DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment filed November 20, 2025, has been received and entered.
Claims 3, 4, 6, 7, 9, 10, 12, 13, 16, 18, 19, 21, 23, 24, 27, 28, 30, 32-35, 38, 39, and 42-44 are canceled.
Claims 1, 2, 5, 8, 11, 14, 15, 17, 20, 22, 25, 26, 29, 31, 36, 37, 40, and 41 are pending.
Claims 29, 31, 36, 37, 40, and 41 are withdrawn.
Claims 1, 2, 5, 8, 11, 14, 15, 17, 20, 22, 25, and 26 are examined on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 5, 8, 11, 14, 15, 17, 20, 22, 25, and 26 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 is rendered indefinite by the recitation “(in-vivo)” in line 6. It is unclear how this recitation in parentheses modifies the recitation “wherein said solid tissue or SOL is within a body of the subject.” The term “in vivo” has a definition of “within a living body,” so it is unclear how it modifies the limitation regarding the solid tissue or SOL being within a body of the subject, particularly because of the use of the parentheses around the term. For the purpose of applying prior art, step (i) is being interpreted as being carried out in-vivo. Since claim 1 is indefinite, then its dependent claims, claims 2, 5, 8, 11, 14, 15, 17, 20, 22, 25, and 26, are rendered indefinite. Thus, claims 1, 2, 5, 8, 11, 14, 15, 17, 20, 22, 25, and 26 are rejected under 35 U.S.C. 112(b).
Claim 2 is indefinite because it is unclear how step (iii) is extracting the at least one cellular-component into at least one of the at least one electroporation-electrode, since parent claim 1 recites that this extraction is “via an extraction element dedicated to a molecular collection.” It is unclear whether claim 2 is requiring that (a) the “extraction element dedicated to a molecular collection” is “at least one of said at least one electroporation-electrode,” or (b) extracting the at least one cellular-component into both the “extraction element dedicated to a molecular collection” and the “at least one of said at least one electroporation-electrode.” If it is the former interpretation (option (a)), then it is confusing how the extraction element can be ate least one of the at least one electroporation-electrode because electroporation-electrodes are not “dedicated to a molecular collection” (as recited for the extraction element in claim 1) as electroporation-electrodes are also used for applying a pulsed electric field (that is, an electroporation-electrode is not dedicated to a molecular collection since it is also used for another purpose).
Claim 15 is indefinite because it is unclear how the extraction in step (iii) is by suction via at least one hollow electroporation-electrode, since parent claim 1 recites that this extraction is “via an extraction element dedicated to a molecular collection.” It is unclear whether claim 15 is requiring that (a) the “extraction element dedicated to a molecular collection” is at least one hollow electroporation-electrode, or (b) extracting the at least one cellular-component via both the “extraction element dedicated to a molecular collection” and the at least one hollow electroporation-electrode. If it is the former interpretation (option (a)), then it is confusing how the extraction element can be at least one hollow electroporation-electrode because electroporation-electrodes are not “dedicated to a molecular collection” (as recited for the extraction element in claim 1) as electroporation-electrodes are also used for applying a pulsed electric field, and claim 15 also requires inserting at least one liquid into the solid tissue, or into the SOL or in proximity thereto, via the at least one hollow electroporation-electrode, and also suctioning that least one liquid via the at least one hollow electroporation-electrode (that is, the at least one hollow electroporation-electrode is not dedicated to molecular collection since it is used for other purposes). Since claim 15 is indefinite, then its dependent claim, claim 17, is rendered indefinite. Therefore, claims 15 and 17 are rejected under 35 U.S.C. 112(b).
Claim 20 is indefinite because it is unclear how the extraction in step (iii) is by suction via the cannula of the at least one electroporation-electrode, since parent claim 1 recites that this extraction is “via an extraction element dedicated to a molecular collection.” It is unclear whether claim 20 is requiring that (a) the “extraction element dedicated to a molecular collection” is the retentive cannula of the at least one electroporation-electrode, or (b) extracting the at least one cellular-component via both the “extraction element dedicated to a molecular collection” and the cannula of the at least one hollow electroporation-electrode. If it is the former interpretation (option (a)), then it is confusing how the extraction element can be the retentive cannula of at least one hollow electroporation-electrode because electroporation-electrodes (thus their cannula) are not “dedicated to a molecular collection” (as recited for the extraction element in claim 1) as electroporation-electrodes are also used for applying a pulsed electric field, and claim 20 also requires inserting at least one liquid into the solid tissue, or into the SOL or in proximity thereto, via the cannula of the at least one electroporation-electrode, and also suctioning that least one liquid via the cannula of the at least one electroporation-electrode (that is, the cannula of at least one electroporation-electrode is not dedicated to molecular collection since it is used for other purposes). Since claim 20 is indefinite, then its dependent claim, claim 22, is rendered indefinite. Therefore, claims 20 and 22 are rejected under 35 U.S.C. 112(b).
