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 .
Status of the Claims
Claims 42-61 are pending in the application.
Claim 61 is withdrawn.
Claims 42-60 are the subject of this office action.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 42-60 in the reply filed on 19 February 2026 is acknowledged.
Claim 61 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 19 February 2026.
Priority
The instant application is a 371 National Stage of PCT/EP2021/079072, filed 20 October 2021.
The instant application claims benefit of foreign application FR2010766, filed 20 October 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 20 April 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See at least:
Specification. Pg. 38, Ln. 4
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
In claim 42: “a coating capable of targeting the superparamagnetic beads to a cell element or compartment of interest or of penetrating a cell or group of cells”
This limitation is interpreted under 112(f) because it claims an element by its desired function without providing sufficient structure to support that function. That is, any generic “coating” is not necessarily capable of performing the recited function of targeting or penetrating. As such, the term is interpreted in light of the specification which provides that a coating capable of targeting the superparamagnetic beads to a cell element or compartment of interest is a protein, antibody, or lectin that specifically binds to a target moiety (e.g. Pg. 5, Ln. 21-24). Interpretation regarding a coating capable of penetrating a cell or group of cells is discussed further in the 112(b) section below.
In claim 44: “a biocompatible oil capable of causing the superparamagnetic beads to penetrate into a cell or a group of cells”
This limitation is interpreted under 112f because it claims an element by its desired function without providing sufficient structure to support that function. That is, any generic “biocompatible oil” is not necessarily capable of performing the recited function of causing superparamagnetic beads to penetrate into a cell or a group of cells. Further interpretation of this limitation is discussed in the 112(b) section below
In claim 45: “a biological coating capable of specifically targeting the superparamagnetic beads to a cell element or compartment of interest, a cell or a group of cells”
This limitation is interpreted under 112(f) because it claims an element by its desired function without providing sufficient structure to support that function. That is, any generic “biological coating” is not necessarily capable of performing the recited function of specifically targeting the superparamagnetic beads to a cell element or compartment of interest, a cell or a group of cells. As such, the term is interpreted in light of the specification which provides that a coating capable of targeting the superparamagnetic beads to a cell element or compartment of interest is a protein, antibody or lectin that specifically binds to a target moiety (e.g. Pg. 5, Ln. 21-24).
In claim 54: “at least one bait protein capable of recognizing a prey protein on the cell element or compartment of interest”
This limitation is interpreted under 112(f) because it claims an element by its desired function without providing sufficient structure to support that function. That is, the term “bait protein” and “prey protein” do not provide an indication of the specific structure or physical requirements that support the recited function. Further discussion of the interpretation of this limitation is given in the 112(b) section below.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 42-60 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 42 is vague regarding “said beads”. This term lacks antecedent basis because the only beads previously introduced in the claim are “superparamagnetic beads”, such that there is a lack of antecedent basis for the generic term “said beads” in the claim.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 42 recites “at least one millimetre or submillimetre sized magnet” wherein a submillimetre sized magnet is a narrower range than a millimetre sized magnet. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The recitation “at least one millimetre or submillimetre sized magnet” in claim 42 is additionally rejected as indefinite because the meaning of the limitation is unclear. The particular meaning of the term “sized” in this context is unclear. Does this refer to one particular dimension of the magnet? Does it refer to all dimensions of a magnet? Does a magnet which is submillimetre in one or some dimensions but larger in other dimensions meet this limitation? Does “millimetre sized” mean that the magnet must be exactly one millimetre or less, or does it encompass some range of millimetres (i.e. does it refer to a precise measurement or some order of magnitude)? Pg. 15, Ln. 23-30 of the specification provides: “a magnetic core made of a superposition of millimetre or submillimetre sized magnets…preferably the magnet or magnetic form the magnetic core and have a diameter comprised between 1 and 5 millimetres”. This indicates that a “millimetre or submillimetre sized magnet” may have a diameter greater than one millimetre, but it is unclear what the upper boundary of this limitation is. Clarification is required.
Claim 42 indicates that the claimed method is specifically in vitro or ex vivo, however both the specification and the instant claims (dependent claim 47) recite performance of the method in a living embryo and thus appear to encompass an in vivo embodiment of the claimed method. As such, the metes and bounds of the claim are unclear. Clarification is required. For the purposes of applying prior art in the instant application, a method performed in a living embryo is understood to be capable of reading on the instant claim, even if it is described as an in vivo method rather than ex vivo or in vitro.
