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 .
The amendment filed 06 November 2025 has been received, entered and considered. The following information has been made of record in the instant amendment:
1. Claim 15 has been canceled.
2. No new Claims have been added.
3. Claims 4 and 13 have been amended.
4. Remarks drawn to rejections under 35 USC 112, 103, and double patenting.
The following objection(s)/rejection(s) has/have been overcome:
5. The rejection of Claims 4 and 13 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and the rejection of Claim 4 under 35 U.S.C. 112, 4th paragraph, have been overcome by amendment.
6. The rejection of Claims 1-2, and 5-14 provisionally under 35 U.S.C. 101 as claiming the same invention as that of claims 1-2, and 5-14 of copending Application No. 16/469,559 (reference application), and the rejection of Claim 3 provisionally on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 3 of copending Application No. 16/469,559 (‘559) in view of Mckernan et al (US 2009/0191566 A1; cited in IDS filed 05/01/2025) and further in view of Tereba et al (US 6,673,631; cited in IDS filed 05/01/2025) has been rendered moot since Application No. 16/469,559 (‘559) has been abandoned.
Claims 1-14 are pending in the case.
The following rejections are necessitated by Applicant's amendment filed 06 November 2025 wherein the limitations in pending claims 4 and 13 have been amended. Support for the amendment is seen at paragraphs 0021 and 0046 in the specification.
Claim Rejections - 35 USC § 103
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 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 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.
Claims 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Mckernan et al (US 2009/0191566 A1; cited in IDS filed 05/01/2025; of record) in view of Tereba et al (US 6,673,631; cited in IDS filed 05/01/2025; of record).
Mckernan teaches a method of selectively isolating nucleic acids present in a mixture by using a solid phase having magnetic microparticles and adsorbing the nucleic acid mixture on it and applying a magnetic field (Abstract; paras 0070-0071, 0110, part of the limitations of claim 1 and claim 13, parts (a), (c), (e)). According to Mckernan incubation in the presence of buffer and a solid phase carrier solution helps remove endotoxins (para 0061 and Example 6 at paras 0184-0186; as in claims 1(w2) and 13(b)). The solid phase carrier having the nucleic acid can be contacted with a washing buffer solution like aqueous salt solution. At paras 0130-0167, the examples disclosed teach dropping the magnetic particles in the washing solution (as in claim 1). This teaching of Mckernan tells one of ordinary skill in the art that the magnetic particles can be dropped into the washing solution in step (w1) in the absence of the magnetic field since in this step the magnetic particles are brought into contact with the nucleic acid so that they can be mixed well and then adsorbed on to the magnetic particles. Suitable wash solutions include the use of MgCl2 (para 0111, 0113; step w1 in claim 1). At para 0113, McKernan teaches that wash buffer solutions can be used to remove impurities from the solid phase carriers without solubilizing the target nucleic acid. The pH of the wash buffer can be adjusted according to the impurities expected. At para 0150 McKernan teaches an example of a wash buffer with a pH of 7.3. Since the pH can be adjusted and a wash buffer having a pH of 7.3 has been used, it would be obvious to the artisan to use water having a pH of 7, which is close to 7.3, as the washing solution as in claim 4. Even though McKernan teaches examples of wash solutions that have a total salt concentration of more than 100mM and also suggests a salt concentration of greater than about 0.1M (or 100mM) one of ordinary skill in the art will find it obvious to use a wash solution having a total salt concentration of 10-100mM for the purpose of optimization. Using a lower concentration of salt solution will also lower the cost of the process.
Mckernan teaches that many salts can be used in its method and suitable levels of the concentration can be empirically determined by one of ordinary skill in the art. The salt concentration can be from about 0.005M to about 5M (para 0101). The salts include NaCl and MgCl2. This is for adsorption. At para 0113, Mckernan teaches that aqueous salt solutions can also be used as wash solutions, and teaches salts like NaCl and MgCl2 for this purpose. One of the wash solutions taught has 0.1M NaCl, Tris (e.g., 10mM) and EDTA (e.g., 0.5mM). In this example NaCl is the only salt used which is 100mM. In view of this teaching one of ordinary skill in the art would find it obvious to use a washing solution having a total salt concentration below 100mM and below 25mM as in claims 1 and 3 in order to look for a lower salt concentration that would be optimal for the washing step. The artisan would also use a wash solution wherein the salt concentration is below 25mM in order to look for the lowest possible concentration that would remove impurities in the wash step. This would reduce the cost of the process. It would also be obvious to the artisan to include a pre-washing step wherein washing is done using an aqueous solution having a total salt concentration above 500mM as in claim 9 since the salt solutions remove impurities associated with the nucleic acid (para 0013). A pre-washing step would ensure removal of most of the impurities before contact with the solid phase carrier having the magnetic particles.