Claim 25 is rendered indefinite by the recitation “the at least one cellular-component released to the extracellular matrix is analyzed or identified in step (iv) outside the body of the subject after releasing said at least one cellular-component therefrom” in the last three lines of the claim. Because of order of the word “therefrom” in relation to “the body of the subject” in the recitation, the recitation in the last line of the claim sets forth releasing at least one cellular-component from the body of the subject. However, this lacks antecedent basis since parent claim 1 recites releasing at least one cellular-component from the solid tissue or SOL (see step (ii)), as opposed to releasing at least one cellular-component from the body of the subject. It is noted that claim 25 does not require that the at least one cellular-component is reversibly adsorbed, associated with, and/or linked to the adhesive material of the solid rod of the at least one electroporation-electrode – the recited capability of the adhesive material does not signify that the reversible association/linking is performed.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 5, 8, 11, 14, 15, 17, 20, 22, 25, and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The limitation in claim 1 of “an extraction element dedicated to a molecular collection” is not supported by the specification as filed. The specification discloses an extraction element, but does not disclose an extraction element that is dedicated to a molecular collection. In particular, the specification discloses a “cellular-components extraction-element” (paragraph [011]), without stating that the extraction element is dedicated to a “molecular collection.” Though the specification teaches molecular harvesting in paragraph [112], that same paragraph teaches that tissue liquid is extracted with a needle, wherein the needle is an electroporation-electrode-needle. Therefore, the extraction element of paragraph [112], a needle, is not dedicated to a molecular collection since it has other purposes (electroporation, extracting tissue liquid which comprises other materials in addition to molecules).
While Applicant was in possession of a portion of the claimed invention, the full scope of the claimed invention, specifically an extraction element dedicated to a molecular collection, is not fully described in the specification. As such, Applicant was not in possession of the full scope of the claimed invention at the time of filing. Because the specification as filed fails to provide clear support for the new claim language, a new matter rejection is clearly proper.
Notice Re: Prior Art Available Under Both Pre-AIA and AIA
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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5, 8, 11, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Onik (US 2016/0367310. Previously cited) in view of Franzen (Molecular Oncology. 2018. 12: 1415-1428. Available online August 9, 2018. Previously cited).
Onik discloses a method of non-thermally ablating undesirable soft tissue in the body of a subject, such as cancerous tumors and non-cancerous tissue, using pulsed electrical fields (abstract; paragraph [0059]; claim 1 of Onik). The undesirable soft tissue may or may not be malignant (paragraph [0048]). Thus, the undesirable soft tissue targeted by Onik can be a solid tissue of a subject comprising a tumor that is benign (i.e. not malignant) or malignant, meeting limitations of the claimed invention.
In the invention, electrical pulses are delivered to generate an appropriate electric field, and the electrical field is generated by therapeutic probes placed in proximity to the soft tissue or cancerous cells within the body of the subject (paragraph [0016]). Claim 1 of Onik refers to the probes as at least one electrode, and Onik discloses that typically from 1 to 6 needle type probe electrodes are used (paragraph [0048]). The probes, i.e. electrodes, of Onik are directed to ‘at least one electroporation-electrode’ as claimed since any electrode is suitable for electroporation. Additionally, Onik discloses that the electrodes are introduced into position in and around the treatment site (paragraphs [0018] and [0048]). With reference to Figure 9, Onik teaches that the therapeutic probes 20 (electrodes) are inserted directly into, or placed around the target tissue 11 (paragraph [0039]). Therefore, Onik discloses step (i) of instant claim 1 since Onik teaches placing at least one electroporation-electrode within a solid tissue (comprising a tumor which may or may not be malignant) or in proximity thereto, wherein said solid tissue or SOL is within a body of the subject. Since the probes are inserted into the tissue in a living subject (claim 1 of Onik), then the placement of the probes is in vivo, meeting the Examiner’s interpretation of step (i) of instant claim 1 (see rejection under 35 U.S.C. 112(b) of claim 1).