Claim 44 is rejected as indefinite over the recitation “the superparamagnetic beads comprising a hydrophobic coating are mixed with a biocompatible oil capable of causing the superparamagnetic beads to penetrate into a cell or group of cells”. This limitation is confusing because the superparamagnetic beads are already recited to have a coating which may make them capable of targeting or penetrating a cell or group of cells, such that the additional functional contribution and structural requirements of the oil which is specifically defined by this function are unclear. Clarification is required.
Claim 49 is vague regarding “the distance”. There is no prior introduction of “a distance” between the magnetic tip and the biological sample in the claims, such that there is insufficient antecedent basis for this limitation. Additionally, it is not clear at what point in the method such a distance is measured. For example, if a magnetic tip is brought into contact with a biological sample at some point during the method, this would imply that there is some point in time where the distance between the magnetic tip and the biological sample is between 10 micrometres and 1 millimetre. Clarification is required.
Claim 50 is vague regarding “the biological coating of the beads”. There is no prior introduction of a biological coating in claim 50 or in claim 42 from which claim 50 depends, and as such there is insufficient antecedent basis for this limitation in the claims.
Claim 50 is vague regarding “the tip” and “the beads”. There is antecedent basis in the claims for “the magnetic tip” and “the superparamagnetic beads” but there is insufficient antecedent basis for the generic recitations of “the tip” and “the beads”.
Additionally, claim 50 recites that “the biological coating is selected according to the cell element or compartment of interest” wherein it is unclear what relationship this requires between the biological coating and the cell element or compartment of interest. Similarly, the meaning of the recitations “a preliminary step of preparing the tip and/or superparamagnetic beads” and “calibrating the tip and beads” is unclear. What is actually required by these steps? What are the tip or beads prepared for and how? What are the tip and beads calibrated for and how? Clarification is required.
Claim 52 is rejected as indefinite over the recitation “a hydrophobic coating selected from butyl, methyl, ethyl, octyl, propyl, or octadecyl” because these are prefixes which refer particular alkyl groups but which are not themselves standalone compounds or coatings. Additionally, not all compounds which contain the recited alkyl groups are hydrophobic, such that there is disagreement between the genus (hydrophobic coating) and its recited species.
Claim 53 is vague regarding “the biocompatible oil”. There is no prior introduction of “a biocompatible oil” in claim 53 or in claim 42 from which it depends, therefore there is insufficient antecedent basis for this limitation in the claim.
Claim 53 is also indefinite due to the recitation “an oil of the (C15-C46) alkane type” both because “the (C15-C40) alkane type” lack antecedent basis and because what exactly is meant by or required of an oil of this “type” is unclear.
Claim 54 is vague regarding “the biological coating” there is no prior introduction of “a biological coating” in claim 54 or in claim 42 from which it depends, therefore there is insufficient antecedent basis for this limitation in the claim.
Claim 56 is rejected as indefinite because it contains abbreviations which are not defined upon their first appearance in the claims, such that the precise meaning of these abbreviations is unclear.
Claim 57 is vague regarding “the solution”. There is no prior introduction of “a solution” in claim 57 or in claim 42 from which it depends, therefore there is insufficient antecedent basis for this limitation in the claims.
Claim 58 is vague regarding “the internal or external cell membrane”. There is no prior introduction of an internal or external cell membrane in claim 58 or in claim 42 from which it depends, therefore there is insufficient antecedent basis for this limitation in the claims.
Claim 59 is rejected as indefinite over the recitation “a size comprised between 100 nm and 100 um” because the metes and bounds of the limitation are unclear. The term “a size” is unclear in this context. What dimension does this refer to? The metes and bounds of a bead having a radius within the recited range are different than the metes and bounds of a bead having a diameter within the recited range or a circumference within the recited range. Clarification is required.
The recitation of “a biological coating” in claim 60 is unclear. Claim 42 recites a generic “coating” on the superparamagnetic beads. Does the recitation of a “biological coating” further limit the coating that is previously introduced in claim 42, or is it itself a different coating that is applied in addition to the coating previously introduced in claim 42? Clarification is required.
