Ex Parte Cerrina et alDownload PDFPatent Trial and Appeal BoardNov 8, 201712430572 (P.T.A.B. Nov. 8, 2017) Copy Citation United States Patent and Trademark Office UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O.Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 12/430,572 04/27/2009 Franco Cerrina 00300-0122 3384 96854 7590 Bell & Manning, LLC 2801 West Beltline Highway Ste. 210 Madison, WI 53713 EXAMINER LANDAU, SHARMILA GOLLAMUDI ART UNIT PAPER NUMBER 1653 NOTIFICATION DATE DELIVERY MODE 11/13/2017 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docketing @ bellmanning, com cbell @ bellmanning. com pporembski @ bellmanning. com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte FRANCO CERRINA and TAO WANG Appeal 2017-000701 Application 12/430,572 Technology Center 1600 Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and RYAN H. FLAX, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134(a) involving claims to a microfluidic system. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Statement of the Case Background “By incorporating solid-phase chemical synthesis with semiconductor fabrication technologies, several innovations, i.e. ink-jet, electrochemical, optical and microfluidic methods, allow parallel in-situ syntheses of oligonucleotides” (Spec. 13). “However, these systems produce only one oligonucleotide sequence per reactor and, therefore, require complex, multi- 1 Appellants identify the Real Party in Interest as the Wisconsin Alumni Research Foundation (see App. Br. 2). Appeal 2017-000701 Application 12/430,572 reactor systems in order to provide for parallel synthesis of oligonucleotides.” (Id.). “The present invention relates to methods and devices for the parallel synthesis of chain molecules, such as oligonucleotides, in a multi-stream laminar flow” (Spec. 12). The Claims Claims 17, 18, 21—28 and 31 are on appeal. Independent claim 17 is representative and reads as follows: 17. A micro fluidic system comprising: (a) a microfluidic cell comprising a microfluidic channel comprising a first set of particle holders and a second set of particle holders, wherein the microfluidic channel is dimensioned to support a two-stream laminar flow; (b) a plurality of particles, each held in one of the particle holders, wherein the particles are surface-functionalized with nucleotide bases comprising blocking groups, the blocking groups characterized in that they prevent the nucleotide bases from undergoing oligonucleotide synthesis reactions with other nucleotide bases; and (c) a particle trapping apparatus configured to create a trap for at least one of the particles; wherein the microfluidic cell further comprises a first inlet port in fluid communication with the microfluidic channel and configured to introduce a first laminar stream of fluid along the first set of particle holders and a second inlet port in fluid communication with the microfluidic channel and configured to introduce a second laminar stream of fluid along the second set of particles holders. 2 Appeal 2017-000701 Application 12/430,572 The Issues A. The Examiner rejected claims 17, 18, 21—26, 28, and 31 under 35 U.S.C. § 103(a) as obvious over Chou2 and Sundararajan3 (Final Act. 3—9). B. The Examiner rejected claims 17, 18, 21—26, 28, and 31 under 35 U.S.C. § 103(a) as obvious over Chou, Sundararajan, and Tan4 (Final Act. 9-10). A. 35 U.S.C. § 103(a) over Chou and Sundararajan The Examiner finds Chou teaches an apparatus comprising physical barriers in a microfluidic device for holding or trapping particles at preselected positions (i.e.: a first set of particle holders and a second set of particle holders), wherein the microfluidic channel has a height or width 200 pm or less (i.e.: dimensioned to support a two-stream laminar flow, as evidenced by instant claim 22), and one or more positioning mechanisms, such as optical tweezers (i.e.: a particle trapping apparatus[)]. (Final Act. 3). The Examiner finds “Example 3 further demonstrates at least two different laminar flows in the channel” and “two inlet ports in communication with the microfluidic channel and configured to introduce a first laminar stream along the first set of particle holders and a second laminar stream along a second set of particle holders” {Id. at 4). 2 Chou et al., US 2004/0072278 Al, published Apr. 15, 2004. 3 Sundararajan et al., US 2005/0221333 Al, published Oct. 6, 2005. 4 Tan et al., A trap-and-release integrated microfluidic system for dynamic microarray applications, 104 Proc. Nat’l Acad. Sci. USA 1146—51 (2007). 