The method of Onik uses electrical pulses that cause immediate cellular membrane breakdown non-thermally so that sensitive tissue structures are spared and the intra-cellular and membrane proteins are spilled into the extracellular space without denaturing (paragraph [0013]). See also claim 1 of Onik, disclosing an electric field (generated by the at least one electrode) sufficient to cause electrical membrane breakdown of a plurality of cells of the soft tissue, causing immediate and simultaneous spillage of all intracellular components into an extracellular space. Since the membrane of the cells are broken down, then the cells are permeabilized. Also, the extracellular space inherently comprises the extracellular matrix. Therefore, the spillage of the intracellular components into the extracellular space is directed to the release of the intracellular components (directed to ‘at least one cellular-component’) to an extracellular matrix between and surrounding the ablated cells. As such, Onik discloses step (ii) of instant claim 1 since Onik teaches applying pulsed electric field (PEF) via the at least one electroporation-electrode to thereby induce permeabilization of cells of the solid tissue, and consequently release at least one cellular-component therefrom to an extracellular matrix between and surrounding said cells.
Onik differs from the claimed invention in that Onik does not discloses a method for determining if a solid tissue of a subject comprises a benign or malignant tumor, or if a space occupying lesion (SOL) within said solid tissue is malignant or benign, nor does Onik disclose step (iii) of extracting the at least one cellular-component from the extracellular matrix via an extraction element dedicated to a molecular collection, and step (iv) of identifying or analyzing the at least one cellular-component extracted so as to identify or determine the presence and type of the tumor within the solid tissue or determine if the SOL is malignant or benign.
However, Onik discloses that their method may include the biopsy of a portion of the treated target tissue to verify treatment efficacy immediately after completion of the treatment while the patient is still in position for additional treatment (paragraph [0053]). Alternatively, because the intracellular environment comprises a unique chemical composition, spillage of the cell contents can be detected by methods such as placing one or more needle probes into critical locations of the treatment area to measure chemical levels using chemical reagents, electrical impedance or resistance measurements, pH measurements, spectroscopy, or the like (paragraph [0054]). Needle probes that are outfitted with one or more sensors have the added benefit of allowing the treatment provider to observe and quantify the level of target cell destruction (paragraph [0055]). Measurement techniques for cellular contents are not limited to those described in Onik, but may be carried out by any means known in the art of measuring chemical compositions of a targeted treatment area in vivo and/or in real time (paragraph [0056]).
Franzen discusses fine-needle aspiration (FNA) biopsy for providing ready access to relevant tissues (abstract). FNA sampling is a well-established cancer diagnostic procedure, wherein tissue fragments and/or fluid may be recovered from tumor tissue via puncture using a thin-gauge needle (page 1416, left column, second paragraph). The minimally traumatic FNA is often used for diagnosis of small nonpalpable, deeply located, or otherwise hard-to-reach lesion, both for primary tumors and for metastases (page 1416, left column, second paragraph). Also, FNA samples have proven useful for mRNA profiling via RT-PCR to strengthen the diagnosis (page 1416, left column, third paragraph).
Franzen discloses a study which explored molecular profiling of FNA samples, primarily at the protein level but also via RNA (page 1416, left column, second-to-last paragraph). Two different technology platforms were selected for analysis of FNA cell lysates from leftover FNA-needle material: protein profiling using proximity extension assays (PEA), mRNA expression profiling by NanoString (page 1416, left column, second-to-last paragraph through right column, second paragraph). FNA samples were taken from patients with mammography-detectable lesions (paragraph bridging pages 1416 and 1417), cells were collected (page 1417, left column, second paragraph), and cells were lysed (page 1417, left column, third paragraph). Protein profiling and mRNA profiling were performed on the samples (page 1417, right column, second paragraph through page 1418, left column, first paragraph). The study included protein-based modeling of cancer versus benign lesions (page 1423). The study summarized differences between cancer and benign lesions as protein signatures through multiple regression modeling (page 1423, left column). The algorithm identified an 11-protein signature that appears to completely discriminate benign samples from malignant lesions (page 1423, right column). Franzen concluded that their results show that PEA-based protein profiles in FNA samples may allow reliable distinction of cancer and benign lesions and thus provide support for a conclusive diagnosis, which would be very important for early diagnosis of breast cancer (BC) (page 1426, left column, second paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to obtain a biopsy of the spilled intracellular components in the extracellular space (directed to the claimed ‘extracting said at least one cellular-component from said extracellular matrix’ of step (iii)), and then perform protein profiling and/or mRNA profiling to diagnose cancer from the spilled intracellular components, including determining whether the tumor is benign or malignant in the case when the tumor is a mammography-detectable lesion suspected of being breast cancer, when performing the method of Onik. One of ordinary skill in the art would have been motivated to do this because the diagnosis of cancer is desirable in patients. There would have been a reasonable expectation of obtaining a biopsy of the spilled intracellular components because Onik discloses obtaining a biopsy of the treated target tissue and because biopsies such as fine-needle aspiration (FNA) biopsies are well-established cancer diagnostic procedures, as indicated in Franzen. Also, there would have been a reasonable expectation of diagnosing cancer from the intracellular components because proteins and mRNA obtained from tumor lysates had been successfully used for diagnosing cancer, including determining whether a mammography-detectable lesion is malignant or benign, as indicated in Franzen; the intracellular components of Onik inherently include proteins and RNA. In the invention rendered obvious by Onik in view of Franzen, protein profiling and/or mRNA profiling of the intracellular components is directed to ‘identifying/analyzing the at least one cellular-component extracted’ of step (iv) of instant claim 1, and the cancer diagnosis is directed to the claimed ‘identify/determine the presence and type of the tumor within said solid tissue’ of step (iv) of instant claim 1, wherein type of tumor is malignant or benign.