The claim limitations regarding a coating capable of causing superparamagnetic beads to penetrate into a cell in claims 42 and 44 (identified in the claim interpretation section above) invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function.
While the specification repeats these limitations and provides examples of hydrophobic coatings and oils (Pg. 4, Ln. 11-14; Pg. 6, Ln. 31; Pg. 5, Ln. 17-20), the specification does not provide sufficient structure to link these coatings to the specifically recited function. That is, the limitation requires that it is the coating itself that facilitates the function of penetration, and the specification does not support this assertion. All examples provided in the specification which comprise penetration of the superparamagnetic bead into a cell comprise a specific method of injection or introduction of the bead into the cell, wherein it appears that penetration is specifically facilitated by the method of introduction and not specifically or solely by the particular coating of the bead (Pg. 28, Ln. 9-13; Pg. 27, Ln. 11-14; Pg. 36 “Magnetic Bead Injection”; Pg/ 37, “Injection of beads mixed with oil”). As such, the particular structural requirements and physical features of a coating that independently facilitates this function are not clear in the specification, and the specification does not appear to support the limitation that it is the coating itself and in particular that produces the recited penetration.
The claim limitations regarding a “bait protein” and “prey protein” in claim 54 (identified in the claim interpretation section above) invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function.
In the claim the proteins are described by their functional relationship to one another without sufficient structural detail to support that function. The specification Pg. 12, Ln. 21-26 defines these terms, wherein the “prey protein” is described as the protein of interest, and the “bait protein” is described as a protein capable of recognizing, interacting, and binding with the prey protein. These definitions fail to render the terms definite because they simply repeat the description of the elements by their desired function and relationship to one another and not by their structural or physical features, such that the specification does not provide sufficient structure to support the recited function.
Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Dependent claims 43-60 are rejected as indefinite because they depend from an indefinite claim and fail to remedy its deficiencies.
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.
Claims 42-43, 45-46, 48-51, 54, and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over McDowell et al (Spectral domain phase microscopy for local measurements of cytoskeletal rheology in single cells. Journal of Biomedical Optics, July/August 2007, pp. 044008-1-04408-11, No. 12, No. 4; IDS entered) in view of Salle et al (Asymmetric division through a reduction of microtubule centering forces. J Cell Biol. 2019 Mar 4;218(3):771-782. Epub 2018 Dec 18; previously cited).
Regarding claim 42, McDowell teaches a method for characterizing at least one mechanobiological property of at least on element, at least one cell compartment, at least one cell, or at least one group of cells in a biological sample (Abstract), the method comprising:
Introducing superparamagnetic beads into the biological sample, said beads comprising a coating capable of targeting the superparamagnetic beads to a cell element or compartment of interest or of penetrating a cell or group of cells (Abstract: ligand coated magnetic beads attached to integrin receptors on cell surfaces; Pg. 0044008-5, Section 3.1: superparamagnetic beads comprising an iron oxide core with a coating of polystyrene and fibronectin);
Applying a magnetic field to the superparamagnetic beads in order to apply a force to the biological sample (Abstract: magnetic tweezers designed to apply a vertical force to magnetic beads);
Measuring at least one mechanobiological property of the cell element or compartment in the biological sample (Abstract: investigate mechanical properties of the cytoskeleton of MCF-7 cells. SDPM was used to resolve cell surface motions induced by applied stress. The cells response data were fit to several models for cytoskeletal rheology. We correlated displacement measurements to physical characteristics of individual cells);
Said biological sample being a cell or a multicellular biological sample (Abstract: MCF-7 cells); and
The magnetic field being applied by a magnetic tip (Abstract: magnetic tweezers designed to apply a vertical force to magnetic beads).
McDowell teaches that the magnetic field is applied by a magnetic tip comprising at least one magnet extended by a metal tip (Pg. 044008-5, Col. 1, Section 3.2: electromagnet created by a 0.1mm copper wire coil). The magnet taught by McDowell is understood to read on the “millimetre or submillimetre sized” limitation of the claim in that it has at least one submillimeter dimension and multiple dimensions that can be measured in millimeters. However, in light of the 112(b) issues with this limitation identified above, McDowell may also be combined with the teachings of Salle discussed below to read on this limitation.