3 Appeal 2017-000701 Application 12/430,572 The Examiner acknowledges Chou does “not specifically teach wherein the particle holders have an upstream opening and a downstream opening” (Final Act. 5). The Examiner finds Sundararajan teaches “barriers for holding particles in a microfluidic channel which comprise an upstream opening and a downstream opening, wherein the upstream opening is larger than the downstream opening” (Id.). The Examiner finds Sundararajan teaches “optical traps utilizing a laser light source and that optical tweezers are tightly focused beams of laser light” and “dimethoxytrityl protected nucleic acids attached to particles” (Id.). The Examiner finds it obvious to utilize particle holders with an upstream and downstream opening as taught by Sundararajan et al. at the desired sizes in the microfluidic device taught by Chou et al. One would have been motivated to do so in order to in order to allow a nucleotide, a nucleic acid molecule, and/or a protein to pass through the restriction barrier as taught by Sundararajan et al. (see [0027]) or in order to allow fluid to flow more easily through the channel without interrupting fluid flow. (Id.). The Examiner also provides the alternate rationale that it would have been obvious to substitute one known element (i.e.: the particle holders taught by Sundararajan et al.) for another known element (i.e.: the particle holders taught by Chou et al.) using known methods (i.e.: the methods taught by all the cited references) with no change in their respective functions, and the substitution would have yielded the predictable results of a microfluidic apparatus comprising particle holders with an upstream opening and a downstream opening. (Id. at 6). 4 Appeal 2017-000701 Application 12/430,572 The issue with respect to this rejection is: Does the evidence of record support the Examiner’s conclusion that Chou and Sundararajan render claim 17 obvious? Findings of Fact 1. Chou teaches: “Particle manipulations and analyses are performed in microfluidic systems. . . . Microfluidic systems carry fluid in predefined paths through one or more microfluidic passages” (Chou 1123). 2. Chou teaches “positioning mechanisms generally comprise any mechanisms in which a force acts directly on a particle(s) to position the particle(s) within a microfluidic network. . . . Suitable optical positioning mechanisms include ‘optical tweezers,’ which use an appropriately focused and movable light source to impart a positioning force on particles” (Chou 1191). 3. Chou teaches: “Microfluidic systems may include one or more retention mechanisms . . . retention mechanisms, also referred to as capture or trapping mechanisms, may retain any suitable number of particles, including single particles or groups/populations of particles” (Chou 1211). 4. Figure 11C of Chou is reproduced below: 5 Appeal 2017-000701 Application 12/430,572 FIG. 11C shows a retention mechanism 410 that may be used in system 250 or any other suitable microfluidic system to form a positioned, two-dimensional array of retained particles. Mechanism 410 includes an array of individual traps 412 oriented to receive particles from inlet channel 414. Traps 412 form a two-dimensional array of particle retention sites. . . . Each trap 412 may be dimensioned to hold one or plural particles and may include size-selective channels or similar features to allow fluid to flow through portions of the traps. Traps 412 may be disposed within a common chamber 416 having a[] single or plural outlet channels 418. (Chou 1392). 5. Chou teaches: The microfluidic systems described in [Example 3] position a plurality of particles or (particle populations) and/or reagents along distinct, transversely disposed flow paths or regions within a channel or flow stream. The transversely disposed flow paths may be defined by introducing the particles and/or reagents into the channel along distinct laminar flow paths, by joining separate inlet channels (or inlet flow streams) carrying the particles and/or reagents. (Chou 1398). 6. Chou teaches “pump(s) is started that drives flow of the focusing buffer through the focusing channels. Valves that control the flow of particles from inlets 1 and 2 are opened. Particles enter confluence 444, but are focused to spaced, intermediate, laminar flow streams 454, 456” (Chou 1409). 7. Chou teaches “methods for genotypic assays may include polymerase-mediated amplification of nucleic acids, for example, by thermal cycling (PCR) or by isothermal strand-displacement methods” (Chou 1302). 