DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/12/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 37 is objected to because of the following informality: in line 3, “locally-heated” is recommended to be written as “locally heated” to match the format of the phrase used in the previous line. Appropriate correction is required.
Claim 38 is objected to because of the following informality: in line 2, “the denaturation temperature” should read “the denaturing temperature” to match the specific language used in claim 32, from which this claim depends. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 48-49 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.
Both claims 48 and 49 recite the limitation "the local heating element" in line 1. There is insufficient antecedent basis for this limitation in the claim, as “a local heating element” is not described in claim 47, from which both of these claims depend. This term will be interpreted as referring to “a heating element” as is described in claim 47.
Claim Interpretation
Regarding claim 47, it is noted that no actual amplification or particular reaction need occur in the claim, as the claim is drawn to a product. The term “reaction vessel” will be considered to be any vessel that is capable of holding a claimed reaction solution, and the term “reaction solution” will be considered any solution that holds a target nucleic acid.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 47 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bertling (US 5,985,555; cited in Applicant’s IDS).
Bertling teaches means for processing nucleic acids in a reaction mixture involving temperature control (Abstract). Specifically, nucleic acids can be amplified in a reaction mixture (which would act analogously to the claimed reaction vessel containing a reaction solution) in a manner such that a heated surface adjoining the reaction mixture and its immediate surroundings are temperature regulated, but where the main space of the reaction mixture is essentially isothermal (column 1, para. 7, see also column 3, para. 3). The surface of the heating element can directly adjoin the reaction mixture (column 3, para. 6), and column 4, para. 2 of Bertling states that the, “…advantage of the process according to the invention is that the device containing the heating and cooling elements can for example also be inserted into a large vessel containing the reaction mixture…”
Column 5, para. 2 states that the nucleic acids to be processed can be bound to the surface by physical means, such as by a magnet. In this scenario, the nucleic acids are bound to magnetic particles. A magnetic field can then be used to bind the particles to the surface (which comprises the heating element), where the magnet that produces the field can be behind the surface.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Bertling (US 5,985,555; cited in Applicant’s IDS).
Bertling teaches the device of claim 47, as described above.
Regarding claim 49, Figure 1 of Bertling shows the setup of a device encompassed by their invention, where the heating element is character 5 and the reaction vessel is character 3 (see column 2, para. 2). In this scenario, the heating element acts as an upper wall in the reaction vessel. Though it is not clear that such an embodiment is taught for use with an invention as described by Bertling in the rejection of claim 47 above, by using this structure with the teachings described above in the rejection of claim 47, the magnetic particles would be capable of directly interacting with said heating element without hindrance, and thus it would be motivating for the ordinary artisan to use, as this would ensure that the magnetic particles can easily interact with the heating element and that subsequent amplification would proceed as desired.
Thus, claim 49 is prima facie obvious over Bertling.
Claims 32-43, 46, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Bertling (US 5,985,555; cited in Applicant’s IDS) in view of Zilch et al. (US 2011/0008797 A1).
Bertling teaches means for processing nucleic acids in a reaction mixture involving temperature control (Abstract). Specifically, nucleic acids can be amplified in a reaction mixture in a manner such that a heated surface adjoining the reaction mixture and its immediate surroundings are temperature regulated, but where the main space of the reaction mixture is essentially isothermal (column 1, para. 7, see also column 3, para. 3; instant claim 37). The surface can be composed of a heating element and a cooling element, where the heating element may be a metal foil that can be heated via electric means (column 3, para. 4; instant claim 33). The surface of the heating element can directly adjoin the reaction mixture (column 3, para. 6), and column 4, para. 2 of Bertling states that the, “…advantage of the process according to the invention is that the device containing the heating and cooling elements can for example also be inserted into a large vessel containing the reaction mixture…”
Column 5, para. 2 states that the nucleic acids to be processed can be bound to the surface by physical means, such as by a magnet. In this scenario, the nucleic acids are bound to magnetic particles. A magnetic field can then be used to bind the particles to the surface (which comprises the heating element), where the magnet that produces the field can be behind the surface. Thus, the magnets would be bound to the heating element, where the heating element locally heats the reaction mixture (instant claim 34).
As the heating and cooling elements of Bertling are intended for nucleic acid amplification (see columns 1-2), it would be logical that in the magnetic particle embodiments of Bertling described above, said amplification would have to occur after the magnetic particles are already in place on the surface, otherwise the amplification of Bertling would not occur as intended (e.g. in a small area of the reaction mixture).
However, the reference does not clearly teach that the magnetic particles can have primer sequences, nor does the reference teach distinct removal of the sample liquid and the addition of amplification reaction solution. It is noted that regarding primers, the joining para. of columns 4-5 teaches that oligonucleotides bound to the surface can be primers that are used for elongation during amplification.