Regarding claim 42, Salle teaches a magnetic tip comprising at least one millimeter or submillimeter sized magnet extended by a metal tip which is used in conjunction to superparamagnetic beads (Abstract; Pg. 778, Col. 2, Par. 4: the magnetic probe was built from three rod shaped strong neodymium magnets (diameter 4mm, height 10mm) prolonged by a sharpened steel piece with a tip radius of 50um to create a magnetic gradient).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the invention of McDowell to use the magnetic tip comprising at least one millimeter and submillimeter sized magnet extended by a metal tip (as taught by Salle) in place of the electromagnet taught by McDowell. One of ordinary skill in the art would be motivated to make this modification because permanent magnets such as those taught by Salle have the advantage of being able to provide a consistent magnetic field without the need for additional instrumentation for provided an electrical current to an electromagnet, making the apparatus cheaper and simpler to use. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both McDowell and Salle teach methods comprising the use of a magnetic tip in conjunction with superparamagnetic beads which are used to investigate and analyze mechanobiological properties of cells.
Regarding claim 43, McDowell further teaches that the coating is a hydrophobic coating (i.e. polystyrene) (Pg. 0044008-5, Section 3.1: superparamagnetic beads comprising an iron oxide core with a coating of polystyrene and fibronectin).
Regarding claim 45 McDowell further teaches that the coating is a biological coating capable of specifically targeting the superparamagnetic beads to a cell element or compartment of interest, a cell or a group of cells (i.e. fibronectin) (Pg. 0044008-5, Section 3.1: superparamagnetic beads comprising an iron oxide core with a coating of polystyrene and fibronectin).
Regarding claim 46, McDowell further teaches that the superparamagnetic beads comprising a biological coating are mixed with a solution before being introduced into the biological sample (Pg. 0044008-9, Col. 1, Par. 2: microspheres added in solution).
Regarding claim 48, McDowell further teaches that the force applied to the biological sample is between 0.001 pN and 5000 nN (Pg. 044008-6, Section 3.4: the magnet applied 500 pN of force).
Regarding claim 49, McDowell further teaches that the distance between the magnetic tip and the biological sample is between 10 micrometers and 1 millimeter (Fig. 4). See also Salle Fig, 3C. Both McDowell and Salle indicate that in order to apply McDowell’s specified force of 500pN, the distance between the magnetic tip and the biological sample should be between 10 micrometers and 1 millimeter. As such, in the modified invention of McDowell in view Salle which uses the permanent magnetic tip taught by Salle, a distance between 10 micrometers and 1 millimeter would be required to achieve the applied force indicated in the method of McDowell.
Regarding claim 50, McDowell further teaches the method comprising a step of calibrating the tip and beads (Pg. 044008-5, Section 3.2: force calibration was performed by using the electromagnet to drag the magnetic beads through a fluid of known viscosity).
Regarding claim 51, McDowell further teaches the method wherein the mechanobiological properties are selected from rheology, kinematics, mechanical strength, elasticity, stiffness, plasticity, viscoelastic properties, and any combination thereof (Abstract: investigate mechanical properties of the cytoskeleton of MCF-7 cells. SDPM was used to resolve cell surface motions induced by applied stress. The cells response data were fit to several models for cytoskeletal rheology. We correlated displacement measurements to physical characteristics of individual cells).
Regarding claim 54, McDowell further teaches that the biological coating of the superparamagnetic beads is a protein coating comprising at least one bait protein capable of recognizing a prey protein on the cell element or compartment of interest (i.e. McDowell teaches that the superparamagnetic particles are coated with fibronectin which binds to integrin receptors on the cell surface).
Regarding claim 57, McDowell teaches that the superparamagnetic beads comprising a biological coating are mixed with a solution before being introduced into the biological sample (Pg. 0044008-9, Col. 1, Par. 2: microspheres added in solution). McDowell differs from the instant claim in that it does not specifically teach that the solution is a buffer solution.
