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 . 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.
Priority
The instant application is a 371 of PCT/CN2019/124473 filed on 12/11/2019 and claims foreign priority to Chinese application no. CN201811514682.2 filed on 12/12/2018. The certified copy of the foreign priority application CN201811514682.2 filed on 06/11/2021 is acknowledged.
Status of the Claims
The claim amendments and remarks filed on 01/26/2026 are acknowledged. Claim 1 is amended. Claims 2-5, 13-16, 20-23, and 25-27 are cancelled. Claims 1, 6-12, 17-19, 24, and 28-33 are pending.
Claims 8-12, 17-19 and 30-32 were previously withdrawn in the office action dated 06/17/2025 from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable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.
Accordingly, claims 1, 6-7, 24, 28-29, and 33 are being examined on the merits herein.
Withdrawn Rejections
The cancellation of claim 3 renders the 35 USC 112(b) and 103 rejections over this claim moot.
The following grounds of rejection are new, maintained, and amended as necessitated by Applicant’s amendments.
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.
Claim 29 is 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 29 recites “wherein chemical entity is Universal Linker”.
There is insufficient antecedent basis for the limitation “chemical entity” in the claim because there is no prior recitation of a “chemical entity” in the claim.
For purposes of examination, claim 29 is being interpreted as wherein the linker molecule is Universal Linker.
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.
Claim(s) 1, 6-7, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over CN’741 (CN101948741B in PTO-892 dated 06/17/2025, an English translation is also included in PTO-892 dated 06/17/2025 and used as the basis for this rejection) in view of Padmanabhan et al. (US20130078390A1 in PTO-892 dated 01/06/2025) and Stanislaw et al. (US 20130196880 in PTO-892 dated 01/06/2025).
CN’741 discloses a microfluidic gene chip matched with a new generation low-cost high-throughput nucleic acid sequencing system (see first paragraph on page 1). CN’741 discloses that the chip comprises a set of reaction cells composed of a plurality of microfluidic channels. The microfluidic gene chip is tightly combined by two solid substrates. The surface is processed with a microfluidic channel reaction cell groove and a fluid input and output hole. The upper solid substrate is a solid material substrate, and the lower solid substrate is a transparent solid material substrate. A micro solid bead particle array is fixed on the inner lower surface of the transparent solid material substrate. A chemical layer is bonded to the underlying transparent solid material substrate, and a large number of nucleic acid molecules are immobilized on the array of tiny solid bead particles (see second paragraph on page 2). CN’741 discloses that the lower transparent solid material substrate is one of transparent glass, quartz, organic polymer material, or a composite composed of two or more of them (see fourth paragraph on page 2).
The difference between CN’741 and the claimed invention is that CN’741 does not disclose a surface treated with a silanizing reagent and a linker molecule capable of initiating a DNA/RNA synthesis reaction. Furthermore, CN’741 does not disclose a code having a specific characterization for the identity of the biochip such as a 2-dimensional bar code.
Padmanabhan et al. teaches a method of attachment of chemical moieties to matrices by the use of microwave technology (see Abstract). Padmanabhan et al. discloses that suitable matrices include but are not limited to, controlled pore glass (CPG), glass in the form of any glass surface natural or modified including beads or powders, silica gel, alumina, polystyrene, tentagel, polyethylene glycol, cellulose, Teflon, and their derivatives, ceramic, zeolite, clay, as well as, matrices such as, Ti, Carbon, Si, gold, or other metal surfaces (see paragraph 0018). Padmanabhan et al. teaches that their attachment methods can be used in applications including oligonucleotide synthesis, peptide synthesis, immunoassays, microarrays, proteomics, and medical diagnostics (see Abstract). Padmanabhan et al. discloses that there is a need for a more efficient process for attaching chemical moieties to different types of matrices, and that commonly employed loading processes are inefficient because of an incomplete reaction that results in “uncapped” functionalities on the solid matrix (see paragraph 0007).