Zilch teaches the performing of thermally controlled reactions such as PCR in the context of magnetic beads (Abstract). The reference teaches that the magnetic particles themselves may contain primers that can be used to perform PCR on target sequences (paras. 11 and 64 and Figure 1). Para. 6 of the reference states that the combination of nucleic acids with magnetic beads is known, and para. 8 of the reference states, “The separation of the target structure or of the target molecule from the remainder of the sample and its subsequent purification takes place by means of the application of a magnetic field which concentrates and reversibly fixes the magnetic beads out of the suspension and in one region. The supernatant can then be disposed of and for example be replaced by a washing buffer in order to purify the target molecules bound to the beads.” Para. 55 notes that the same type of magnets used for moving the magnetic nanoparticles can be used as the magnetic component of the magnetic nanoparticles themselves, and, “This contributes significantly to the simplicity and compactness of a diagnostic measurement system.” Zilch also teaches specific amplification reaction components (see para. 67).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Zilch in the method of Bertling to arrive at the method of claim 32. Specifically, Zilch first teaches that the magnetic particles themselves can have the primers needed for amplification. The ordinary artisan would be motivated to structure the primers in this manner in the teachings of Bertling described above, rather than have the primers on the surface heating element, as this would prevent interference from capture elements on the particles and primers on the heating element surface. This would lead to an increase in amplification efficiency in these embodiments. At least some of the amplification products would then also remain attached to the beads, which would result in easier transfer/further manipulation of these products if it was desired. There would be a reasonable expectation of success as Bertling already teaches the attachment of primers to surfaces.
Additionally, Zilch teaches that magnetic particles can be used to localize targets in a solution, where the remaining solution can then be removed and the particles saved for downstream use. Thus, rather than simply add amplification reagents to the initial solution of Bertling, this teaching would motivate the ordinary artisan to localize the magnetic particles to the area of the heating element using the magnet/magnetic field taught by the reference, then remove the rest of the initial solution before adding the amplification solution (containing the necessary polymerase, dNTPs, etc.). This would reduce unwanted amplification as non-target nucleic acids would no longer be present, which would reduce noise in amplification product analyses and further increase amplification efficiency. Zilch teaches an amplification solution, as described above, as does Bertling (see the joining para. of columns 10-11, for example), and so the separate existence of such a solution is well-known in the art, and the ordinary artisan would be capable of its separate addition, providing a reasonable expectation of success.
Thus, claim 32 is prima facie obvious over Bertling in view of Zilch.
Regarding claim 35, Bertling states, “In the method according to the invention the heating element is used to heat until the surface and its immediate vicinity have been heated to the desired temperature. In this process a pronounced temperature gradient will form near the surface whereas the remaining part of the reaction mixture remains isothermal,” (column 3, para. 8).
Regarding claims 38-39, the adjoining para. of columns 3 and 4 of Bertling states, “The heating process can be completed within fractions of a second and in favourable cases even is milliseconds. The same applies to the cooling. The reaction space which is heated to the desired temperature can be very small, it is preferably less than 0.2 mm particularly preferably less than 0.5 µm deep.”
MPEP 2144.05 I states, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976)… Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Regarding the distance limitations of claim 38 and the timing limitations of claim 39, the instant specification does not indicate that either of these values are critical or produce unexpected results. Para. 46 of the instant specification states the diffusion distance range of claim 38, along with other diffusion distance ranges, and similarly, para. 48 lists the duration of denaturation of claim 39, along with other duration of denaturation times. There is no indication that the claimed values produce any particular result that would be superior to the other listed values. Thus, as Bertling teaches values that overlap with those of the instant claims, and the heating system of Bertling is used in Bertling in view of Zilch, Bertling in view of Zilch renders these claims prima facie obvious.
Regarding claim 36, as noted above, Bertling in view of Zilch teaches the method of instant claim 35, and as noted in the rejection of instant claims 38-39, also notes a reaction space for heating that can be from 0.2 mm to less than 0.5 µm deep (column 4, para. 4). In instant claim 36, the temperature gradient is stated to halve over a length between 1-10 µm. This overlaps with the space for heating taught by the reference, and so there would naturally be scenarios in which the gradient would halve over the claimed length, as heating/gradient lengths greater than 1-10 µm are encompassed by the reference. Thus, as the heating system of Bertling is used in Bertling in view of Zilch, Bertling in view of Zilch renders these claims prima facie obvious.
Regarding claim 40, as noted above in the rejection of claim 32, Zilch teaches that the magnet used and the magnetic particle can be made out of the same material, which would lead to a simpler and more compact system. Zilch also specifically teaches the use of ferromagnetic particles (paras. 23, 28, 39, and 44). Thus, it would be prima facie obvious that the magnet itself would also be made of a ferromagnetic material. As the use and manipulation of these materials is well-known in the art, as evidenced by Zilch, there would be a reasonable expectation of success.