The nucleic acids that can be separated include DNA and RNA (paras 0068-0069, 0073; as in claim 2). The solid phase carrier can be silica (para 0080; as in claims 1 and 11). Example 3 at paras 149-150 discloses doing the washing with salt solution for 5 minutes (as in claims 5). The nucleic acids can be eluted from the solid phase carrier using a low ionic strength buffer. This indicates that during elution the mechanical force acting on the carrier containing the nucleic acid is gravity and it is acting in a vertical direction (para 0111; as in claims 8, 10, and 13(f)). Mckernan teaches that its process is highly automatable (para 0125; as in claim 14).
Since Mckernan teaches the purification of DNA and RNA in general the artisan would recognize from its teaching that nucleic acids having the chain lengths as in claims 6-7 could be isolated via the method of Mckernan.
McKernan teaches elution of the target nucleic acids after washing, but does not expressly teach step w3 in claim 1, and does not teach the use of chaotropic salts like guanidine hydrochloride as a component in the sample solution as in claim 12.
Tereba et al, drawn to isolation of DNA, teaches the use of chaotropic salts to a sample solution containing the nucleic acid and magnetic particles including silica magnetic particles (col. 5, lines 18-35; as in claim 12). It would be obvious to the artisan to use a sample solution having a chaotropic salt in the method of Mckernan since Tereba teaches that such salts make the nucleic acids thermodynamically more stable (col. 10, lines 54-67).
In view of the teachings of Mckernan it would be obvious to one of ordinary skill in the art that after washing the magnetic particles the nucleic acid adsorbed thereto can be separated from the washing solution instead of elution of the target nucleic acids as taught by Mckernan (as in claim 1, step w3), and use all the steps in claims 8 and 13, and also adjust the duration of the washing step as in claims 5 and 7 for the purpose of optimization. It would also be obvious to the artisan to separate the magnetic particles with the nucleic acid adsorbed thereto from the washing solution as in claim 1 step (w3).
MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.'" KSR, 550 U.S. at, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
According to the rationale discussed in KSR above, the rationale in (G) above is seen to be applicable here since based on the prior art teachings, nucleic acids have been isolated in a pure form using the claimed steps and reagents. Thus, it is obvious to combine prior art elements to arrive at the claimed method of nucleic acid isolation from a sample.
Thus, the claimed invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention over the combined teachings of the prior art.
The artisan would be motivated to use the claimed method (also taught by Mckernan and Tereba) since the steps are simple to carry out and give pure nucleic acid from different sources that are also free of endotoxins (Mckernan). The artisan would also prefer to use the steps of a method that is known in the art to give pure nucleic acids.
Response to Applicant’s Remarks
Applicant has traversed the rejection of the claims under 35 USC 103 arguing that: Neither Mckernan not Tereba individually or in combination teach or suggest “wherein the magnetic particles are dropped into the washing solution in step (w1) by switching off, removing, or relocating the magnetic field”. The invention is advantageous because an efficient removal of salt, ethanol and/or other contaminants form the target nucleic acid is achieved without significant reduction in nucleic acid yield. The intermediate state that is formed, in which the forces between the magnetic particles and nucleic acid molecules temporarily prevent the release of the nucleic acid molecules from the particles. The inventive process is advantageous since a drying step for evaporating organic solvents, although still possible, is not necessary. This saves time. The method is also efficient and relatively simple, nucleic acids can be purified at high yields and with high purity with low number of steps.
When dropping the magnetic particles into the solution by switching off, removing or relocating the magnetic field, the artisan would have expected an intimate interaction between target nucleic acid and washing solution and thus would have avoided low salt non-binding conditions at a total salt concentration of below 100mM. Even if adjusting salt concentration below 100mM the artisan would then have an incentive to agitate the solution as little as possible and would not have dropped the magnetic particles into the washing solution by switching off, removing or relocating the magnetic field. The combination of features as in claim 1 would not be obvious.
Different conditions are required for washing of nucleic acids on magnetic particles or the elution from magnetic particles. Mckernan teaches a broad range of about 0.005M to about 5M. This is a large range across which to optimize with no reasonable expectation of success. Mckernan teaches that salt may be added to the reagent to cause precipitation of the nucleic acid and/or peptide in the mixture on to the solid phase carriers. Mckernan’s disclosure suggests that more salt would be preferable in a washing buffer rather than less salt. At para 0113 Mckernan teaches that a suitable salt concentration is greater than about 0.1M and is preferably about 0.5M. This a teaching away from the salt concentration being below 100mM as in claim 1. Mckernan uses a salt concentration of 110mM (para 0113). It does not give a teaching of a salt concentration below 0.1M. Since all solutions used by Mckernan are above 100mM salt the artisan would understand sufficiently high salt to mean greater than 100mM salt.
