DETAILED ACTION
Election/Restrictions
Applicant’s election of Group I, claims 1-10, in the reply filed on July 13, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claim 1-10 will be examined.
Claim Objections
Claim 1 is objected to because of the following informalities: (1) “at least one iteration of an alternation of” should be “performing following steps for multiple times”; (2) “a step of” should be “moving”; (3) “a first direction of flow” should be “a first direction”; and (4) “during which the sample is subjected to a first difference in electric potential whose action on the nucleic acid molecules is opposite to the first direction of flow and causes the nucleic acid molecules to be retained in the capillary” should be “during moving the laminar flow of the nucleic acid sample through a capillary of a device in a first direction, applying an electric potential opposite to the first direction to the laminar flow of the nucleic acid sample such that the nucleic acid molecules in the sample are concentrated a concentration junction of the device”.
Claim 2 is objected to because of the following informality: “during the step of the laminar flow of the sample in the second direction of flow, the sample is subjected to a second difference in electric potential whose action on the nucleic acid molecules is opposite to the first direction of flow” should be “said moving the laminar flow of the sample in a second direction is finished by applying a pressure opposite to the first direction to the laminar flow of the nucleic acid sample in the capillary” in view of the specification (see paragraphs [0197] to[0208] and [0216], and Figure 10 of US 2024/0401115 A1, which is US publication of this instant case).
Claim 3 or 5 is objected to because of the following informalities: (1) “at least one step of flowing in the first direction of flow” should be “said moving the laminar flow of the nucleic acid sample through the capillary in a first direction”; and (2) “the amperage measured” should be “the amperage”.
Claim 4 or 6 is objected to because of the following informality: “this measured amperage” should be “the amperage”.
Claim 7 is objected to because of the following informality: “which comprises after an iteration of the alternation” should be “comprises, after performing the following steps once of the multiple times”.
Claim 8 is objected to because of the following informalities: (1) “the method” in line 1 should be “A method”; and (2) “which comprises the steps of the method for desalting and concentrating a nucleic acid sample according to claim 1” should be “comprises desalting and concentrating the nucleic acid sample using the method of claims 1”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Scope of enablement
Claims 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for moving a laminar flow containing a nucleic acid sample through a capillary, does not reasonably provide enablement for desalting and concentrating a nucleic acid sample more conductive than an analysis buffer using the methods recited in claims 1-7 and analyzing a nucleic acid sample using the methods recited in claims 8-10. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The Nature of The Invention
The claims are drawn to a method for desalting and concentrating a nucleic acid sample more conductive than an analysis buffer and a method for analyzing a nucleic acid sample. The invention is a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The Breadth of The Claims
Claims 1-7 encompass a method for desalting and concentrating a nucleic acid sample more conductive than an analysis buffer, comprising at least one iteration of an alternation of:
a step of the laminar flow of the sample through a capillary in a first direction of flow, the capillary being equipped with at least one local restriction in its cross-section and comprising the analysis buffer, during which the sample is subjected to a first difference in electric potential whose action on the nucleic acid molecules is opposite to the first direction of flow and causes the nucleic acid molecules to be retained in the capillary; and a step of the laminar flow of the sample, in a second direction of flow opposite to the first direction of flow. Claims 8-10 encompass a method for analysing a nucleic acid sample, which comprises the steps of the method for desalting and concentrating a nucleic acid sample according to claim 1, and, after the last iteration of the alternation, a step of separation by laminar flow of the sample in the capillary in the first direction of flow, during which the sample is subjected to a difference in electric potential less than or equal to the first difference in potential, whose action on the nucleic acid molecules is opposite to the first direction of flow and causes a partial retention of the nucleic acid molecules in the capillary.
Working Examples
The specification provides 9 examples (see pages 7-15 of US 2024/0401115 A1, which is US publication of this instant case). However, the specification provides no working example for desalting and concentrating a nucleic acid sample more conductive than an analysis buffer using the methods recited in claims 1-10 and analyzing a nucleic acid sample using the methods recited in claims 8-10.
