, 32, 41 and 42 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed September 16, 2021 is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2020/023445, filed on March 18, 2020, which claims the benefit of
US Provisional Patent Application 62/820,719, filed March 19, 2019.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed February 24, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection
not specifically addressed below are herein withdrawn.
Maintained Objections/Rejections
Claim Interpretation: the term “thin” such as recited in claim 1 is interpreted to refer to a porous membrane having any width.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 4, 5, 7, 26, 27, 32, 41 and 42 is maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 is indefinite for the recitation of the term “wherein the cell sample is cultured on a thin, porous membrane at a liquid-air interface” such as recited in claim 1, lines 6-7 because it is unclear whether lines 6-7 refer to a separate cell sample culturing event, and whether the cell sample recited in line 6 is cultured including whether the cell sample is cultured before the step administering; if cell sample is cultured after the step of assessing; and/or if the cell sample referred to is cultured in the presence of the candidate molecule and, thus, the metes and bounds of the claim cannot be determined.
Claim 27 is indefinite for the recitation of the term “wherein measuring the metabolic product from the cell sample comprises isolating the metabolic product…is reacted with an indicator” such as recited in claim 27, lines 1-4 because claim 27 is confusing and unclear. Instant claim 27 does not recite any type of “measuring,” such that it is completely unclear how “measuring” is carried out, when there is no step of “measuring” recited in the claim. Moreover, claim 27 recites additional steps completely unrelated to “measuring” (e.g., reacting with an indicator, etc.) and, thus, the metes and bounds of the claim cannot be determined.
Claim 27 is indefinite for the recitation of the term “in the absence of the cell sample” such as recited in claim 27, line 3 because claim 27 depends from claim 1 and 26, wherein claims 1, 26 and 27 do not recite a step of isolating the metabolic product from the cell sample. Instant claim 27 recites isolating the metabolic product from the serum-free, liquid cell culture medium, but does not recite any further isolation including isolation from the cell sample and, thus, the metes and bounds of the claim cannot be determined.
Claim 27 is indefinite for the recitation of the term “is reacted with an indicator selected from the group consisting of a product of a reduction reaction…and a formazan” such as recited in claim 27, lines 4-6 because claim 27 is confusing and unclear. Instant claim 27 depends from claims 1 and 26, wherein claims 1 and 26 do not recite the presence of redox indicators/metabolic probes, tetrazoles, a reduction reaction, etc. in the cultured cell sample. Moreover, many of the broadly recited components are not indicators (e.g., MTT is the indicator added, which reacts with a viable cell sample to produce a formazan, which is the metabolic product detected). Additionally, it is unclear how the recited “indicators” react with the cell sample in claim 27, when claim 27 recites that the cell sample is absent and, thus, the metes and bounds of the claim cannot be determined.
Claim 32 indefinite for the recitation of the term “wherein the tetrazole is selected from…(MTS) or a salt thereof” such as recited in claim 32, lines 1-5 because claim 32 depends from claims 1, 26 and 27, wherein the tetrazolium compounds recited in claim 32 do not represent the tetrazoles recited in claim 27. Instead, the tetrazolium compounds recited in claim 32 such as MTT, XTT, and MTS are the indicators, which form a detectable product (e.g., a formazan) is produced when a tetrazole is metabolized by a viable cell. Thus, claim 27 broadly recites the metabolic products (as well as, the indicators resazurin and resorufin) and, thus, the metes and bounds of the claim cannot be determined.
Claims 4, 5, 7, 26, 41 and 42 are indefinite insofar as the ultimately depend from instant claim 1.
Claim Rejections - 35 USC § 112(d)
The rejection of claims 27 is maintained, and claim 32 is newly rejected, under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 27 recites (in part): “wherein measuring the metabolic product from the cell sample comprises isolating the metabolic product from the serum-free, liquid cell culture medium…a formazan” in claim 27, lines 1-6 because claim 27 depends from claims 1 and 26, wherein claims 1 and 26 do not recite the presence of a viability dyes, indicators and/or metabolic probes in the cultured cell sample comprising a candidate molecule and/or a cell sample coming into contact with, or reacting to form a detectable molecule. Moreover, claim 27 recites a mixture of indicators and the metabolic products that are to be measured; as well as, missing steps that encompass removing the cell sample. Thus, claim 27 is an improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 32 recites (in part): “wherein the tetrazole is selected from the group consisting of…(MTS) or a salt thereof” in claim 32, lines 1-5 because claim 32 depends from instant claims 1, 26 and 27, wherein the tetrazolium compounds recited in claim 32 do not represent the tetrazoles recited in claim 27. Instead, the tetrazolium compounds recited in claim 32 such as MTT, XTT, and MTS are the indicators, which form a detectable product (e.g., a formazan) when metabolized by a viable cell. Thus, claim 32 is an improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 4, 5, 7, 26, 41 and 42 is maintained under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Nadauld et. al. (hereinafter “Nadauld”) (US Patent Application Publication No. 20140302491, published October 9, 2014; of record) as evidenced by Pricella (Elabscience, 2025, 1-2; of record); and Capricorn Scientific (Capricorn Scientific, 2025, 1-3; of record); and Myles et al. (hereinafter “Myles”) (US Patent No. 7541187, issued June 2, 2009).