6 Appeal 2017-000701 Application 12/430,572 8. Chou teaches This example describes a microfluidic system that serially traps small sets of particles at preselected positions within the system, allowing treatment of the trapped particles in parallel with desired reagents. Due to serial trapping of input particles, a single loading of particles into one inlet may be used to supply particles to an entire array of traps. Thus, this design may be used to integrate a large number of traps into a single system. This microfluidic system also reduces the number of control lines required, as single control lines regulate sets of fluidic channels, such as perfusion channels, that individually interface with each of the traps. Accordingly, single control lines provide parallel control for fluidic delivery to, or output from, each of the traps. Such parallel control allows similar particles that are retained by each trap to be individually treated with distinct reagents. (Chou 1440). 9. Sundararajan teaches a nucleic acid molecule restrained in the restriction barrier can be analyzed using methods other than by exonuclease treatment in a sequencing reaction. For example, the system can be used to amplify a nucleic acid molecule attached to the surface of the particle using known amplification methods, such as the polymerase chain reaction. (Sundararajan 119). 10. Figure 1 of Sundararajan is reproduced below: Microfluidic channel 100 7 Appeal 2017-000701 Application 12/430,572 FIG. 1 illustrates an exemplary microfluidic channel 100 for performing methods provided herein that involves trapping a bead 150 with an attached single nucleic acid molecule 160 in a restriction barrier 140. The microfluidic channel 100 includes an immobilization structure, which in certain aspects of the invention is a restriction barrier 140. The restriction barrier 140 in this example includes a first angled wall 120 and a second angled wall 130 between which a single particle is captured. The first angled wall 120 and second angled wall 130 are spaced apart to allow a molecule such as a nucleotide molecule, a nucleic acid molecule and/or a protein such as an exonuclease, to flow between them. However, the first angled wall 120 and second angled wall 130 are spaced close enough to each other to retain the particle 150. (Sundararajan 1 53). 11. Sundararajan teaches a “first angled wall to form a first opening at least 1 micron in width or diameter and a second opening less than 10 microns in width or diameter, wherein the first opening has a greater width or diameter than the second opening. In certain aspects, the second opening is less than 1 micron in width or diameter” (Sundararajan 121). 12. Sundararajan teaches particles “can be a wide range of sizes, shapes, and materials, provided that a nucleic acid can be attached to the surface of the particle, the particle can be captured, transported, and released by optical tweezers, and movement of the particle can be restrained in a restriction barrier” (Sundararajan 1 59). 13. Sundararajan teaches “the particles can be surface- fimctionalized microsphere beads” (Sundararajan 1 59). 8 Appeal 2017-000701 Application 12/430,572 14. Figure 3 of Sundararajan is reproduced below: Fluidic Alignment FIG, 3 A tphosphorsmidites) have toetter access to the end of the DNA, thus ve i> etter yield FIG. 3C Flui die A li gum ait exposes the ends of the Molecules FIG, 3B The methods provided are useful, for example, for improving the yield of an oligonucleotide synthesis reaction, as illustrated in FIG. 3. Accordingly, molecules contacted in methods disclosed herein include reactants typically used in nucleic acid synthesis, such as the well known phosphoramidite method. Typically, the first molecule is a nucleotide or a growing nascent nucleic acid molecule 310 to which monomers 320, phosphoramidite nucleotides, (i.e. the second molecule) are incorporated. A nascent nucleic acid molecule 310 that is attached to a solid support 330 can be aligned using fluidic alignment (FIG. 3A). Fluidic alignment exposes the ends of the nucleic acid molecules 310 (FIG. 3B). As a result of the fluidic alignment, monomers (i.e. phosphoramidite nucleotides 320) have better access to the end of the nucleic acid 310 (FIG. 3C), which is expected to result in better yield. (Sundararajan 192). 