Furthermore, it would have been obvious to the person of ordinary skill in the art to use a tool such as a fine-needle (as in fine-needle aspiration biopsies taught in Franzen) in order to obtain the biopsy of the spilled intracellular components in the extracellular space since such a biopsy cannot be performed by hand and tools such as a fine-needle are recognized for biopsies. A tool such as fine-needle is directed to an ‘extraction element dedicated to a molecular collection’ of step (ii) of instant claim 1 because the biopsy sample of the spilled intracellular components comprises molecules.
Thus, Onik in view of Franzen renders obvious instant claim 1.
Regarding instant claim 5, the electric field of Onik inherently is characterized by pulse number, pulse duration, electric field strength, and pulse frequency. Moreover, Onik discloses that important characteristics of the applied electric field include the field strength, frequency, duration, and number (paragraph [0017]). Thus, the invention rendered obvious by Onik in view of Franzen meets the claimed limitation of ‘wherein said PEF is characterized by pulse number, pulse duration, electric field strength, and pulse frequency.’ Instant claim 5 also recites alternative embodiments (i)-(iv) (“or” is recited before the last embodiment “(iv)” in the last line). Onik discloses that it is preferred that a series of not less than 100 electric pulses in a pulse train is applied (paragraph [0017]). See also claim 8 of Onik. This range of pulse number overlaps the claimed range of ‘from 1 to about 10,000’ of (i) of instant claim 5, thereby rendering it obvious. Also, Onik discloses that the pulse duration is preferably from 100 to 1,000 µs (paragraph [0017]). 100 µs converts to 100,000 ns, and 1,000 µs converts to 0.001 second. Thus, the preferred pulse duration of Onik overlaps the claimed range of ‘from about 50 ns to about 1 s’ of (ii) of instant claim 5, thereby rendering it obvious. Additionally, Onik discloses that the electric field strength is preferably in the range of 1,500 V/cm to 10,000 V/cm (paragraph [0017]), i.e., 1.5 to 10 kV/cm. This range overlaps the claimed range of ‘from about 0.1 to about 100 kV/cm’ of (iii) of instant claim 5, thereby rendering it obvious. Since Onik in view of Franzen renders obvious embodiments (i)-(iii) of instant claim 5, then instant claim 5 is rendered obvious.
Regarding instant claim 8, the references do not expressly disclose repeating steps (ii) and (iii), and optionally step (iv), several times, each time at a different location within the solid tissue, without removing the electrode(s) (directed to the claimed ‘at least one electroporation-electrode’) therefrom, and wherein the intracellular components (directed to the claimed ‘at least one cellular-component’) that is released into the extracellular matrix at each location, is kept apart for separate analysis in step (iv). However, Onik discloses verifying treatment efficacy by biopsy of a portion of the treated target tissue, and additional treatment may be immediately administered based on the biopsy result and visual determination of treatment efficacy (paragraph [0053]). Based on this, it would have been obvious that the ablation of Onik may not include all portions of the entire tissue, including portions that are undesirable (e.g. malignant tumor). As such, it would have been prima facie obvious to the person of ordinary skill in the art to repeat steps (ii)-(iv) rendered obvious by Onik in view of Franzen to ensure that ablation of additional portions of the treated tissue, including the undesirable portions where ablation is desired, and also to ensure cancer diagnosis is made for all ablated portions of the treated tissue. Therefore, instant claim 8 is rendered obvious.