Regarding claims 1, 4, 5 and 7, Nadauld teaches that cultured explants of the invention can be continuously grown in culture for a year or more (interpreted as cells being cultured continuously, claim 1) (Abstract, lines 7-8; and paragraph [0005], lines 7-10). Nadauld teaches that tissue can be obtained by any convenient method, such as by biopsy, during endoscopy, during surgery, by needle, etc., and is typically obtained as aseptically as possible; and upon removal, the tissue is immersed in cold buffered solution such as PBS, Hams F12, MEM, culture medium, etc. (interpreting tissue as a cell sample; obtained by any method including surgically, biopsy, needle, etc.; and Hams F12 and culture medium is interpreted to include serum-free cell culture medium, claims 1, 36 and 38) (paragraph [0074], lines 1-5). Nadauld teaches that the container is placed into an outer container containing a suitable medium, such as HAMs F-12 medium supplemented with fetal calf-serum (FCS) at a concentration of about 1 to about 25% (interpreted as comprising serum-free medium, claim 1) (paragraph [0074], lines 15-18), where HAMs F-12 is used for serum-free culture of CHO cells as evidenced by Pricella (pg. 1, product information). Nadauld teaches that the arrangement allows the tissue to grow in a gel with an air-liquid interface as shown in Figure 1A, using primary intestinal organoids, wherein an example of an air-liquid interface culture system is provided in Ootani et al. in Nat. Med, 2009, 15(6):701-6, and is incorporated in its entirety by reference (interpreted as culturing the cell sample in an air-liquid interface; and the sample comprises primary cells, claims 1 and 34) (paragraphs [0010; [0075]; and Figure 1A). Figure 1A is shown below:
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Figure 1A
Nadauld teaches that the term "gel substrate" has the conventional meaning of a semi-solid extracellular matrix and includes without limitations, collagen gel, Matrigel, extracellular matrix proteins, fibronectin, collagen in various combinations with one or more of laminin, entactin (nidogen), fibronectin, and heparin sulfate; human placental extracellular matrix (interpreted to form a thin, porous membrane, claim 1) (paragraph [0029]), wherein it is known that Matrigel is an extracellular matrix that can be coated onto microporous membranes having a pore size of 0.5-30 microns for the in vitro growth of as evidenced Myles (col 1, lines 64-66; col 2, lines 62-64; and col 6, lines 13-15). Nadauld teaches that candidate agents are screened for biological activity by adding the agent to at least one and usually a plurality of explant or cell samples, usually in conjunction with explants not contacted with the agent, such that the change in parameters in response to the agent is measured, and the result evaluated by comparison to reference cultures, e.g. in the presence and absence of the agent, obtained with other agents, etc. (interpreted as cell samples; culturing the agent with the cell; assessing viability; including a first agent and a second agent; and measuring, claims 1 and 26) (paragraph [0098]). Nadauld teaches that the agents are conveniently added in solution, or readily soluble form, to the medium of cells in culture, wherein the agents can be added in a flow-through system, as a stream, intermittent or continuous, or added as a bolus of the compound, singly or incrementally, to an otherwise static solution, such that in a flow-through system, two fluids are used, where one is a physiologically neutral solution, and the other is the same solution with the test compound added, such that the first fluid is passed over the cells, followed by the second, where in a single solution method, a bolus of the test compound is added to the volume of medium surrounding the cells (interpreted as culturing the agents with the cells; adding a first agent; and then adding a second agent, claims 1 and 4) (paragraph [0099]). Nadauld teaches that a sample, such as a human tumor sample, can be taken from an individual; the sample can be cultured using the subject methods; the cultured sample can be contacted with the therapeutic agent, such as chemotherapy, antibody therapeutic, small molecule therapeutic; and the effect of the therapeutic agent on the sample can be determined by measuring one or more parameters, where an effect of the therapeutic agent on the sample is predictive of the effect that the therapeutic agent will have on the individual; and/or the explant van be a tissue from a healthy individual