Padmanabhan et al. teaches an example of their attachment method, in which the surface of controlled porous glass (CPG) was aminated (surface treated) with a mixture of APTES (silanzing agent) and PTES at a 1:1 ratio or 50% APTES (see page 13, paragraphs [0105-0107] and Table 4), which can be succinylated and coupled to a nucleoside for use in the synthesis of oligonucleotides (see page 3-4, Scheme 1). Here, the linking molecule structure shown in Scheme 1 of Padmanabhan et al. meet the limitation of the linker molecule recited in instant clam 1 because a nucleoside (monomer) is linked to the CPG via a linking molecule that is succinylated with a succinylating agent (reaction reagent), and the structure also shows an initial amino group end that is reacted with a succinylating agent as well as the linking molecule structure having a nucleoside that has a DMT-protected hydroxyl group. Padmanabhan et al. further teaches that their method of attachment can be applied for loading of supports with small molecules, nucleic acids, amino acids, antibodies, and other macromolecules (see paragraph 0047). Padmanabhan et al. discloses that nucleoside loadings of up to 90 micromole/g has been achieved in accordance with the invention, which is much higher than the 30 to 50 micromol/g loadings obtained by prior art protocols (see paragraph 0037).
Stanislaw et al. discloses devices such as an oligonucleotide array (see paragraph [0034]), which is being interpreted as a “biochip” according to the disclosed specification (see specification, paragraph [0003]). Stanislaw et al. teaches that their devices carry an information code such as a 2-dimensional data code, and that the code can be an optically decipherable pattern on the surface of the device (See Figure 3 and paragraph [0009]), which is also being interpreted as a “non-polished single-sided 2-dimensional bar code”. Stanislaw et al. discloses that the information code on their devices can be computer readable to correlate a particular address on the array with information about the sample (see paragraph [0100]), which is interpreted to having “a specific characterization for the identity of the biochip”.
It would have been prima facie obvious to combine CN’741 with Padmanabhan et al. and Stanislaw before the effective filing date of the claimed invention by modifying the nucleic acid immobilization onto the biochip of CN’741 with the attachment method disclosed by Padmanabhan et al. and further including a 2-dimensional bar code as disclosed by Stanislaw onto the biochip of CN’741 to arrive at the claimed invention. One of ordinary skill in the art would have made these modifications with a reasonable expectation of success because Padmanabhan et al. provides guidance that their attachment chemistry can be applied to a variety of application including oligonucleotide synthesis as well as on various solid supports such as the substrates disclosed in CN’741, and further provides motivation that their attachment methods yield a higher loading of nucleosides than prior art protocols. Therefore, an ordinary skilled artisan would have been motivated to use the attachment chemistry disclosed in Padmanabhan for the biochip disclosed in CN’741 in order to obtain the described advantage with a reasonable expectation of success. Furthermore, Stanislaw et al. provides motivation of including an information code such as a 2-dimensional bar code that is machine readable to relay information about the biochip sample. Therefore, an ordinary skilled artisan would also be motivated to include an information code such as the codes disclosed in Stanislaw for the biochip of CN’741 in order to relay information about the biochip with a reasonable expectation of success.
Furthermore, the modified biochip as disclosed by the combined teachings of CN’741, Padmanabhan, and Stanislaw described above meets the limitations of “the linker molecule capable of initiating a DNA/RNA synthesis reaction and reacting with a reaction reagent, thereby linking a monomer in the reaction reagent to a terminal of the linker molecule, wherein the linker molecule has a functional group capable of reacting with amino at the beginning end and hydroxyl with an acid-labile protecting group at the terminal” because as discussed above, the attachment method of Padmanabhan can be used for oligonucleotide synthesis, and the linking molecule structure shown in Scheme 1 of Padmanabhan et al. shows a nucleoside (monomer) being linked to the CPG via a linking molecule that is succinylated with a succinylating agent (reaction reagent), and the structure also shows an initial amino group end that is reacted with a succinylating agent as well as the linking molecule structure having a nucleoside that has a DMT-protected hydroxyl group.
Lastly, the modified biochip as disclosed by the combined teachings of CN’741, Padmanabhan, and Stanislaw described above would be capable of performing the intended use “for synthesis of nucleic acids” because all of the structural limitations of the biochip is met as described above. Furthermore, Padmanabhan provides guidance that their attachment method can be used for oligonucleotide synthesis.
MPEP 2111.02 II states that “To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim.”
Claim(s) 24 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over CN’741 (CN101948741B in PTO-892 dated 06/17/2025, an English translation is also included in PTO-892 dated 06/17/2025 and used as the basis for this rejection) in view of Padmanabhan et al. (US20130078390A1 in PTO-892 dated 01/06/2025) and Stanislaw et al. (US 20130196880 in PTO-892 dated 01/06/2025), as applied to claims 1-3, 6-7, and 28 above, and further in view of Pirrung et al. (Angewandte Chemie International Edition, 2002 in PTO-892 dated 06/17/2025)
The combined teachings of CN’741, Padmanabhan et al. and Stanislaw et al. are as described above.