9 Appeal 2017-000701 Application 12/430,572 15. Sundararaj an teaches Existing technologies attempt to direct a reactant to a desired position by specific binding, such as by DNA hybridization . . . Synchronization of multiple-molecule polymer reactions is another unsolved problem. For example in exonuclease DNA sequencing, also called direction DNA sequencing, individual DNA molecules bind to an exonuclease with different rates . . . To synchronize nucleic acid sequencing reactions, the use of thermostable and photoactivating enzymes has been disclosed. . . Another presently unsolved problem is that site-specific reactions on molecules often give lower yield due to side reactions. For example, in solid-phase oligo-nucleotide synthesis . . . Provided herein are methods that overcome these shortcomings of current methods, by using fluidic alignment to lock the conformation and orientation of a reactant before confining a reaction to a very small area (Sundararajan || 83—87). Principles of Law “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Analysis We adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Final Act. 3—9; FF 1—15) and agree that the claims are rendered obvious by Chou and Sundararajan. We address Appellants’ arguments below. Appellants contend “Chou does not teach that the apparatus described therein are suitable for use in synthesizing oligonucleotides. Nor does Chou 10 Appeal 2017-000701 Application 12/430,572 teach the use of particles that are surface-functionalized with nucleotide bases comprising blocking groups.” (App. Br. 5). Appellants contend that “Sundararajan teaches certain apparatus that are designed for DNA sequencing, hybridization, and PCR amplification, and also teaches other, different apparatus that are designed for oligonucleotide synthesis” (Id. at 6). Appellants contend the “Examiner has articulated no reason that one of ordinary skill in the art would extract the dimethoxytrityl blocking group- functionalized particles from Sundararajan’s oligonucleotide synthesis apparatus and place them into Chou’s cell/particle assay apparatus to arrive at the invention of claim 17” (Id.) We find this argument unpersuasive because it substantially focuses on whether it would have been obvious to modify Chou with Sundararajan’s blocking group particles. However, “where a rejection is predicated on two references each containing pertinent disclosure ... we deem it to be of no significance, but merely a matter of exposition, that the rejection is stated to be on A in view of B instead of on B in view of A, or to term one reference primary and the other secondary.” In re Bush, 296 F.2d 491, 496 (CCPA 1961). In this case, the Examiner relies upon Sundararajan to teach a microfluidic system for nucleic acid analysis or oligonucleotide synthesis (FF 9, 10, 14) that comprises (a) a microfluidic cell with particle holders (FF 10—12), (b) a plurality of particles held in the particle holders (FF 11) that may be surface functionalized (FF 13) for use in a phosphoramidite oligonucleotide synthesis method (FF 14), and (c) a particle trapping apparatus such as optical tweezers (FF 12). 11 Appeal 2017-000701 Application 12/430,572 While the Examiner does not rely upon Sundararajan to teach two stream laminar flow with two sets of particles holders as in the “wherein” clause of claim 17, the Examiner relies upon Chou to teach micro fluidic systems (FF 1—3) that comprise multiple sets of particle holders and a two- stream laminar flow (FF 4—6) and the use of these systems in nucleic acid analysis methods (FF 7). The Examiner reasons that the combination of Sundararajan and Chou would have been obvious because improvement of Sundararajan through the use of multiple particle holders and flow streams as disclosed by Chou would “enable increased throughput and analysis of multiple samples simultaneously” (Ans. 9). Chou specifically supports this logic, teaching that the use of multiple traps allows “treatment of the trapped particles in parallel with desired reagents” and permits “each trap to be individually treated with distinct reagents” (FF 8). We agree with the Examiner’s reasoning that incorporating Chou’s parallel microfluidic processing for DNA assays into Sundararajan’s microfluidic oligonucleotide synthesis in order to allow increase throughput of multiple samples for improved oligonucleotide synthesis would have been a predictable variation obvious to the person of ordinary skill in order to increase throughput. “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR, 550 U.S. at 417. Appellants contend that the Examiner’s rationales are all related to the number - not the type - of particles being processed. As such, none of the