that is experimentally modified to model the disease by, e.g., genetic mutation, such as determining the responsiveness of an individual to therapy should that individual develop a disease, where parameters such as explant growth, cell proliferation, cell viability, cell ultrastructure, tissue ultrastructure, etc. find particular use as output parameters in such screens (interpreted as assessing cell viability; measuring; and tumor sample, claims 1, 34, 36 and 42) (paragraph [0110]). Nadauld teaches that trans-well inserts are wells with permeable supports, e.g. microporous membranes, that are designed to fit inside the wells of a multi-well tissue culture dish (interpreted to form a thin, porous membrane, claim 1) (paragraph [0120], lines 14-17). Nadauld teaches in Example 1, the general methodology for preparing air-liquid interface cultures including using cell culture inserts placed into secondary outer dishes containing medium such as HAMs F-12 with 20% FCS, wherein medium is changed every 7 days, such that organoids can be prepared and maintained for a year or more; and mammalian tissue is removed and the tissue and immediately immersed in ice-cold PBS or other culture media/tissue preservative solution such as Hams F12 medium without serum, the tissue is washed, and minced; the cell-containing collagen gel is poured onto the inner dish, which is placed in the outer dish; and after solidifying the cell-containing gel, the culture media is poured into the outer dish (interpreted as air-liquid interface culture; and serum-free media, claim 1) (paragraphs [0132]-[0137]; Example 1), where it is known that Ham’s F-12 is a liquid media as evidenced by Capricorn Scientific (pg. 2, Description). Nadauld teaches that candidate agents of interest for screening include known and unknown compounds that encompass numerous chemical classes, primarily organic molecules, which can include organometallic molecules, inorganic molecules, genetic sequences, etc. including to evaluate candidate drugs, including toxicity testing (interpreted as assaying candidate molecules; and assessing viability, claim 1) (paragraph [0086]). Nadauld teaches that the term "contacting" refers to the placing of candidate or candidate agents into the explant culture as described herein, wherein contacting also encompasses co-culture of candidate cells with tissue explants for at least 1 hour, or more than 2 hrs or more than 4 hrs in culture medium (interpreted as encompassing at least 1 day, more than 1 day, claims 1, 4 and 5) (paragraph [0048]). Nadauld teaches that a primary organoid can be cultured directly from tissue fragments; and in vitro validation of putative cancer drivers from TCGA and similar genome-scale surveys ideally utilize primary cells (interpreted as primary tumor cell sample, claim 34) (paragraphs [0121]; and [0126], lines 1-5). Nadauld teaches that tissue can be obtained by any convenient method, such as by biopsy, during endoscopy, during surgery, by needle, etc., and is typically obtained as aseptically as possible; and upon removal, the tissue is immersed in cold buffered solution such as PBS, Hams F12, MEM, culture medium, etc. (interpreting tissue as a cell sample; obtained by any method including surgically, biopsy, needle, etc.; and Hams F12 and culture medium is interpreted to include serum-free cell culture medium, claims 1, 36 and 38) (paragraph [0074], lines 1-5). Nadauld teaches that the tissue-containing gel substrate is allowed to solidify, and the container is placed into an outer container containing a suitable medium (interpreted as encompassing a serum-free medium, claim 1) (paragraph [0074], lines 10-16).
Regarding claim 26, Nadauld teaches that the explant cells can be modified by altering patterns of gene expression, such as by providing reprogramming factors to induce pluripotency or otherwise alter differentiation potential, or to determine the effect of a gain or loss of gene activity on the ability of cells to form an explant culture or on the ability of cells to undergo tumor transformation, wherein the explant cells can be modified such that they are transformed into proto-oncogenic or oncogenic cells, e.g. by providing cancer drivers-oncogenic factors or inhibitors of tumor suppressor genes, such as nucleic acids for the overexpression of KrasG12 genes, nucleic acids that suppress expression of APC, p53, or Smad4, etc.- for example, to assess the effects of the therapeutic agents on tumors (interpreted as measuring a metabolic product, claim 26) (paragraph [0080]).