The Amount of Direction or Guidance Provided and The State of The Prior Art
The specification provides 9 examples (see pages 7-15 of US 2024/0401115 A1, which is US publication of this instant case). However, the specification provides no working example for desalting and concentrating a nucleic acid sample more conductive than an analysis buffer using the methods recited in claims 1-7 and analyzing a nucleic acid sample using the methods recited in claims 8-10. Furthermore, there is no experimental condition and/or experimental data in the specification to support the claimed invention. During the process of the prior art search, the office has not found a prior art related to desalt and concentrate a nucleic acid sample more conductive than an analysis buffer using the methods recited in claims 1-7 and analyze a nucleic acid sample using the methods recited in claims 8-10.
Level of Skill in The Art, The Unpredictability of The Art, and The Quantity of Experimentation Necessary
While the relative skill in the art is very high (the Ph.D. degree with laboratory experience), there is no predictability whether a nucleic acid sample more conductive than an analysis buffer can be desalted and concentrated using the methods recited in claims 1-7 and a nucleic acid sample can be analyzed using the methods recited in claims 8-10.
Applicant’s invention is related to a known technique, µLAS technology since the specification teaches that “[T]he device described in documents PCT/FR2016/051774 and WO/2017/009566 enables the size profile of the cfDNA to be determined easily and economically. In order to analyse the DNA, the device operates in two steps, concentration and separation, performed in line. First of all, the DNA is concentrated by means of a capillary system formed of the junction of one capillary and another with a larger cross-section. The researchers make a solution containing the DNA flow in a laminar way in the large capillary, and use an electric field to slow down the migration. Because of the shearing from the laminar flow, this counter-electrophoresis produces a transverse force, dependent on the size of the DNA, which pushes the DNA towards the walls. The change in the speed of flow and in the electric field at the location of the constriction makes it possible to halt the DNA and concentrate it like a ‘clump’. In effect, upstream from the constriction, the flow and counter-electrophoresis are slow, causing a weak transverse force. The DNA is therefore in the bulk of the flow, and moves towards the constriction. On the other hand, downstream from the constriction, the flow and counter-electrophoresis are rapid, pressing the DNA firmly against the wall at a location where the laminar flow is very low and where the counter-electrophoresis dominates. The DNA therefore moves back towards the constriction, by counter-electrophoresis, along the wall. This clump is then released by the progressive decrease in the electric field, which also makes it possible to carry out the separation operation according to the size of the fragments. This technology is called ‘µLAS’ in the rest of the description” (see paragraph [0014] of US 2024/0401115 A1, which is US publication of this instant case) and the website of applicant’s company describes the principle of µLAS technology: “[A]ccording to Poiseuille law, when a viscous fluid flows through a capillary, its speed at the walls is zero, increasing steadily to reach its maximum at the centre. The additional application of an electric field in the direction opposite to the flow, creates on each flow-carried particle a transverse force towards walls. Besides, the bigger is a particle, the stronger is the transverse force. Thus, particles of different sizes migrate at different heights and therefore move at different speeds. This enables to separate DNA fragments depending on their size. After the first capillary is located a second one of smaller diameter. At this level, each size of DNA fragment is going stop when and where electrophoretic speed compensates for the hydrodynamic speed. This is how DNA is concentrated depending on its size. Besides, while DNA fragments are stopped, in situ purification occurs since the buffer still flows, carrying away impurities. Each pool of DNA size fragments can then be collected” (see “Discovery our technology: A one step concentration and purification technology of cfDNA analysis” from adelis-tech.com). Since the specification teaches that “[F]IG. 10 shows a typical sequence of operation of a DNA analysis with the method that is the subject of the invention implemented with two returns and the device 40. The distal capillary 47 is not shown in this figure. FIG. 10 shows the concentrated DNA in black, and the salts in cross-hatching”, “[D]uring an operation 61, the sample is injected into the device, by applying pressure for a given duration”, “[D]uring an operation 62, the injected sample is pushed by pressure to the centre of the injection chamber 44”, “[D]uring operations 63 and 64, the DNA is concentrated at the concentration junction 48 of the injection chamber 44, by applying a first pressure causing a flow in a first direction of flow (from left to right in FIG. 10) and a first difference in electric potential whose action on the nucleic acid molecules is opposite to the first direction of flow and causes the retention or deceleration of