The difference between the combined teachings of CN’741, Padmanabhan et al., and Stanislaw et al. and the instant invention is that the combined teachings of CN’741 and Padmanabhan et al. do disclose a biochip having a size of less than 2x2mm or a size of 0.5x0.5mm.
Pirrung et al. discloses the manufacture and applications of DNA microarray or chips (see Abstract). Pirrung et al. discloses that DNA chips have a promising ability to obtain information on nucleic acid levels and sequences faster, simpler, and cheaper than traditional methods, and that nucleic acid elements are readily synthesized and can often be reused. Pirrung et al. discloses that two key parameters of a microarray are the number of different probe sites (spots) per unit area, which reflects its information density (also called complexity), and the number of probe molecules per unit area within an individual probe site (see page 1277, left and right column). Pirrung et al. discloses that small arrays reduce the biological sample needed and list several DNA chips in Table 1 having array features such as 128x148 microns and 256x200 microns (see Table 1 on page 1278).
It would have been prima facie obvious to combine CN’741, Padmanabhan, and Stanislaw with Pirrung before the effective filing date of the claimed invention by optimizing the dimensions of the biochip of CN’741 based on guidance from Pirrung et al. to arrive at the claimed invention. One of ordinary skill in the art could have performed routine optimization to arrive at the recited biochip because Pirrung et al. provides guidance to reduce the array size of DNA-based microchips for increasing efficiency and reducing cost, and discloses similar DNA-based biochips having dimensions such as 128X148 microns and 256X200 microns. See MPEP 2144.05 II.
Claim(s) 29 is rejected under 35 U.S.C. 103 as being unpatentable over CN’741 (CN101948741B in PTO-892 dated 06/17/2025, an English translation is also included in PTO-892 dated 06/17/2025 and used as the basis for this rejection) in view of Padmanabhan et al. (US20130078390A1 in PTO-892 dated 01/06/2025) and Stanislaw et al. (US 20130196880 in PTO-892 dated 01/06/2025), as applied to claims 1-3, 6-7, and 28 above, and further in view of Ravikumar et al. (Organic Process Research & Development, 2008 in PTO-892 dated 06/17/2025).
The combined teachings of CN’741, Padmanabhan et al., and Stanislaw et al. are as described above.
The difference between the combined teachings of CN’741, Padmanabhan et al., and Stanislaw et al. and the instant invention is that the combined teachings of CN’741 and Padmanabhan et al. do disclose the linker molecule being Universal Linker.
Ravikumar et al. discloses a novel universal linker (UnyLinker) for use in efficient and scalable synthesis of oligonucleotides (see Abstract). Here, the UnyLinker molecule of Ravikumer et al. (see structure in Abstract graphic) is the same “Universal Linker” of the instant application because the instant specification discloses an identical structure that is referred to as “Universal Linker” (see paragraph 0045, page 9 in disclosed specification). Ravikumar et al. discloses that their UnyLinker molecule enables efficient synthesis of multiple oligonucleotide drugs using a single raw material, thereby eliminating a difficult to characterize nucleoside-loaded polymer matrix used as a starting material (see Abstract), and that their linker molecule can be used with various modified surface chemistries and scaled up to several kilogram quantities, thereby reducing costs associated with developing different linker support molecules (see Abstract, Conclusions, see page 401 left and right column). Ravikumar et al. demonstrates that their UnyLinker can be attached to several supports including a controlled pore glass (CPG) that are generally functionalized with amino or hydroxyl groups (see page 404, left column).
It would have been prima facie obvious to combine CN’741, Padmanabhan et al., and Stanislaw with Ravikumar et al. before the effective filing date of the claimed invention by substituting the linking molecule for attaching nucleic acids to the modified biochip as disclosed by the combined teaching of CN’741, Padmanabhan et al., and Stanislaw et al. described above with the Unylinker of Ravikumar et al. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Ravikumar et al. discloses their Unylinker can be used on solid supports such as those disclosed in the combined teaching of CN’741, Padmanabhan et al., and Stanislaw et al., and further discloses that their Unylinker has an expressed advantage of enabling efficient oligonucleotide synthesis using a single raw material. Therefore, an ordinary skilled artisan would have been motivated to use the Unylinker for the modified biochip as disclosed by the combined teaching of CN’741, Padmanabhan et al., and Stanislaw et al. described above with a reasonable expectation of success.
Response to Arguments
Applicant’s arguments filed on 01/26/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
Applicant states that CN’742 only teaches that their microfluid gene chips are used for nucleic acid sequencing rather than nucleic acid synthesis.