Regarding claims 41 and 42, Nadauld teaches that candidate agents including antibodies, polypeptides, and biomolecules can be obtained from a wide variety of sources including libraries of synthetic or natural compounds, wherein known pharmacological agents can be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce structural analogs (interpreted as candidate molecules; encompassing biological and chemical molecules; and antibodies, claims 1, 41 and 42) (paragraphs [0091]; and [0096]-[0097]). Nadauld teaches screens for agents with anti-tumorigenic or anti-tumoral activity, wherein a candidate agent is screened for activity that is anti-tumorigenic (i.e. inhibiting cancer initiation) or anti-tumoral (i.e. inhibiting cancer progression, such as proliferation, invasion, metastasis), where the explant culture includes cancer cells, including cells suspected of being cancer stem cells, such that assessment of anti-tumor activity can include measurements of one or more parameters including explant growth, the rate or extent of cell proliferation, the rate or extent of cell death, etc. (interpreted as assessing viability; and measuring, claim 1) (paragraphs [0104]-[0105]). Nadauld teaches that a sample, such as a human tumor sample, can be taken from an individual; the sample may be cultured using the subject methods; the cultured sample can be contacted with the therapeutic agent, such as chemotherapy, antibody therapeutic, small molecule therapeutic; and the effect of the therapeutic agent on the sample can be determined by measuring one or more parameters, where an effect of the therapeutic agent on the sample is predictive of the effect that the therapeutic agent will have on the individual; and/or the explant van be a tissue from a healthy individual that is experimentally modified to model the disease by, e.g., genetic mutation, such as determining the responsiveness of an individual to therapy should that individual develop a disease, where parameters such as explant growth, cell proliferation, cell viability, cell ultrastructure, tissue ultrastructure, etc. find particular use as output parameters in such screens (interpreted as assessing cell viability; measuring; and tumor sample, claims 1, 34, 36 and 42) (paragraph [0110]).
Nadauld does not specifically exemplify the metabolic products recited in claims 27 and 32 (claims 27 and 32).
Nadauld meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Response to Arguments
Applicant’s arguments filed February 24, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Nadauld does not teach any structure other than a gel matrix, and definitely does not disclose a “thin, porous membrane” for cell culture as recited in amended claim 1 (Applicant Remarks, pg. 7, first and second full paragraphs); and (b) in paragraph [0138] Nadauld teaches that Ham’s F12 is supplemented with 20% fetal calf serum and gentamicin; and the limitation “serum-free, liquid cell culture medium” is a negative limitation (Applicant Remarks, pg. 7, last full paragraph through pg. 8, second full paragraph.)
Regarding (a), although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed.
Cir. 1993). Moreover, MPEP 2112.01(I) indicates that,
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) (underline added).
MPEP 2123(I) states:
"The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. See In re Heck, 699 F.2d 1331, 1332-33,216 USPQ 1038, 1039 (Fed. Cir. 1983); In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275,277 (CCPA 1968); Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); and Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (underline added).
Applicant’s assertion that Nadauld does not teach any structure other than a gel matrix, and definitely does not disclose a “thin, porous membrane” for cell culture as recited in amended claim 1, is not found persuasive. As an initial matter, instant claim 1, the instant as-filed Specification (filed September 16, 2021), and original claims do not define the term “thin, porous membrane;” and the instant claims do not recite any specific “thin, porous membrane.” Applicant is reminded that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. As noted supra, the Examiner has interpreted the term “thin” to refer to a porous membrane having any width. The Examiner asserts that Nadauld teaches all of the limitations of claim 1, for example:
Nadauld teaches:
An "air-liquid interface" is the interface to which the intestinal cells are exposed to in the cultures described herein, wherein the primary tissue can be mixed with a gel solution which is then poured over a layer of gel formed in a container with a lower semi-permeable support, e.g. a membrane (interpreting the membrane as a thin, porous membrane; and as culturing the cell sample at the air-liquid interface, claim 1) (paragraph [0030]).
The term "gel substrate" has the conventional meaning of a semi-solid extracellular matrix and includes without limitations, collagen gel, Matrigel, extracellular matrix proteins, fibronectin, collagen in various combinations with one or more of laminin, entactin (nidogen), fibronectin, and heparin sulfate; human placental extracellular matrix (interpreted to form a thin, porous membrane, claim 1) (paragraph [0029]).
wherein it is known that Matrigel is an extracellular matrix that can be coated onto microporous membranes having a pore size of 0.5-30 microns for the in vitro growth of as evidenced Myles.
Tissue is grown in a gel with an air-liquid interface as shown in Figure 1A (interpreted as culturing the cell sample on a thin, porous membrane at the air-liquid interface, claim 1) (paragraph [0075]).
Trans-well inserts are wells with permeable supports, e.g. microporous membranes, that are designed to fit inside the wells of a multi-well tissue culture dish (interpreted as culturing the cell sample on a thin, porous membrane at the air-liquid interface, claim 1) (paragraph [0120], lines 14-17).