the nucleic acid molecules in the capillary. The separation capillary 45 fills with the sample solution, except for the largest DNA fragments, which remain retained at the concentration junction 48”, “[T]he migration speed of the smallest DNA fragments is slower than the average speed of the flow. In contrast, the ions forming the salts are too small for the development of a transverse force pushing them towards the wall, and they advance at the average speed of the flow, greater or less than their speed of electrophoresis depending on their positive or negative charge”, “[D]uring an operation 65, a flow of the sample, in a second direction of flow opposite to the first direction of flow, is caused by applying a second pressure in the opposite direction to the pressure exerted on the sample solution. A portion of the sample solution that had entered the separation capillary 45 flows back into the injection chamber 44, carrying DNA fragments which therefore return into the injection chamber 44. In the description, the operation 65 is called a ‘return’”, “[T]herefore, the concentration operation is stopped before the smallest fragments arrive at the end of the separation capillary, and a second pressure is applied in the opposite direction to the first pressure to take the volume from the separation capillary 45 back into the injection chamber 44”, “[D]uring an operation 66, the DNA is again concentrated at the concentration junction 48 of the injection chamber 44, by applying the first pressure causing a flow in the first direction of flow and the first difference in electric potential whose action on the nucleic acid molecules is opposite to the first direction of flow and causes the retention of nucleic acid molecules in the capillary. The separation capillary 45 fills with the sample solution, except for the largest DNA fragments, which remain retained at the concentration junction 48. Thus a new concentration step is carried out’, “[D]uring a second return operation 67, a flow of the sample, in the second direction of flow, is caused by applying a second pressure in the opposite direction to the pressure exerted on the sample solution. A portion of the sample solution that had entered the separation capillary 45 flows back into the injection chamber 44, carrying DNA fragments which therefore return into the injection chamber 44”, “[D]uring an operation 68, the DNA is again concentrated at the concentration junction 48 of the injection chamber 44, by applying the first pressure causing a flow in the first direction of flow and the first difference in electric potential whose action on the nucleic acid molecules is opposite to the first direction of flow and causes the retention of nucleic acid molecules in the capillary. The separation capillary 45 fills with the sample solution”, “[T]herefore, this alternation of return and concentration phases is reiterated. The salts are therefore evacuated progressively from the device, while the DNA molecules are mainly retained. The small DNA fragments can therefore be analysed correctly, which was impossible with the devices and methods of the prior art”, “[D]uring an operation 69, the DNA is separated according to size by a progressive decrease in the electric field applied between the inlet 41 and the outlet 42, the pressure generally being maintained constant” and “[P]referably, during the steps 65 and 67 of the laminar flow of the sample in a second direction of flow, the sample is subjected to a second difference in electric potential whose action on the nucleic acid molecules is opposite to the first direction of flow. The second difference in potential can therefore be identical to the first difference in potential. The molecules still close to the walls of the separation capillary therefore return more rapidly into the injection chamber than during a return by pressure alone, as described above” (see paragraphs [0197] to[0208] and [0216], and Figure 10 of US 2024/0401115 A1, which is US publication of this instant case), the specification clearly indicate that this application is to use µLAS technology for desalting and concentrating a nucleic acid sample containing different nucleic acid fragments and then separating these nucleic acid fragments according to their sizes, and requires several critical steps: (1) injecting a nucleic acid sample comprising different nucleic acid fragments and a salt to an injection chamber of a device and forming a laminar flow comprising the nucleic acid sample and the salt; (2) moving the laminar flow from the injection chamber to a capillary of the device and through the capillary in a first direction by applying a pressure to the laminar flow in the first direction; (3) during said moving the laminar flow through the capillary in the first direction, applying an electric potential to the laminar flow in the capillary of the device in a direction opposite to the first direction such that the largest nucleic acid fragments of the nucleic acid sample retain at a concentration junction of the injection chamber and the migration speed of the smallest nucleic acid fragments of the nucleic acid sample in the capillary is slower than the average speed of the laminar flow; (4) moving a portion of the laminar flow from the capillary back into the injection chamber in a second direction by applying a pressure to the laminar flow in the second