Regarding instant claim 11, as discussed above, Onik discloses that typically from 1 to 6 needle type probe electrodes are used (paragraph [0048]). Also, as shown in Figure 9 of Onik, one or more therapeutic probes 20 (electrodes) are inserted directly into, or placed around the target tissue 11 (paragraph [0039]). Thus, Onik in view of Franzen renders obvious using two electrodes (directed to two electroporation-electrodes) to generate the pulsed electric field between them. Since the electrodes are inserted directly into, or placed around the target tissue, then it would have been obvious to insert the electrodes (including the embodiment of two electrodes) in any of these locations. An electrode placed around the target tissue meets the claimed limitation of placement in proximity to the solid tissue. Also, since the electrodes are inserted directly into the target tissue (paragraph [0039] of Onik), then the references also meet the claimed limitation of positioning the other electrode in the body of the subject. Thus, the references render obvious (1) both electroporation-electrodes placed within said solid tissue, or in proximity thereto; and (2) one electroporation-electrode is placed within said solid electrode, or in proximity thereto, and the other electroporation-electrode is positioned in the body of said subject. As such, instant claim 11 is rendered obvious.
Regarding instant claim 26, the mRNA profiling disclosed in Franzen is via RT-PCR (page 1416, left column, third paragraph). Also, the protein profiling disclosed in Franzen uses a proximity extension assay (PEA) which is an immunoassay in which microfluidic qPCR is used to measure the amount of a target protein (page 1416, paragraph bridging left and right columns). Therefore, performing the protein profiling and/or mRNA profiling of the invention rendered obvious by Onik in view of Franzen is directed to analyzing or identifying the intracellular components (directed to the claimed ‘at least one cellular-component’) by PCR, and wherein the cancer diagnosis (directed to identifying or determining the presence and type of tumor) is according to at least one of the identified or analyzed intracellular components. Thus, instant claim 26 is rendered obvious.
Claim 14, 15, 17, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Onik and Franzen as applied to claims 1, 5, 8, 11, and 26 above, and further in view of Lax (US 5,486,161. Previously cited).
As discussed above, Onik in view of Franzen renders obvious claims 1, 5, 8, 11, and 26. Regarding claim 14, since the electrodes (directed to the claimed ‘at least one electroporation-electrode’) are inserted into the target tissue or in proximity to it (paragraphs [0018], [0039], and [0048] of Onik), then the electrodes penetrate into the target tissue, or in proximity thereto. Therefore, Onik in view of Franzen meets the limitation ‘wherein said at least one electroporation-electrode each independently is designed to enable penetration into said solid tissue…or in proximity thereto’ of claim 14. The references differ from claim 14 in that they do not expressly disclose that each electrode (directed to claimed ‘electroporation-electrode’) is: (i) a hollow tube; (ii) a solid rod engulfed in a retentive cannula; or (iii) a solid rod at least partially coated with an adhesive material capable of reversibly adsorbing, associating with, and/or linking at least one of the at least one cellular-component.
The references further differ from claim 15 in that they do not expressly disclose that the electrode(s) (the claimed ‘at least one electroporation-electrode’) is a hollow tube, and the intracellular components (directed to the claimed ‘at least one cellular-component’) released to the extracellular matrix are extracted in step (iii) by suction via the hollow electrode(s), and wherein said method further comprises a step of inserting at least one liquid into the soft tissue (directed to the claimed ‘solid tissue’), or into a SOL or in proximity thereto, via the hollow electrode(s), and the intracellular components released to the extracellular matrix are extracted in step (iii) by suction together with said at least one liquid via said at least one hollow electroporation-electrode. The references further differ from claim 17 in that they do not expressly disclose that the at least one liquid is: (i) an aqueous solution, wherein the intracellular components (directed to the claimed ‘at least one cellular-component’) released to the extracellular matrix are diluted therein for extraction; (ii) an oil, wherein the intracellular components (claimed ‘at least one cellular-component’) released to the extracellular matrix are encapsulated by said oil to form a micelle that is then extracted by suction; or (iii) an aqueous solution and an oil inserted sequentially in that order, wherein the intracellular components (claimed ‘at least one cellular-component’) released to the extracellular matrix are first diluted in the aqueous solution, and then encapsulated by said oil to form a micelle that is extracted by suction.