Thus, the rejection is maintained.
Regarding (b), Applicant’s assertion that Nadauld teaches that Ham’s F12 is supplemented with 20% fetal calf serum and gentamicin, which is inconsistent with claim 1; and the limitation “serum-free, liquid cell culture medium” is a negative limitation, is not found persuasive.
MPEP 211.03(I) states:
The transitional term “comprising,” which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) ("[L]ike the term ’comprising,’ ‘the terms ‘containing’ and ‘mixture’ are open-ended."). Invitrogen Corp. v. Biocrest Manufacturing, L.P., 327 F.3d 1364, 1368, 66 USPQ2d 1631, 1634 (Fed. Cir. 2003) ("The transition ’comprising’ in a method claim indicates that the claim is open-ended and allows for additional steps."); Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997) (“comprising” is a term of art used in claim language which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim); Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261, 229 USPQ 805 (Fed. Cir. 1986); In re Baxter, 656 F.2d 679, 686, 210 USPQ 795, 803 (CCPA 1981); Ex parte Davis, 80 USPQ 448, 450 (Bd. App. 1948) (“comprising” leaves "the claim open for the inclusion of unspecified ingredients even in major amounts"). In Gillette Co. v. Energizer Holdings Inc., 405 F.3d 1367, 1371-73, 74 USPQ2d 1586, 1589-91 (Fed. Cir. 2005) (underline added).
Thus, instant claim 1 uses the term “comprising”, which is open-ended and does not exclude additional, unrecited elements or method steps, including serum-free, liquid cell culture medium supplemented with fetal calf serum, antibiotics, nutrients, etc. Additionally,
Nadauld teaches:
That upon removal, tissue is immersed in buffered solution, such as Ham’s F12, MEM, culture medium, etc. (interpreted as serum-free, liquid culture medium, claim 1) (paragraph [0074]).
The tissue-containing gel substrate is allowed to solidify, and the container is placed into an outer container containing a suitable medium including HAMs F-12 medium supplemented with fetal calf serum (FCS) from about 1 to about 25% (interpreted as encompassing a serum-free medium, claim 1) (paragraph [0074]).
Tissue immersion in culture media/tissue preservative solution such as Ham’s F12 without serum (paragraph [0135]).
Nadauld clearly teaches Ham’s F12, a serum-free cell culture medium. The Examiner suggests that if Applicant wishes to exclude media supplemented with serum, that Applicant consider using the transitional phrase “consisting of” in the place of “comprising.” Nadauld teaches all of the limitations of claim 1. Thus, the rejection is maintained.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 4, 5, 7, 26, 27, 32, 41 and 42 is maintained under 35 U.S.C. 103 as being unpatentable over Skardal et al. (hereinafter “Skardal”) (US Patent Application Publication 20210324311, published October 21, 2021; also as WO2018/071354, published April 19, 2018; effective filing date October 14, 2016) in view of Stern et. al. (hereinafter “Stern”) (US Patent No. 12203124, issued January 21, 2025; also published as WO2018119434, published June 28, 2018) as evidenced by Alarcon et al. (hereinafter “Alarcon”) (US Patent Application Publication No. 20160186266, published June 30, 2016); and Riss et. al. (hereinafter “Riss”) (National Institutes of Health, US National Library of Medicine, The Assay Guidance Manuel, 2016, 1-25).