Thus, claim 40 is prima facie obvious over Bertling in view of Zilch.
Regarding claim 42, Figure 1 of Bertling shows the setup of a device encompassed by their invention, where the heating element is character 5 and the reaction vessel is character 3 (see column 2, para. 2). In this scenario, the heating element acts as an upper wall in the reaction vessel. By using this structure with the teachings described above in the rejection of claim 32, the magnetic particles would be capable of directly interacting with said heating element, particularly in view of the fact that in Figure 1 of Bertling, oligonucleotides are shown to be directly interacting with the heating element.
Regarding claim 41, this differs from claim 42 in the specific wording, where claim 41 states that “the heating element is formed on a vessel wall of the reaction vessel” while in claim 42 the heating element “forms part of a vessel wall of the reaction vessel.” If the heating element is arranged as described above in the rejection of claim 42, then the heating element does form part of the wall, but is also formed on a wall of the reaction vessel, as the heating element is settled between the outer portions of the device, which also function as part of the upper wall.
Thus, these teachings of Bertling render both instant claim 41 and instant claim 42 prima facie obvious over Bertling in view of Zilch.
Regarding claim 43, as noted above in the rejection of claim 42, the heating element can form a wall of the reaction vessel. As stated in column 5, para. 2 of the reference, when magnetic particles/magnets are used, the magnet is located behind the surface heating element, and not on the side the particles bind to. Thus, when a magnet is used in such a scenario as described above in the rejection of claim 42, it would be oriented on a side of the heating that is away/averted from the reaction vessel.
Regarding claim 46, as noted above, Zilch teaches in para. 8 that when magnetic particles are moved to their desired location near the associated magnet, the liquid in a reaction container can be removed and replaced by a washing buffer to purify the target molecules. Re-suspension can then occur when desired by removing the magnetic field. Bertling also generally teaches washing steps to remove excess reagents (e.g. column 9, para. 3 and column 11, para. 3). It would thus be prima facie obvious that in the scenario described above in the rejection of claim 32, in which the initial sample solution is removed and replaced with amplification solution, that a wash step could be conducted in-between these steps to further purify the magnetic particles containing the target nucleic acids. This would ensure that no other nucleic acids or potential interfering reagents/molecules that may have been present in the initial sample still remain in the reaction vessel, which would increase the accuracy of the downstream amplification and subsequent detection or other analyses (such as sequencing, see Bertling, column 7, para. 5). The wash buffer could then be removed in a manner similar to the initial solution, with the target nucleic acids still attached to the magnetic particles/surface, and then amplification could proceed after the wash step once the amplification solution is introduced. There would be a reasonable expectation of success as washing is a well-known technique in the art, as evidenced by Bertling and Zilch.
Thus, claim 46 is prima facie obvious over Bertling in view of Zilch.
Regarding claim 48, Bertling teaches the device of claim 47, as described above. However, the reference does not teach the material that the heating element/metal foil is to be made of.
Zilch teaches the performing of thermally controlled reactions such as PCR in the context of magnetic beads (Abstract). Para. 6 of the reference states that the combination of nucleic acids with magnetic beads is known, and para. 8 of the reference states, “The separation of the target structure or of the target molecule from the remainder of the sample and its subsequent purification takes place by means of the application of a magnetic field which concentrates and reversibly fixes the magnetic beads out of the suspension and in one region. The supernatant can then be disposed of and for example be replaced by a washing buffer in order to purify the target molecules bound to the beads.” Para. 55 notes that the same type of magnets used for moving the magnetic nanoparticles can be used as the magnetic component of the magnetic nanoparticles themselves, and, “This contributes significantly to the simplicity and compactness of a diagnostic measurement system.” Zilch also specifically teaches the use of ferromagnetic particles (paras. 23, 28, 39, and 44).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Zilch to make the magnet and the magnetic particles in Bertling out of the same material in order to obtain the simplicity and compactness benefits described by Zilch, which also teaches methods of manipulating magnetic particles with magnets. As Zilch teaches that the use of ferromagnetic materials is known and that these materials can be used for magnetic components, there would be a reasonable expectation of success. Thus, it would be prima facie obvious that the magnet itself would also be made of a ferromagnetic material.
Thus, claim 48 is prima facie obvious over Bertling in view of Zilch.
Claims 44-45 are rejected under 35 U.S.C. 103 as being unpatentable over Bertling (US 5,985,555; cited in Applicant’s IDS), in view of Zilch et al. (US 2011/0008797 A1), and further in view of Kanai et al. (US 2021/0129158 A1).
Bertling in view of Zilch teaches the method of claim 32, as described above. Regarding claims 44-45, it is noted that while the claimed magnet must be “variable” in that it should be capable of changing position and/or orientation relative to the reaction vessel, there is no requirement in the claim that the magnet in claim 32 actually move in such a manner. Thus, the claims will be interpreted as requiring a magnet that is capable of the stated movement.