Regarding claim 57, Salle teaches that superparamagnetic beads may be mixed with a buffer solution prior to their introduction into the biological sample (Pg. 778, Col. 2, Par. 2-3: beads mixed with PBS solution).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the invention of McDowell to specifically use the PBS solution taught by Salle. One of ordinary skill in the art would be motivated to make this modification because McDowell teaches the beads in solution, but is generic regarding what the solution comprises. Salle teaches that PBS is an appropriate solution for suspension and use of superparamagnetic beads, and thus one would be motivated to us the appropriate solution for the application. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both McDowell and Salle are directed to similar methods comprising the use of superparamagnetic beads in solution which are introduced to a biological sample.
Regarding claim 58, McDowell further teaches the method wherein the cell element or compartment is the internal or external membrane of at least one cell of the biological sample (Abstract).
Regarding claim 59, McDowell further teaches that the superparamagnetic beads have a size between 100 nm and 100 um (Pg. 0044008-5, Section 3.1: superparamagnetic beads having a diameter of 4.5 micrometers).
Claims 55-56 are rejected under 35 U.S.C. 103 as being unpatentable over McDowell et al (Spectral domain phase microscopy for local measurements of cytoskeletal rheology in single cells. Journal of Biomedical Optics, July/August 2007, pp. 044008-1-04408-11, No. 12, No. 4; IDS entered) in view of Salle et al (Asymmetric division through a reduction of microtubule centering forces. J Cell Biol. 2019 Mar 4;218(3):771-782. Epub 2018 Dec 18; previously cited) as applied to claims 42 and 54 above, and further in view of Marjoram et al (“Using magnets and magnetic beads to dissect singaling pathways activated by mechanical tension applied to cells” Methods, available online September 30, 2015, pp. 19-26, Vol. 94.; IDS entered) and Choi et al (KR 2018/0049323 A).
Regarding claim 54-56, McDowell in view of Salle teaches the method of claim 54 as described above, wherein the superparamagnetic beads comprise a protein coating comprising at least one bait protein capable of recognizing a prey protein on the cell element or compartment of interest. McDowell differs from the instant claim 55 in that the biological coating is not an antibody or lectin, and is instead a fibronectin coating which targets the superparamagnetic particles to the cell membrane via binding of fibronectin to integrins on the cell membrane.
Similar to McDowell, Marjoram teaches a method for measuring a mechanobiological property of at least one element, at least one cell compartment, at least one cell, or at least one group of cells in a biological sample (Abstract), the method comprising:
Introducing superparamagnetic beads into the biological sample, said beads comprising a coating capable of targeting the superparamagnetic beads to a cell element or compartment of interest (Abstract; Pg. 21, Col. 1, last Par.-Col. 2, first Par.);
Applying a magnetic field to the superparamagnetic beads in order to apply a force to the biological sample (Abstract); and
Measuring at least one mechanobiological property of the cell element or compartment in the biological sample (Abstract; Fig. 1);
The biological sample being a cell or multicellular biological sample (Abstract);
The magnetic field being applied by a magnetic tip (Abstract).
Regarding claims 54-56, Marjoram specifically teaches that the coating of the superparamagnetic particles may be an antibody or a lectin (Pg. 21, Col, 1, last Par.-Col. 2, first Par.: ligands for cell targeting may be covalently linked to the superparamagnetic beads, wherein the ligand may be an antibody targeting a cell surface protein).
Regarding claims 54-56, Choi teaches that magnetic particles conjugated to anti-EGFR antibodies can be used to bind EGFR on the surface of MCF-7 cells (Pg. 3, Section 1-3: Magnetic particles conjugated to EGFR antibody bind to surface proteins on MCF-7 cells).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the invention of McDowell and Salle to replace the fibronectin coating taught by McDowell with the anti-EGFR antibody coating taught by Marjoram and Choi. One would be motivated to make this modification because an antibody coating facilitates more specific targeting of a particular cell surface protein. Additionally, since both the fibronectin coating taught by McDowell and the antibody coating taught by Marjoram and Choi are protein coatings used to target a superparamagnetic particle to a cell surface protein in a similar method, one of ordinary skill in the art would recognize that substitution of an antibody taught by Marjoram and Choi for the fibronectin taught by McDowell amounts to simple substitution of known elements to achieve predictable results with a reasonable expectation of success. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both McDowell and Marjoram disclose methods comprising superparamagnetic beads coated with protein ligands for the purpose of targeting the beads to cell surface proteins. Further, Marjoram teaches that the beads may be coated with an antibody targeting a cell surface protein, and while Choi teaches magnetic beads coated with an antibody that binds to a particular cell surface protein (EGFR) expressed on the MCF-7 cells used in the method of McDowell.