Regarding claim 1, Skardal teaches a multi-tissue body-on-a-chip apparatus having at least a first, second, and third chamber in fluid communication with one another and with at least one tissue in each chamber such as, for example, a liver tissue in the first chamber; cardiac tissue in the second chamber; and lung tissue in the third chamber; and common aqueous growth media in each chamber, wherein additional chambers can include different additional tissues such as testicular or ovarian tissue, vascular endothelial, skeletal muscle, kidney, nerve, brain, and intestinal tissue (interpreting aqueous growth media as a liquid; and an intact tissue sample, claim 1) (Abstract). Skardal teaches detecting a pharmacological or toxicological response to the test compound in at least one, or a plurality of tissues present in the apparatus (interpreted as an intact tissue sample contacted with a candidate molecule, claim 1) (paragraph [0008]). Skardal teaches in Figure 15, the generation of layered 3D lung organoids with a polarized epithelial surface exposed to the air-liquid interface, and an endothelium forming a thin vascular barrier exposed to liquid media, wherein the layered organoids can be maintained in culture for over 4 weeks (interpreted as an ALI; culturing over 4 weeks as culturing continuously for at least two days; liquid medium; and cell viability, claims 1 and 5) (paragraph [0025], lines 1-12; and Figure 15). Skardal teaches screening at least one test compound for physiological activity and/or toxicity by: (a) providing an apparatus of the present invention; (b) optionally circulating a growth medium (e.g., the common aqueous growth medium) from a first chamber to a second chamber; (c) administering at least one test compound to the tissue constructs in the apparatus (e.g., by adding the test compound to the growth medium); and (d) detecting a pharmacological and/or toxicological response to the at least one test compound (interpreted as SF medium; administering a first and/or second candidate molecule; and assessing viability resulting from contact with the candidate molecule, claim 1) (paragraphs [0112]-[0116]). Skardal teaches in Figure 18, a viability assessment of cardiac organoids in response to rofecoxib and valdecoxib drug screens, wherein green represents calcein AM-stained viable cells; and red represents ethidium homodimer-stained dead cells (interpreted as assessing a viability response resulting from contact with the candidate molecule, claim 7) (paragraph [0028]; and Figure 18). Skardal teaches that the term "growth media" as used herein can be any natural or artificial growth media (typically an aqueous liquid) that sustains the cells used in carrying out the present invention including, but not limited to, an essential media or minimal essential media (MEM), or variations thereof such as Eagle's minimal essential medium (EMEM) and Dulbecco's modified Eagle medium (DMEM) (interpreting any growth media as encompassing a liquid, serum-free medium, claim 1) (paragraph [0050], lines 1-7). Skardal teaches that Figure 1D illustrates cell culturing endothelium or fibroblast epithelium on a porous membrane (Figure 1D). Figure 1D is shown below:
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Skardal teaches that Figure 3I shows endothelial cells on top of a porous membrane (Figure 3I). Figure 3I is shown below:
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Skardal teaches that common aqueous growth media can comprise a serum-free endothelial cell media and/or testicular cell media including a 1:1 mix of serum-free endothelial cell media and testicular cell media (interpreting SF endothelial cell media and testicular cell media as serum-free media, claim 1) (paragraphs [0084], lines 3-5; and [0135], lines 6-8). Skardal teaches that at least one test compound comprises at least two distinct test compounds that are administered concurrently with one another (interpreted as administering a candidate molecule, claim 1) (paragraph [0117]). Skardal teaches that organoids of the present invention can comprise and/or be prepared using high functioning cells, such as, but not limited to, primary cells and/or stem cells, e.g., induced pluripotent stems and/or differentiated iPS-derived cells (interpreted as encompassing a patient primary tumor sample, claim 34) (paragraph [0057], lines 3-7). Skardal teaches that cells are tumor cells, such as, e.g., patient biopsy-derived tumor cells, and organoids prepared from such cells can be used to screen potentially effective drugs and/or treatments (interpreted as patient biopsy sample encompassing a needle biopsy, claim 36) (paragraph [0057], lines 3-7), where it is known in the art that biopsy techniques include a needle biopsy such as “core-needle biopsy” of a tumor mass, or a “fine-needle biopsy,” which generally obtains a suspension of cells from within the tumor mass as evidenced by Alarcon (paragraph [0111], lines 10-12 and 17-19). Skardal teaches n apparatus comprises at least six chambers with each chamber comprising one of six different tissues, such as, for example, a liver tissue, a heart tissue, a brain tissue, a lung tissue, a vasculature tissue, or either a testes tissue or an ovary tissue (interpreted as encompassing intact tissue, claim 1) (paragraph [0083]). Skardal teaches that vascular modules are formed by culturing endothelial cells on one side of a semi-porous silicon membrane, wherein the planar construct is fitted in a micro-reactor device (interpreted as culturing on a thin, porous membrane, claim 1) (paragraph [0193]).
Regarding claim 4, Skardal teaches that isoproterenol and quinidine are used separately below as test compounds to examine them independently, while propranolol and epinephrine are administered concurrently or in combination with one another as test compounds to examine the interaction there between (interpreted as administering an additional candidate molecule for at least 24 hours, claim 4) (paragraph [0051], lines 5-10).
Regarding claim 5, Skardal teaches in Figure 2 that viability was shown to be relatively high at both days 7 and 14 as visualized by LIVE/DEAD staining and imaging by macro-confocal microscopy (Fig. 2, panels A-B) (interpreted as culturing for at least 2 days; and assessing viability resulting from contact with the additional candidate molecule, claim 5) (paragraph [0135], lines 8-11; and Figure 2).