direction, wherein the second direction is an opposite direction of the first direction; (5) moving the portion of laminar flow from the injection chamber to the capillary of the device and through the capillary in a first direction by applying a pressure to the laminar flow in the first direction; (6) during said moving the portion of the laminar flow through the capillary in the first direction, applying an electric potential to the laminar flow in the capillary of the device in the second direction; (7) repeating steps (4) to (6) for multiple times such that the different nucleic acid fragments of the nucleic acid sample are finally concentrated in the concentration junction of the injection chamber, thereby desalting and concentrating the nucleic acid sample; and (8) after step (7), separating the different nucleic acid fragments of the nucleic acid sample according to their size by progressively decreasing an electric potential applied to the laminar flow in the capillary of the device in the second direction. Although claim 1 requires at least one iteration of an alternation of: a step of the laminar flow of the sample through a capillary in a first direction of flow, the capillary being equipped with at least one local restriction in its cross-section and comprising the analysis buffer, during which the sample is subjected to a first difference in electric potential whose action on the nucleic acid molecules is opposite to the first direction of flow and causes the nucleic acid molecules to be retained in the capillary and a step of the laminar flow of the sample, in a second direction of flow opposite to the first direction of flow, since claim 1 does not include several critical steps: (1) injecting a nucleic acid sample comprising different nucleic acid fragments and a salt to an injection chamber of a device and forming a laminar flow comprising the nucleic acid sample and the salt; (2) moving the laminar flow from the injection chamber to a capillary of the device and through the capillary in a first direction by applying a pressure to the laminar flow in the first direction; (3) during said moving the laminar flow through the capillary in the first direction, applying an electric potential to the laminar flow in the capillary of the device in a direction opposite to the first direction such that the largest nucleic acid fragments of the nucleic acid sample retain at a concentration junction of the injection chamber and the migration speed of the smallest nucleic acid fragments of the nucleic acid sample in the capillary is slower than the average speed of the laminar flow; (4) moving a portion of the laminar flow from the capillary back into the injection chamber in a second direction by applying a pressure to the laminar flow in the second direction, wherein the second direction is an opposite direction of the first direction; (5) moving the portion of laminar flow from the injection chamber to the capillary of the device and through the capillary in a first direction by applying a pressure to the laminar flow in the first direction; (6) during said moving the portion of the laminar flow through the capillary in the first direction, applying an electric potential to the laminar flow in the capillary of the device in the second direction; and (7) repeating steps (4) to (6) for multiple times such that the different nucleic acid fragments of the nucleic acid sample are finally concentrated in the concentration junction of the injection chamber, thereby desalting and concentrating the nucleic acid sample, without above critical steps (1) to (7), it is unpredictable how a nucleic acid sample more conductive than an analysis buffer can be desalted and concentrated using the methods recited in claims 1-10. Furthermore, although claim 8 requires desalting and concentrating a nucleic acid sample according to claim 1, and, after the last iteration of the alternation, a step of separation by laminar flow of the sample in the capillary in the first direction of flow, during which the sample is subjected to a difference in electric potential less than or equal to the first difference in potential, whose action on the nucleic acid molecules is opposite to the first direction of flow and causes a partial retention of the nucleic acid molecules in the capillary, since claim 8 does not have a step for separating the different nucleic acid fragments of the nucleic acid sample according to their size by progressively decreasing an electric potential applied to the laminar flow in the capillary of the device in the second direction, without above separating step, it is unpredictable how the nucleic acid sample can be separated such that a nucleic acid sample cannot be analyzed using the methods recited in claims 8-10. In addition, since claim 1 or 8 does not require that the nucleic acid sample contains fluorescent nucleic acid molecules having different lengths, it is unpredictable how a fluorescence time profile of fluorescent nucleic acid molecules can be measured and how nucleic acid molecules of different lengths can be concentrated by utilizing a fluorescence profile of a calibration sample.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art”. The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genentech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “[I]t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement”.