proffered rationales provides any reason to include Sundararajan’s dimethoxytrityl blocking group-functionalized particles into 12 Appeal 2017-000701 Application 12/430,572 Chou’s apparatus. Rather, at best, these provide motivation to include a plurality of particles, each held in one of the particle holders, in an apparatus. (App. Br. 7). We remain unpersuaded by this argument because Appellants’ focus on the Examiner’s particular order of references in the rejection, rather than addressing the combination of teachings as a whole, fails to properly consider the combination of Sundararajan and Chou for the reasons given above. Prior art “must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.” In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Here, it is the combination of teachings of Sundararajan and Chou that render the claimed apparatus obvious because, as the Examiner notes, the combination would permit oligonucleotide synthesis using Sundararajan’s dimethoxytrityl blocking group- functionalized particles with Chou’s microfluidic apparatus “in order to increase efficiency and throughput of nucleotide synthesis” (Ans. 9). Appellants contend “[tjhese apparatus have very different configurations, including different flow streams. Thus, Sundararajan actually supports the conclusion that apparatus for oligonucleotide synthesis, apparatus for DNA sequencing, and apparatus for biological assays are not art recognized equivalents” (App. Br. 8). We are not persuaded. Sundararajan expressly teaches “methods that overcome . . . shortcomings of current methods, by using fluidic alignment” including hybridization, sequencing, and oligonucleotide synthesis methods (FF 15). Thus, Sundararajan teaches that the same micro fluidic device can improve all of these methods, demonstrating that for purposes of 13 Appeal 2017-000701 Application 12/430,572 microfluidic improvements, these methods and fluidic devices were recognized as equivalent. See In re Mehta, 347 F.2d 859, 863 (CCPA 1965) (“No invention can be seen in obvious equivalents of the prior art.”) Appellants contend “a reconfiguration is not suggested by Chou, Sundararajan, or any other reference . . . Rather, the motivation for this reconfiguration is gleaned entirely from the present application and is, therefore, based on impermissible hindsight” (App. Br. 8). We find this argument unpersuasive. While we are fully aware that hindsight bias may plague determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36 (1966), we are also mindful that the Supreme Court has clearly stated that the “combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR, 550 U.S. at 416. As discussed extensively above, Sundararajan teaches a microfluidic system for DNA-manipulating methods including hybridization, sequencing, and oligonucleotide synthesis that differs from claim 17 solely in the absence of two sets of particle holders designed for two-stream laminar flow (FF 9—15). Chou teaches microfluidic systems for hybridization and sequencing with two sets of particles designed for two-stream laminar flow (FF 3—7) that, when combined with Sundararajan’s oligonucleotide synthesis system predictably results in a microfluidic device with improved efficiency because it allows “treatment of the trapped particles in parallel with desired reagents” and permits “each trap to be individually treated with distinct reagents” (FF 8). Conclusion of Law 14 Appeal 2017-000701 Application 12/430,572 The evidence of record supports the Examiner’s conclusion that Chou and Sundararajan render claim 17 obvious. B. 35 U.S.C. § 103(a) over Chou and Sundararajan, and Tan Appellants do not separately argue this obviousness rejection, instead relying upon their arguments to overcome the combination of Chou and Sundararajan. The Examiner provides sound fact-based reasoning for combining Tan with these references (see Final Act. 9—10). Having affirmed the obviousness rejection of claim 17 over Chou and Sundararajan for the reasons given above, we also find that the further combination with Tan renders the rejected claims obvious for the reasons given by the Examiner. SUMMARY In summary, we affirm the rejection of claim 17 under 35 U.S.C. § 103(a) as obvious over Chou and Sundararajan. Claims 18, 21—26, 28 and 31 fall with claim 17. We affirm the rejection of claims 17, 18, 21—26, 28 and 31 under 35 U.S.C. § 103(a) as obvious over Chou, Sundararajan, and Tan. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 15 Copy with citationCopy as parenthetical citation