The references further differ from claim 20 in that they do not expressly disclose that the electrode(s) (directed to the claimed ‘at least one electroporation-electrode’) is a solid rod engulfed in a retentive cannula, and the intracellular components (directed to the claimed ‘at least one cellular-component’) released to the extracellular matrix are extracted in step (iii) by suction via said cannula after extraction of the solid rod therefrom, and wherein said method further comprises a step of inserting at least one liquid into the soft tissue (directed to the claimed ‘solid tissue’), or into a SOL or in proximity thereto, via said cannula, and the intracellular components (the claimed ‘at least one cellular-component’) released to the extracellular matrix are extracted in step (iii) by suction together with said at least one liquid (interpreted as ‘said at least one liquid’) via said cannula. The references further differ from claim 22 in that they do not expressly disclose the at least one liquid is: (i) an aqueous solution, wherein the intracellular components (directed to the claimed ‘at least one cellular-component’) released to the extracellular matrix are diluted therein for extraction; (ii) an oil, wherein the intracellular components (claimed ‘at least one cellular-component’) released to the extracellular matrix are encapsulated by said oil to form a micelle that is then extracted by suction; or (iii) aqueous solution and an oil inserted sequentially in that order, wherein the intracellular components (claimed ‘at least one cellular-component’) released to the extracellular matrix are first diluted in the aqueous solution and then encapsulated by said oil to form a micelle that is extracted by suction.
Lax discloses a device and method for penetrating body tissues for medical purposes such as reducing tissue mass and fluid substance delivery, for example (column 1, lines 21-24). The device penetrates tissue to the precise target selected in order to deliver energy to the tissue and/or deliver substances (column 1, lines 24-26). The device is suitable for reducing the mass of tissues of any type, such as cancer and noncancerous tumors (column 1, lines 33-35). The medical ablation device of Lax comprises a flexible RF electrode wire or tube, terminal portion thereof extending through an insulating sleeve axially moveable thereon (column 2, lines 43-46). The electrode and surrounding sleeve extend through a portion of a rigid tube having a distal end adapted to be inserted into the body of a patient (column 2, lines 46-48). An electrode wire is directed to a ‘solid rod,’ so an electrode wire in a surrounding sleeve and rigid tube is directed to a solid rob engulfed in a retentive cannula (the surrounding sleeve and tube are each directed to a cannula), meeting (ii) of instant claim 14. Additionally, Lax teaches that the electrode can also be a hollow tube (column 2, line 59). This meets (i) of instant claim 14.
For an electrode that is a hollow tube, the proximal end thereof is adapted to be connected to a suction source for aspiration of tissue adjacent its distal end (column 2, lines 61-63). Also, when the electrode is a hollow tube, it can be a conduit for aspiration during treatment (column 5, lines 6-7). Lax also discloses the device comprising a hollow Rf electrode having an electrode lumen serving as a fluid conduit for delivering fluid through the open, distal end of the electrode, wherein fluid is delivered through the electrode lumen to irrigate the tissue ablation site (claim 1 of Lax).
Before the effective filing date of the claimed invention, it would have been obvious to substitute the electrode(s) of the method rendered obvious by Onik in view of Franzen with a device comprising an electrode wire or an electrode that is a hollow tube, wherein the electrode is extended through an insulating sleeve, and wherein the electrode and the surrounding sleeve extend through a portion of a rigid tube having a distal end adapted to be inserted into the body of a patient, as in the invention of Lax. It would have been a matter of simple substitution of electrodes for insertion into a subject’s body for delivering energy to a tissue for other such electrodes. Also, a person of ordinary skill in the art would have been motivated to make the substitution because it would have permitted delivering the electric field to difficult to access tissues, based on Lax’s teaching regarding the object of their invention (column 2, lines 35-37). There would have been a reasonable expectation of using said device for applying electrical pulses to cause cellular membrane breakdown such that intracellular contents spill into the extracellular space as required by Onik (e.g., paragraph [0013]) because an electrode in general would have been suitable for delivering the electric field taught by Onik. Therefore, Onik in view of Franzen and further in view of Lax renders obvious instant claim 14 (either of embodiments (i) and (ii)).
Regarding instant claims 15 and 17, when the electrode is a hollow tube for performing the method rendered obvious by Onik, Franzen, and Lax, it would have been obvious to also connect the electrode to a suction source and deliver a fluid through the electrode’s lumen in order to irrigate the ablated tissue, according to Lax. One of ordinary skill in the art would have been motivated to do this because it would have permitted aspiration of the treated area, thereby permitting the biopsy of the method rendered obvious by Onik in view of Franzen discussed above (biopsy by aspiration was taught Franzen) and foregoing the need for a separate device (e.g. a fine-needle as taught in Franzen) for performing aspiration for a biopsy. In making this modification, then instant claim 15 is rendered obvious. Moreover, it would have been obvious to use an aqueous solution as the fluid delivered through the electrode’s lumen when performing the method rendered obvious by Onik, Franzen, and Lax because any fluid, including an aqueous solution, would have been suitable for irrigation and aspiration of ablated tissue (in particular, its intracellular contents in the extracellular space). Thus, instant claim 17 (embodiment (i)) is rendered obvious.