Regarding claim 7, Skardal teaches in Figure 18, a viability assessment of cardiac organoids in response to rofecoxib and valdecoxib drug screens, wherein green represents calcein AM-stained viable cells; and red represents ethidium homodimer-stained dead cells (interpreted as assessing a viability response resulting from contact with the candidate molecule, claim 7) (paragraph [0028]; and Figure 18).
Regarding claim 26, Skardal teaches in Figure 16, the generation of 3D testis organoids and drug toxicity testing, wherein Panel (D) shows drug effect on human testicular cells; and cells (2D culture in upper panel versus 3D organoids in lower panel) exposed to drugs for 48 hours prior to determination of ATP content via CellTiter-Glo Luminescent Cell Viability assays (interpreting ATP as a metabolic product resulting from contact with the candidate molecule, claim 26) (paragraph [0026], lines 1-2 and 11-15; and Figure 16).
Regarding claims 41 and 42, Skardal teaches that the term “test compound" or "candidate compound" as used herein can be any compound for which a pharmacological or physiological activity, on cardiac tissue and/or other tissue, or an interaction between two test compounds, is to be determined, wherein any compound can be used, typically organic compounds such as proteins, peptides, nucleic acids, and small organic compounds (aliphatic, aromatic, and mixed aliphatic/aromatic compounds) can be used (interpreting the test compound as a candidate molecule; biological or chemical molecule; and including a peptide, claims 41 and 42) (paragraph [0051], lines 1-5 and 11-15).
Although Skardal does not specifically teach a core-needle biopsy, Skardal does teach that cells can be obtained from a subject, wherein cells are tumor cells, and that organoids are prepared from tumor cells such as patient biopsy-derived tumor cells, where it is known in the art that biopsy techniques can include needle biopsy such as core-needle biopsy as evidenced by Alarcon, such that one of ordinary skill in the art would at the time the invention was made would clearly recognize that a variety of biopsy techniques can be used to obtain a cell sample from a patient including a core-needle biopsy.
Skardal does not specifically exemplify a product derived from resazurin, resorufin, a tetrazole and a formazan (claim 27); wherein the tetrazole is MTT, XTT, or MTS (claim 32).
Regarding claims 27 and 32, Stern teaches improved antimicrobial susceptibility testing for rapid antimicrobial susceptibility testing of clinical samples for efficient and versatile analysis and reliable results (Abstract). Stern teaches a method of determining antimicrobial susceptibility of one or more microorganisms, where the method comprises performing a growth assay comprising: incubating a suspension of a microorganism in the presence of one or more antimicrobials without a metabolic probe present; introducing a metabolic probe in an aqueous-miscible solvent after the incubation of the one or more microorganisms; and determining antimicrobial susceptibility of the one or more microorganisms based on relative microorganism growth (col 3, lines 12-22). Stern teaches that exemplary biological samples can include, but are not limited to, whole blood, organs and tissues including but not limited to, liver, spleen, kidney, lung, intestine, brain, heart, muscle, pancreas, and the like (interpreted as encompassing intact tissue, claim 1) (col 49, lines 58-67; and col 50, lines 1-2). Stern teaches that the methods described herein use the commercially available alamarBlue indicator dye as the metabolic probe that comprises resazurin, where resazurin can undergo a reduction reaction in metabolically active cells, where the resazurin is converted to resorufin, a fluorescent molecule, via reduction reactions of metabolically active cells (interpreted as a metabolic product; a reduction; and resorufin and resazurin, claim 27) (col 27, lines 35-41). Stern teaches that the metabolic probe is a redox active probe such as 7-hydroxy-10-oxidophenoxazin-10-ium-3-one (resazurin), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT); 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl )-2-(4-sulfopheny l)-2H-tetrazolium (MTS); and 2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt (XTT) (interpreted as tetrazoles, resazurin, etc.; and MTT, MTS and XTT, claims 27 and 32) (col 6, lines 62-67; and col 7, lines 1-2 and 28-30), where it is known that the MTT assay, MTS assay and XTT assay are cell viability assays suitable for high-throughput screening, wherein viable cells with active metabolism convert MTT into a purple formazan product (and the number of viable cells) is measured by as evidenced by Riss (pg. 2, first and second full paragraphs). Stern teaches that Figures 21-24 depict AST results when tetrazolium analogues (INT, WST-1, WST-3, and WST-8) were utilized as metabolic probes for determining the antimicrobial susceptibility of various antibiotics on Pseudomonas aeruginosa (col 13, lines 39-42). Stern teaches that the invention provides for performing a metabolic probe assay and a surface-binding probe assay in order to enable accurate rapid determination of a microorganism's susceptibility to an antimicrobial in less than 3, 4, 5, 6, 7 or 8 hours as compared to the Clinical Laboratory Standards Institute overnight reference method (col 19, lines 41-47).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of rapidly determining the susceptibility of microbial cells to antibiotic treatment as exemplified by Stern, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of using LIVE/DEAD stains for assessing the viability of organ-specific tissues in the 3D organoid cultures placed within different chambers of the apparatus as disclosed by Skardal to include the method of assessing the effectiveness of different antimicrobials on the growth of microorganisms using redox active probes such as resazurin, MTT, MTS, XTT, etc. as taught by Stern with a reasonable expectation of success in creating a high-throughput method for assessing the growth and/or viability of the different tissue models when screened against different drugs and/or test compounds; and/or in rapidly determining the extent to which specific organoid cultures are susceptible to, and/or have toxic responses to, the administration of one or more test compounds such as drugs, drug candidates, chemical compounds, biological agents, chemical agents, etc.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103(a) as obvious over the art.