In view of above discussions, the skilled artisan will have no way to predict the experimental results. Accordingly, it is concluded that undue experimentation is required to make the invention as it is claimed. The undue experimentation at least includes to test whether a nucleic acid sample more conductive than an analysis buffer can be desalted and concentrated using the methods recited in claims 1-7 and a nucleic acid sample can be analyzed using the methods recited in claims 8-10.
Conclusion
In the instant case, as discussed above, the level of unpredictability in the art is high, the specification provides one with no guidance that leads one to claimed methods. One of skill in the art cannot readily anticipate the effect of a change within the subject matter to which the claimed invention pertains. Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of any working example related to claimed invention and the no teaching in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
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 4, 6, and 8-10 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 4 is rejected as vague and indefinite. Since, in view of claim 1, the phrase “the number of iterations of the alternation” means a number for repeating two steps in claim 1, it is unclear why the number of iterations of the alternation can be an increasing function of the amperage of a peak of this measured amperage or of a peak of a derivative of this measured amperage. Please clarify.
Claim 6 is rejected as vague and indefinite. Since, in view of claim 5, the phrase “a duration” means a time period, it is unclear why the duration chosen can be a decreasing function of the amperage of a peak of this measured amperage or of a peak of a derivative of this measured amperage. Please clarify.
Claim 8 is rejected as vague and indefinite because the phrase “a step of separation by laminar flow of the sample in the capillary in the first direction of flow, during which the sample is subjected to a difference in electric potential less than or equal to the first difference in potential, whose action on the nucleic acid molecules is opposite to the first direction of flow and causes a partial retention of the nucleic acid molecules in the capillary” does not make sense in view of the specification (see paragraph [0208] of US 2024/0401115 A1, which is US publication of this instant case). Does this phrase mean “separating the nucleic acid sample in the capillary by moving the portion of the laminar flow through the capillary in the first direction based on applying a pressure to the laminar flow in the first direction and applying an electric potential to the laminar flow in the capillary in a direction opposite to the first direction during said moving the portion of the laminar flow through the capillary in the first direction, wherein the electric potential is less than the electric potential in the method of claim 1? Please clarify.
Claim 9 is rejected as vague and indefinite because the claim does not make sense in view of the specification (see paragraph [0208] of US 2024/0401115 A1, which is US publication of this instant case). Does this claim mean that, during said separating the nucleic acid sample in the capillary, the electric potential applied to the laminar flow in the capillary in a direction opposite to the first direction is progressively decreased? Please clarify.
Conclusion
Note that, since this instant application contains poorly written specification and claims due to an improper translation. Applicant is required to rewrite some parts of the specification and claims based on original French priority documents.
No claim is allowed.
Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center. The faxing of such papers must conform with the notices published in the Official Gazette, 1096 OG 30 (November 15, 1988), 1156 OG 61 (November 16, 1993), and 1157 OG 94 (December 28, 1993)(See 37 CAR § 1.6(d)). The CM Fax Center number is (571)273-8300.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph.D., whose telephone number is (571)272-0746. The examiner can normally be reached on Monday-Friday from 9 A.M. to 5 P.M.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Dr. Anne Gussow, Ph.D., can be reached on (571)272-6047.
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/FRANK W LU/Primary Examiner, Art Unit 1683 September 28, 2025