Claims 42-44, 47-53, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Selvaggi et al (Magnetic tweezers optimized to exert high forces over extended distances from the magnet in multicellular systems. Rev Sci Instrum. 2018 Apr;89(4):045106.) in view of Campas et al (US 2016/0116394 A1).
Regarding claim 42-44, and 52-53, Selvaggi teaches a method for measuring a mechanobiological property of at least one element, at least one cell compartment, at least one cell, or at least one group of cells in a biological sample (Abstract), the method comprising:
Introducing superparamagnetic beads into the biological sample, said beads comprising a coating capable of penetrating a cell or group of cells (Pg. 045106-4, Col. 1, last Par.-Col. 2, first Par.: injection of superparamagnetic beads into Drosophila embryos The superparamagnetic beads comprise a polystryrene coating) as best interpreted in light of the 112(b) issues identified above, the beads taught by Selvaggi are understood to comprise a coating capable of penetrating a cell or group of cell because the beads are taught to comprise a coating (i.e. a hydrophobic coating, polystyrene) and are injected into (i.e. penetrate) a cell;
Applying a magnetic field to the superparamagnetic beads in order to apply a force to the biological sample (Abstract; Pg. 045106-4, Col. 2, Par. 3: magnetic tip is used to apply magnetic force to superparamagnetic beads injected into an embryo, thereby applying a force to the biological sample); and
Measuring at least one mechanobiological property of the cell element or compartment in the biological sample (Abstract: determined microrheological properties of embryos; Pg. 045106-5, Col. 1, Par. 1: velocity of the beads corresponding to the applied magnetic force is used to determine the viscosity of the cytoplasm);
The biological sample being a cell or multicellular biological sample (Pg. 045106-4, Col. 1, Par.3-Col. 2, Par. 2: Drosophila embryos);
The magnetic field being applied by a magnetic tip, said magnetic tip comprising at least one millimeter or submillimeter size magnet extended by a metal tip (Pg. 045106-2, Col. 1, last Par-Col. 2, first Par.: electromagnet comprising a solenoid with 904 windings of 0.5mm copper wire wrapped around an aluminum shell. The latter houses a cylindrical core with a tapered tip). The magnet taught by Selvaggi is understood to read on this limitation of the claim as best interpreted in light of the 112(b) issues identified above; that is, Selvaggi is understood to read on a magnetic tip comprising “at least one millimeter or submillimeter size magnet” in that it teaches at least one magnet with at least one submillimeter dimension and with multiple dimensions that can be measured in millimeters.
As discussed above, the teachings of Selvaggi are understood to read on the limitation of claim 42 “said beads comprising a coating capable of…penetrating a cell or group of cells” as best interpreted in light of the 112(b) rejection above. This limitation of the claim can also be taught by combination with Campas, as further discussed below.
Regarding claims 42-44, 52-53, Campas teaches a method for measuring a mechanobiological property of at least one element, at least one cell compartment, at least one cell, or at least one group of cells in a biological sample (Abstract), the method comprising:
Introducing superparamagnetic beads into the biological sample, said beads comprising a coating capable of targeting the superparamagnetic beads to a cell element or compartment of interest (Abstract; Par. 15)
Applying a magnetic field to the superparamagnetic beads in order to apply a force to the biological sample (Abstract; Par. 6); and
Measuring at least one mechanobiological property of the cell element or compartment in the biological sample (Abstract);
The biological sample being a cell or multicellular biological sample (Abstract; Par. 23);
Campas further teaches that the disclosed ferrofluid droplets may comprise a magnetic component dissolved, dispersed, suspended, or otherwise present within the carrier fluid, wherein the magnetic component may be a plurality of superparamagnetic beads (Par. 15). Campas teaches that the carrier fluid in which the beads are suspended is preferably a liquid that is substantially immiscible and chemically inert in the environment in which it is placed, and teaches that in a biological sample, the carrier fluid should be a biocompatible oil such as a fluorocarbon oil which forms a hydrophobic coating around the beads (Par. 12-13). Examples of suitable biocompatible oils which are used as a carrier fluid to form a hydrophobic coating on the beads include methyl coatings (Par. 14). Campas teaches that superparamagnetic particles suspended in such a carrier fluid may penetrate a cell or group of cells in a biological sample such that application of a magnetic force to the superparamagnetic beads may be used to apply force to cells in the sample and measure mechanobiological properties (Abstract; Par. 12-17, 2325-28).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the invention of Selvaggi such that the superparamagnetic beads taught by Selvaggi are suspended in a biocompatible oil (e.g. methyl or fluorocarbon oil), as taught by Campas. One of ordinary skill in the art would be motivated to make this modification because Campas teaches that coating and suspension with a biological oil helps encapsulate particles into a cohesive drop, and ensures that the beads within the droplet remain inert and do not interact with or interfere with internal components of the cell. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both Selvaggi and Campas are directed to methods of measuring mechanobiological properties of cells by injecting superparamagnetic beads into a cell and applying a magnetic force to those beads.