Neither Bertling nor Zilch describe a magnetic that can be variable in position.
Kanai describes a magnetic particle operation device that moves magnetic particles using a moveable holding magnet (Abstract). The magnetic particles are capable of immobilizing a target, such as nucleic acids (para. 44). Para. 78 describes a scenario in which a permanent magnet is held along the side of the device in a slidable position, where the magnetic particles will collect near the permanent magnet and can be moved as the magnet slides. In order to produce a suitable magnetic field, an electric magnet may also be used (para. 79). Kanai teaches that their magnetic methods allow for simple target purification (paras. 7 and 9).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Kanai to inform the magnet setup of Bertling in view of Zilch. Specifically, Bertling teaches that magnets may be used behind the heating surface of their invention, and that an alternating field may be incorporated, but does not provide additional details about how this may be done or magnet orientation generally (column 5, para. 2). Zilch describes multiple magnet orientations (see Figure 2 for example) and describes the use of permanent magnets or electromagnets (para. 57), but does not provide much detail regarding the movement of magnetic particles relative to the magnets or movements of the magnets themselves. Kanai provides a similar context to both inventions in that it deals with magnets and magnetic particles, and directly relates to the desire to move the magnetic particles described in Bertling. Specifically, by providing a magnet that is moveable, this allows for magnetic particles to be moveable as they move along with the magnet, which would be useful in the event they need to be collected from the reaction vessel for further downstream analysis of the target nucleic acids. As Bertling does not specify that their magnet position need be fixed, and only specifies that the magnet must be behind the surface so that the magnetic particles can attach to said surface, after amplification is complete, there would be no strict need for the particles to be directly attached to the surface, and so such additional movement is not precluded by the reference.
Additionally, as Kanai provides a clear method for producing a magnetic field involving the permanent and electric magnets, and Bertling does not specify how their magnetic field may be generated, using the structure/setup described by Kanai would amount to simple substitution. MPEP 2143 I (B) states, “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” As this change would still result in the production of a magnetic field and the magnetic particles moving towards the magnet situated behind the heating element surface, these results would be considered predictable.
Thus, claims 44-45 are prima facie obvious over Bertling, in view of Zilch, and further in view of Kanai.
Claims 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Bertling (US 5,985,555; cited in Applicant’s IDS) in view of Kanai et al. (US 2021/0129158 A1).
Bertling teaches the device of claim 47, as described above. Regarding claims 50-51, it is noted that while the claimed magnet must be “variable” in that it should be capable of changing position and/or orientation relative to the reaction vessel, there is no requirement in the claim that the magnet in claim 47 actually move in such a manner. Thus, the claims will be interpreted as requiring a magnet that is capable of the stated movement.
Bertling does not describe a magnetic that can be variable in position.
Kanai describes a magnetic particle operation device that moves magnetic particles using a moveable holding magnet (Abstract). The magnetic particles are capable of immobilizing a target, such as nucleic acids (para. 44). Para. 78 describes a scenario in which a permanent magnet is held along the side of the device in a slidable position, where the magnetic particles will collect near the permanent magnet and can be moved as the magnet slides. In order to produce a suitable magnetic field, an electric magnet may also be used (para. 79). Kanai teaches that their magnetic methods allow for simple target purification (paras. 7 and 9).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Kanai to inform the magnet setup of Bertling. Specifically, Bertling teaches that magnets may be used behind the heating surface of their invention, and that an alternating field may be incorporated, but does not provide additional details about how this may be done or magnet orientation generally (column 5, para. 2). Kanai provides a similar context in that it deals with magnets and magnetic particles, and directly relates to the desire to move the magnetic particles described in Bertling. Specifically, by providing a magnet that is moveable, this allows for magnetic particles to be moveable as they move along with the magnet, which would be useful in the event they need to be collected from the reaction vessel for further downstream analysis of the target nucleic acids. As Bertling does not specify that their magnet position need be fixed, and only specifies that the magnet must be behind the surface so that the magnetic particles can attach to said surface, after amplification is complete, there would be no strict need for the particles to be directly attached to the surface, and so such additional movement is not precluded by the reference.
Additionally, as Kanai provides a clear method for producing a magnetic field involving the permanent and electric magnets, and Bertling does not specify how their magnetic field may be generated, using the structure/setup described by Kanai would amount to simple substitution. MPEP 2143 I (B) states, “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” As this change would still result in the production of a magnetic field and the magnetic particles moving towards the magnet situated behind the heating element surface, these results would be considered predictable.
Thus, claims 50-51 are prima facie obvious over Bertling in view of Kanai.
Conclusion
No claims are currently allowable.
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/FRANCESCA FILIPPA GIAMMONA/Examiner, Art Unit 1681
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