Regarding instant claims 20 and 22, when the electrode is an electrode wire (directed to the claimed ‘solid rod’) which is engulfed in a retentive cannula (the surrounding sleeve and rigid tube) for performing the method rendered obvious by Onik, Franzen, and Lax, it also would have been obvious to connect the surrounding sleeve and rigid tube to a suction source and deliver a fluid through the sleeve/tube in order to irrigate the ablated tissue. One of ordinary skill in the art would have been motivated to do this because it would have permitted aspiration of the treated area, thereby permitting the biopsy of the method rendered obvious by Onik in view of Franzen discussed above (biopsy by aspiration was taught Franzen) and foregoing the need for a separate device (e.g. a fine-needle as taught in Franzen) for performing aspiration to perform a biopsy. In making this modification, then instant claim 20 is rendered obvious. Moreover, it would have been obvious to use an aqueous solution as the fluid delivered through the sleeve/tube when performing the method rendered obvious by Onik, Franzen, and Lax because any fluid, including an aqueous solution, would have been suitable for irrigation and aspiration of ablated tissue (in particular, its intracellular contents in the extracellular space). Thus, instant claim 22 (embodiment (i)) is rendered obvious.
Response to Arguments
Applicant’s arguments, filed November 20, 2025, with respect to specific deficiencies with respect to the nucleotide and/or amino acid sequence disclosures, the objection to the specification, the objection to claim 5, and the rejections under 35 U.S.C. 112(b) of claims 1, 2, 5, 8, 11, 14, 15, 17, 20, 22, 25, and 26, have been fully considered and are persuasive.
In particular, the substitute specification complies with the specific deficiencies with respect to the nucleotide and/or amino acid sequence disclosures, as well as addressing the objection to the specification.
The claim objection has been overcome by the amendment to claim 5. The rejections under 35 U.S.C. 112(b) have been overcome by the amendments to claims 1, 2, 8,11, 14, 15, 17, 20, 22, 25, and 26.
Therefore, these objections and rejections have been withdrawn.
The amendments to the claims necessitated modifying the rejections under 35 U.S.C. 103 and new rejections under 35 U.S.C. 112(b) and 112(a). The claims remain rejected over the prior art cited in the last Office Action.
Applicant’s arguments are unpersuasive with respect to the rejections under 35 U.S.C. 103. Applicant asserts that an important difference between the claimed invention and the cited references is that the claimed invention is based on an intermediate process of molecular extraction for profiling. Applicant further argues that this intermediate process falls outside the therapeutic (ablation) teaching of Onik and Lax, and also would require fundamentally changing the sample mechanism of Franzen, which relates to a physical biopsy which is asserted as having nothing to do with the presently minimally invasive PEF. However, Onik teaches that their method may include a biopsy of a portion of the treated target tissue, as well as teaching detecting the spillage of the cell contents, such as using needle probes (paragraphs [0053]-[0055]). In applying biopsies, such as fine-needle aspiration biopsies taught in Franzen, to the invention of Onik in order to diagnose cancer from the spilled intracellular components, then the steps of instant claim 1 are rendered obvious. Furthermore, it is unclear how the sample mechanism of Franzen is modified as argued by Applicant when it is applied to the invention of Onik which teaches PEF.
Additionally, Applicant asserts that Onik teaches a therapeutic/ablative procedure whose primary goal is destruction to induce an immune response, which Applicant argues is in contrast to the presently claimed invention requiring preservation and collection of any released molecules for external analysis. Applicant concludes that modifying Onik to achieve these goals would render the teachings of Onik unsuitable for their intended purpose of inducing an immune response. Applicant cites MPEP 2143.01(V), and argues that there would have been no motivation to preserve and collect any released molecules for external analysis, and combining the therapeutic method of Onik with a diagnostic analysis as taught by Franzen is counter-intuitive as it shifts the entire purpose of Onik’s procedure, which requires unexpected technical steps (i.e., extraction for analysis) not disclosed or suggested by Onik. However, performing a biopsy of the spilled intracellular components does not entail removing all the spilled intracellular components, thus performing said biopsy when practicing the method of Onik would not have rendered Onik unsuitable for its intended purpose of inducing an immune response. The sampling of some of the spilled intracellular components would leave spilled intracellular components remaining in the subject’s body that would induce an immunologic response sought by Onik. Additionally, the motivation to obtain the biopsy of spilled intracellular components is to diagnose cancer from the spilled intracellular components. Moreover, Onik recognizes detecting the spilled cellular contents (paragraph [0054]), so Onik recognizes performing diagnostic analysis. As such, the Examiner disagrees with Applicant’s assertions that combining the therapeutic method of Onik with a diagnostic analysis as taught in Franzen is counter-intuitive, shifts the entire purpose of Onik’s procedures, and would require unexpected technical steps.