Regarding claim 47, Selvaggi teaches the method wherein the biological sample is a multicellular biological sample selected from a tissue, an organ, or an embryo (Abstract: embryos of Drosophila melanogaster).
Regarding claim 48, Selvaggi teaches the method wherein the force applied to the biological sample is between 0.001 pN and 5000 nN (Pg. 045106-4, Col. 2, Par. 3: 220 pN).
Regarding claim 49, Selvaggi teaches the method wherein the distance between the magnetic tip and the biological sample is between 10um and 1mm (Pg. 045106-4, Col. 2, Par. 3: distance range of about 60-140um).
Regarding claim 50, Selvaggi teaches the method comprising a step of calibrating the tip and beads (Pg. 045106-4, Col. 1, Par. 2 “Force Calibration”).
Regarding claim 51, Selvaggi teaches the method wherein the mechanobiological properties are selected from rheology, kinematics, mechanical strength, elasticity, stiffness, plasticity, and viscoelastic properties, and any combination thereof (Abstract: determined microrheological properties of embryos; Pg. 045106-5, Col. 1, Par. 1: determined viscosity of cytoplasm).
Regarding claim 58, Selvaggi teaches the method wherein the cell element or compartment is the internal or external cell membrane of at least one cell of a biological sample (beads are injected into embryos such that they may exert forces on the internal membrane of the cell).
Claim(s) 60 is/are rejected under 35 U.S.C. 103 as being unpatentable over Selvaggi et al (Magnetic tweezers optimized to exert high forces over extended distances from the magnet in multicellular systems. Rev Sci Instrum. 2018 Apr;89(4):045106.) in view of Campas et al (US 2016/0116394 A1) as applied to claim 42 above, and further in view of Ganta et al (US 2016/0166507 A1).
Regarding claim 60, Selvaggi in view of Campas teaches the method of claim 42 as described above, and teaches that the superparamagnetic beads may be suspended in a coating of biocompatible oil. Selvaggi teaches that the superparamagnetic beads are injected into a cellular compartment of the biological sample (Pg. 045106-4, Col. 1, last Par.-Col. 2, Par. 2: “Embryo preparation and injection”).
Campas teaches that the carrier oil used may be any biocompatible oil (Par. 13: any biocompatible oil could be used).
Selvaggi and Campas differ from the instant claim in that they do not explicitly teach the method wherein the superparamagnetic beads comprise a biological coating.
Ganta teaches that flaxseed oil is a biocompatible oil (Par. 129).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Selvaggi in view of Campas such that the biocompatible carrier oil comprises flaxseed oil, as taught by Ganta. Since Campas teaches the use of any biocompatible oil as a carrier oil and Ganta teaches that flaxseed oil is a biocompatible oil, one of ordinary skill in the art would recognize this modification as simple substitution of known elements to achieve predictable results with a reasonable expectation of success. Additionally, Selvaggi teaches assaying a biological sample, such that one would be motivated to use a biological oil which would be compatible with the biological sample being assayed. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both Selvaggi and Campas disclose injection of superparamagnetic particles into an embryo sample.
A coating of flaxseed oil on the superparamagnetic beads in understood to read on the claimed “biological coating” because flaxseed oil is made from a plant, i.e. a biological source, and thus is related to a living organism.
Conclusion
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/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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