It should be noted that removal of the desired product is not desirable in washing step. If the aqueous solution used for washing causes removal of the desired product it will lead to loss of the desired species. Therefore, the artisan would not consider the teaching of Mckernan at para 0110 relevant to the development of a washing buffer. For the purpose of optimization, the objective would be to achieve as high a nucleic acid yield per unit of magnetic particles as possible. Increasing the nucleic acid binding to the magnetic particles would allow the use of a smaller quantity of magnetic particles, thereby reducing the cost.
Tereba does not disclose the use of an aqueous solution which has a total salt concentration below 100mM. Tereba teaches the use of wash solution comprising alcohol. The artisan in view of Mckernan and Tereba would seek to test washing solutions comprising different alcohols. For these reasons withdrawal of the rejection is requested (pages 6-16).
Applicant’s arguments have been considered but are not found to be persuasive.
As set forth in the rejection above, Mckernan’s teaching does suggest the magnetic particles being dropped into the washing solution in step (w1). The artisan would recognize that the dropping of the magnetic particles should be done in the absence of the magnetic field since in this step the magnetic particles are brought into contact with the nucleic acid in the sample so that they can be mixed well and then adsorbed on to the magnetic particles by applying a magnetic field. This would create the intermediate state that is formed, in which the forces between the magnetic particles and nucleic acid molecules temporarily prevent the release of the nucleic acid molecules from the particles as argued by applicant. Mckernan teaches isolation of pure nucleic acids in high yields without the use of organic solvents like alcohol. Therefore, the artisan in view of Tereba will not be persuaded to test washing solutions comprising different alcohols. Reducing the salt concentration and using an aqueous solution without an organic solvent like alcohol will reduce the cost of the process. Water is readily available and is cheaper than organic solvents.
Claim 1 recites a salt concentration below 100mM. This recitation does not clearly tell how much below 100mM the concentration should be. One of ordinary skill in the art in view of Mckernan would have a reasonable expectation of isolating the nucleic acid using a salt concentration of 99mM or 98mM or 97mM etc., since these are not very far away from the 100mM or even 110mM concentration of Mckernan. The artisan would experiment with using different salt concentration for the washing solution in order to find the lowest salt concentration range that gives optimal yield and purity of the nucleic acid. The artisan would also adjust the number of magnetic particles depending on the sample size for the optimization. These three adjustments will reduce the cost of the method. The artisan won’t look at just the magnetic particle use alone for the purpose of reducing the cost.
Mckernan’s concentration range of about 0.005M to about 5M may be broad. This tells the artisan that this range can be used and should work. The artisan can and will look for the lowest concentration or concentration range that gives optimal results. This can be done as routine optimization using the teachings of Mckernan.
Mckernan may teach that salt may be added to the reagent to cause precipitation of the nucleic acid and/or peptide in the mixture on to the solid phase carriers. One of ordinary skill in the art will recognize that once the magnetic particles are dropped into the wash solution and mixed well, and then magnetic field is applied this would cause the nucleic acid particles to adsorb on to the magnetic particles leaving behind impurities in the solution. The intermediate state that is formed, in which the forces between the magnetic particles and nucleic acid molecules temporarily prevent the release of the nucleic acid molecules from the particles as argued by the applicant is what is realized in this step and also will be recognized by the artisan. The artisan would not add more salt to cause precipitation since there is a possibility that other contaminants present may also precipitate with the nucleic acid. At para 0113, Mckernan teaches a total salt concentration of 110mM as an example for use since Tris is also a salt according to applicant. 110mM again is not too far away to reduce the salt concentration below 100mM for the artisan for the purpose of optimization. Mckernan’s use of salt concentrations above 100mM will not be understood by the artisan that sufficiently high salt to mean greater than 100mM salt, especially since the Mckernan teaches salt concentration in the range 0.005M to about 5M, which includes concentrations below 100mM.
Tereba is cited for teaching adding chaotropic salts to a sample solution containing nucleic acid and magnetic particles including silica particles. Therefore, one of ordinary skill in the art can adsorb the sample solution containing the nucleic acid and the chaotropic salt to the silica magnetic particles as taught by Tereba followed by the application of magnetic field and at least one of the steps (w) as set forth above. Tereba need not necessarily teach the use of an aqueous washing solution wherein the total salt concentration is below 100mM since Mckernan’s teaching suggests that.
Therefore, the combined teachings of the prior art render the claims obvious. The rejection is maintained.
Conclusion
1. Pending claims 1-14 are rejected.
2. Claim 15 has been canceled.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GANAPATHY KRISHNAN/Primary Examiner, Art Unit 1693