Response to Arguments
Applicant’s arguments filed February 24, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Skardal does not teach the use of intact tissue with its apparatus (Applicant Remarks, pg. 9, first and second full paragraphs); and (b) Skardal does not teach culturing the cell sample on a thin, porous membrane (Applicant Remarks, pg. 9, first full paragraph).
Regarding (a), it is noted that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant’s assertion that Skardal does not teach the use of intact tissue with its apparatus, is not found persuasive. With regard to claim 27, please see the 35 USC 112(b) and 35 USC 112(d) rejections. Instant claim 27 is completely unclear. Moreover, claim 27 is a dependent claim. Additionally, Applicant is respectfully reminded that the instant rejection is based on the combination of Skardal and Stern. The Examiner asserts that both Skardal and Stern teach a cell sample comprising intact tissue. To that end -
Skardal teaches:
Multi-tissue body-on-a-chip apparatus, wherein the apparatus including at least a first, second, and third chamber in fluid communication with one another and with at least one tissue in each chamber including liver tissue, cardiac tissue, and lung tissue (interpreted as encompassing intact tissue, claim 1) (Abstract; and paragraph [0007]).
Detecting a pharmacological or toxicological response to the test compound in at least one, or a plurality of tissues present in the apparatus (interpreted as an intact tissue sample contacted with a candidate molecule, claim 1) (paragraph [0008]).
An apparatus comprises at least six chambers with each chamber comprising one of six different tissues, such as, for example, a liver tissue, a heart tissue, a brain tissue, a lung tissue, a vasculature tissue, or either a testes tissue or an ovary tissue (interpreted as encompassing intact tissue, claim 1) (paragraph [0083]).
Patient biopsy-derived tumor cells (interpreted as encompassing intact tissue, claim 1) (paragraph [0056]).
Histological/molecular response characterization can be performed (interpreted as encompassing intact tissue, claim 1) (paragraph [0221]).
Stern teaches:
Exemplary biological samples can include, but are not limited to, whole blood, organs and tissues including but not limited to, liver, spleen, kidney, lung, intestine, brain, heart, muscle, pancreas, and the like (interpreted as encompassing intact tissue, claim 1) (col 49, lines 58-67; and col 50, lines 1-2).
The combined references teach all of the limitations of the claims. Thus, the rejection is maintained.
Regarding (b), Applicant’s assertion that Skardal does not teach culturing the cell sample on a thin, porous membrane, is not found persuasive. The Examiner contends that Skardal does teach culturing a cell sample on a thin, porous membrane. To that end-
Skardal teaches:
Vascular modules are formed by culturing endothelial cells on one side of a semi-porous silicon membrane, wherein the planar construct is fitted in a micro-reactor device (interpreted as culturing on a thin, porous membrane, claim 1) (paragraph [0193]).
Figure 1D illustrates cell culturing endothelium or fibroblast epithelium on a porous membrane
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Figure 3I shows endothelial cells on top of a porous membrane (Figure 3I). Figure 3I is shown below:
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Stern teaches:
Filters having pores smaller than or equal to 0.45 microns (interpreted as porous filters) (col 30, lines 20-22).
A microbial culture cartridge (col 17, lines 24-25).
The combined references teach all of the limitations of the claims. Thus, the rejection is maintained.
Conclusion
Claims 1, 4, 5, 7, 26, 27, 32, 41 and 42 are rejected.
THIS ACTION IS MADE FINAL. 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.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684