Applicant’s argument described above was not found persuasive because MPEP 2111.02 II states that “To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim.”. Here, the modified biochip as disclosed by the combined teachings of CN’741, Padmanabhan, and Stanislaw described above would be capable of performing the intended uses “for synthesis of nucleic acids” and “initiating a DNA/RNA synthesis reaction” because absent any evidence to the contrary, all of the structural limitations of the biochip is met as described above and is therefore considered for all intents and purposes to be “capable” of carrying out the recited purposes. Furthermore, Padmanabhan provides guidance that their attachment method can be used for oligonucleotide synthesis.
Applicant states that CN’741 doesn’t teach a solid plate substrate that could affect the product purity or synthesis efficiency of DNA synthesis. Applicant states that CN’741 also does not teach the material of the tiny solid particles that could affect nucleic acid sequencing.
Applicant’s argument described above was not found persuasive because MPEP 2144 IV states that “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.”.
Here, CN’741 discloses that their lower transparent solid material substrate is one of transparent glass, quartz, organic polymer material, or a composite composed of two or more of them (see fourth paragraph on page 2). Therefore, an ordinary skilled artisan could have readily chosen the transparent quartz to arrive at the claimed invention.
Furthermore, it is noted that the claims only require that the biochip is a transparent quartz chip and does not require that the surface that is being silanized and modified with a linker molecule is a transparent quartz material. Therefore, the modification discussed above on the tiny solid bead particles meets the limitation of the instant claims.
Applicant states that CN’741 doesn’t teach a surface treated with a silanizing reagent and modified with the recited linker molecule. Furthermore, Applicant states that Padmanabhan, Stanislaw, Pirrung, and Ravikumar do not teach using transparent quartz as a substrate for nucleic acid synthesis.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Here, it is the combined teachings of CN’741, Padmanabhan, and Stanislaw described above and the obviousness rationale discussed above based on these combined references to arrive at the claimed invention.
Applicant states that Padmanabhan does not teach a linker molecule (succinic anhydride) that has a functional group capable of reacting with amino at the beginning end and hydroxyl with an acid-labile protecting group at the terminal.
Applicant’s argument described above was not found persuasive because Scheme 1 Padmanabhan does show that the succinic anhydride reacts with the amino group of the silanized glass (CPG) on one end, and the other end reacting with a hydroxyl group on a DMT-protected (acid labile protecting group) nucleoside.
Lastly, it is noted that Applicant previously argued in the remarks filed on 08/14/2025 and 09/17/2025 that the product purity of DNA synthesis reaction was affected by material of the biochip and the optimal material was transparent quartz chip. Applicant points to Example 3 and Table 3 of the instant application demonstrating a higher product purity using a transparent quartz chip compared to a 100 nm silicon oxide wafer, 300 nm silicon wafer chip, frost quartz chip, and conventional chip as shown in Table 3 of the instant specification.
In response to these arguments, the evidence of an unexpected result must compare the claimed invention with the closest prior art as stated in MPEP 816.02(e). Here, the closest prior art to compare against the stated unexpected result of improved DNA product purity is CN’741.
While Applicant has demonstrated that the transparent quartz chip has a higher purity and single-step synthesis efficiency of the DNA synthesis product over other compared biochip materials such as 100nm silicon oxide wafer chip, 300 nm silicon wafer chip, frost quartz chip, and conventional chip as shown in Table 3 of the instant specification, Applicant has not provided evidence comparing against the closest prior art of CN’741 because CN’741 discloses that their biochip can be made of transparent quartz as well as other materials such as transparent glass, organic polymer material, or a composite composed of two or more of the materials as discussed above, and Applicant does not appear to have provided a comparison to transparent glass biochips or organic polymer material biochips. Furthermore, it is noted that Applicant has not disclosed what material “conventional chip” is made of.
Lastly, the claims do not appear commensurate in scope with the unexpected results because the claims only require that the biochip is a transparent quartz chip and does not require that the surface that is being silanized and modified with a linker molecule is a transparent quartz material. Here, the examples use biochips where the surface that is being treated with the silanzing agent and attaching to the linker is 100nm silicon oxide wafer chip, 300 nm silicon wafer chip, frost quartz chip, transparent quartz chip, and conventional chip (see Example 1, paragraphs 0098-0109). Therefore, the claims do not appear to be commensurate in scope.
Conclusion
No claim is found allowable.
THIS ACTION IS MADE FINAL. 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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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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