Additionally, Applicant asserts that even if one having ordinary skill in the art did attempt to combine the teachings of Franzen with those of Onik, such a person would not be led to the presently claimed invention. Applicant points out that Franzen teaches a Fine-Needle Aspiration (FNA) biopsy, which is the physical collection of a cell/tissue sample, followed by ex-vivo lysis to access the intracellular molecules. Applicant argues that this is fundamentally different from the presently claimed method, which is the extraction of free-floating molecules from the in vivo extracellular matrix after PEF-induced release. However, Franzen recognizes that FNA sampling can be directed to recovering tissue fragments (page 1416, left column, second paragraph). Moreover, if an FNA biopsy is suitable for collection of a cell/tissue sample, then it is suitable for collecting material smaller than cells, such as intracellular molecules.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., method allows for spatial molecular profiling; method allows for the determination of tumor heterogeneity in vivo by performing minimally disruptive sample points) are not recited in the rejected claim(s). 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, 26 USPQ2d 1057 (Fed. Cir. 1993). Applicant argues that the features are an unexpected technical advantage of the claimed method. However, this is unpersuasive because Applicant has not explained spatial profiling and determination of tumor heterogeneity. Thus, it is unclear whether these features are unexpected.
Regarding the addition of Lax to the combination of Onik and Franzen, Applicant asserts combining Lax’s thermal probe with Onik’s non-thermal method to extract molecules for profiling is an inapt combination and would require significant modification of the Lax probe beyond the level of one having ordinary skill in the art to fit the non-thermal context. However, the skilled artisan would have recognized that teachings regarding the structure of an electrode of Lax can be applied to the electrodes of Onik; it is a matter of simple substitution of electrodes suitable for insertion into a subject’s body for delivering energy to a tissue. Such substitution does not involve incorporating applying RF energy to the electrodes of Lax to the invention of Onik, and thus would not have resulted in modifying the invention of Onik in a manner contrary to its intended purpose of non-thermal cellular membrane breakdown (e.g., paragraph [0013]).
Applicant also asserts that Lax fails to suggest the crucial feature of claim 14, which is that the electrode is not only an electrode for performing PEF, but is also a cellular-components extraction-element. However, claim 14 and parent claim 1 do not require that the ‘at least one electroporation-electrode’ and the ‘extraction element’ are one and the same. Instead, claim 1 recites the extraction element is dedicated to a molecular collection.
Applicant also argues that neither Onik nor Lax, alone or combined, teaches or suggests modifying the electrode with a specific molecular-retaining property (e.g., an adsorbing coating) designed for diagnostic collection, as opposed to therapeutic fluid movement. The Examiner agrees. However, claim 14 recites three alternative embodiments ((i), (ii), and (iii)), so claim 14 is met by Onik, Franzen, and Lax while not meeting embodiment (iii) (a solid rod at least partially coated with an adhesive material capable of reversibly adsorbing, associating with, and/or linking at least one of said at least one cellular-component). Since claim 25 is limited to only embodiment (iii) of claim 14, then claim 25 is not rejected over Onik, Franzen, and Lax.
Furthermore, Applicant argues that combining features of the thermal ablation device of Lax with the non-thermal ablation/immunotherapy of Onik, and the physical biopsy/profiling of Franzen, is illogical and would not motivate those skilled in the art to introduce the specific extraction-element required by claim 14 or the molecular extraction step required by claim 1. However, the basis of the rejection of claim 14 is the substitution of the electrodes of Onik with an electrode or an electrode that is a hollow tube, wherein the electrode is extended through an insulating sleeve, and the electrode and the surrounding sleeve extend through a portion of a rigid tube having a distal end adapted to be inserted into the body of a patient. Further still, claim 14 does not require that the at least one electroporation-electrode is an extraction-element.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Sef
/SUSAN E. FERNANDEZ/Examiner, Art Unit 1651
/DAVID W BERKE-SCHLESSEL/Primary Examiner, Art Unit 1651