Jian Han

Patent Trials and Appeals BoardMay 17, 2021

2020005906 (P.T.A.B. May. 17, 2021)

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. 14/089,517 11/25/2013 Jian Han 15759-0005 6137 108412 7590 05/17/2021 MAYNARD COOPER & GALE PC (Huntsville) 655 GALLATIN STREET, SW HUNTSVILLE, AL 35801 EXAMINER SCHULTZ, JAMES ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 05/17/2021 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): ipdocket@maynardcooper.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte JIAN HAN ____________ Appeal 2020-005906 Application 14/089,517 Technology Center 1600 ____________ Before DONALD E. ADAMS, TAWEN CHANG, and RACHEL H. TOWNSEND, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims 20–27 and 29–31 (Appeal Br. 2). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as “iRepertoire, Inc.” (Appellant’s March 10, 2020 Appeal Brief (Appeal Br.) 2). Appeal 2020-005906 Application 14/089,517 2 STATEMENT OF THE CASE Appellant’s disclosure “relates to methods for identifying biomarkers and to methods for identifying T-cell receptor, antibody, and MHC rearrangements in a population of cells” (Spec.2 ¶ 2). Appellant’s claim 20 is reproduced below: 20. A method comprising: (a) selecting at least 2 V gene segment primers; (b) selecting at least 2 J gene segment primers; (c) combining the V gene segment and J gene segment primers with genomic DNA comprising rearranged nucleic acid molecules of a TCR region from lymphocytes obtained from a human or animal subject; (d) amplifying said rearranged nucleic acid molecules from said sample using said V gene segment and J gene segment primers in a first amplification reaction, thereby producing non-identical amplicons sufficient to evaluate an immune response, the non-identical amplicons representing a diversity of TCR genes; wherein each of said at least 2 V gene segment primers is capable of annealing to V gene segment sequence and amplifying V gene segment sequence, and each of said at least 2 J gene segment primers is capable of annealing to J gene segment sequence and amplifying J gene segment sequence, wherein each of said V gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of at least one V gene segment, wherein said second sequence contains a binding site for a common primer, and wherein each of said J gene segment primers comprises a first sequence and a second sequence, wherein said first sequence is complementary to a portion of a J gene 2 Appellant’s November 25, 2013, Specification. Appeal 2020-005906 Application 14/089,517 3 segment, wherein said second sequence contains a binding site for a common primer; (e) rescuing the amplicons from the first amplification reaction by dilution of the amplicons and primers from the first amplification reaction; and (f) amplifying the amplicons from the first amplification reaction in a second amplification reaction using at least one common primer which binds to the at least one common primer binding site. (Appeal Br. A-1–A-2.) Claims 20–27 and 29–31 stand rejected under 35 U.S.C. § 103 as unpatentable over the combination of Van Dongen,3 Arstila,4 Miqueu,5 and Leamon.6 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 1. Van Dongen: [R]elates to PCR-based clonality studies for among others early diagnosis of lymphoproliferative disorders. Provided is a set of nucleic acid amplification primers comprising a forward primer, or a variant thereof, and a reverse primer, or a variant thereof, capable of amplifying a rearrangement selected from the group consisting of a VH-JH IGH rearrangement, a DH-JH IGH rearrangement, a VK-JK IGK rearrangement, a VK/intron-Kde 3 Van Dongen et al., US 2006/0234234 A1, published Oct. 19, 2006. 4 Arstila et al., A Direct Estimate of the Human αβ T Cell Receptor Diversity, 286 SCIENCE 958–61 (1999). 5 Miqueu et al., Statistical analysis of CDR3 length distributions for the assessment of T and B cell repertoire biases, 44 MOLECULAR IMMUNOLOGY 1057–64 (2007). 6 Leamon et al., WO 2006/110855 A2, published Oct. 19, 2006. Appeal 2020-005906 Application 14/089,517 4 IGK rearrangement, a Vλ-Jλ IGL rearrangement, a Vβ-Jβ TCRB rearrangement, a Dβ-Jβ TCRB rearrangement, a Vγ-Jγ TCRG rearrangement, a Vδ-Jδ TCRD rearrangement, a Dδ-Dδ TCRD rearrangement, a Dδ-Jδ TCRD rearrangement, a Vδ-Dδ TCRD rearrangement, or a translocation selected from t(11; 14)(BCL1-IGH) and t(14;18)(BCL2-IGH). The primers can be used in PCR-based clonality studies for early diagnosis of lymphoproliferative disorders and detection of minimal residual disease (MRD). Also provided is a kit comprising at least one set of primers of the invention. (Van Dongen, Abstract; see Ans.7 6 (Examiner finds that “Van Dongen teaches multiplex PCR assays for the detection of clonally rearranged immunoglobulin (Ig) and T cell receptor (TCR) genes, including the Vβ gene,” and further “teaches that their multiplex PCR primer design is capable of detecting virtually all clonal B cell and T-cell populations”).) FF 2. Examiner finds that Van Dongen discloses “specific guidelines for primer design throughout in order to capture the greatest diversity” (Ans. 6 (citing, for example, Van Dongen 8–9 § Primer Design for Multiplex PCR)). FF 3. Examiner finds that Van Dongen does not disclose “primers that have a second sequence that corresponds to a common sequence that may be utilized in a massively parallel sequencing reaction” (Ans. 7). FF 4. Examiner finds that Arstila discloses “amplifying nucleic acids from human subjects using primers specific for the TCR β chain . . . . in order to determine diversity of the TCR β chain” and “a similar technique as described for the determination of TCR β chain diversity to examine TCRα chain diversity” (Ans. 7 (citing Arstila 958: col. 2–3, bridging paragraph)). FF 5. Examiner finds that Miqueu discloses “a method of assessing B cell and T cell repertoire biases . . . in the repertoire usage and clones mobilized 7 Examiner’s June 15, 2020 Answer. Appeal 2020-005906 Application 14/089,517 5 during immunological responses,” wherein “sequencing of all mRNA encoding the CDR3 (i.e. highly variable antibody/TCR regions) can be performed to assess this variability” (Ans. 8 (citing Miqueu, Title; 1057– 1058); see also Ans. 8 (citing Miqueu 1058) (Examiner finds that although Miqueu discloses that its method “is an exhaustive and precise method, it is nevertheless expensive and time-consuming, and is thus difficult to apply in the context of immune monitoring”)). FF 6. Examiner finds that Arstila and Miqueu do not disclose “amplification of the entire immunorepertoire or the use of sequencing primers to do so” (Ans. 8). FF 7. Examiner finds Leamon discloses: [A] method of performing massively parallel nucleic acid sequencing comprising amplification that uses multiple target- specific primer pairs, wherein each primer comprised additional nucleotides which resulted in the addition of a binding sequence for a common (universal) primers, followed by a second amplification using such common (universal) primers. . . . Furthermore, while the claims have been amended to require “rescue” of the amplicons from the first amplification reaction by dilution of the amplicons from the first amplification reaction, Leamon teaches . . . the optional amplification of previously amplified amplicons via several techniques, which include dilution of the original amplification mixture. (Ans. 8 (citing Leamon 21, 23–27).) FF 8. Examiner finds Leamon discloses: [A] method for detecting one or more sequence variants in a nucleic acid population comprising the steps of: (a) amplifying a polynucleotide segment common to said nucleic acid population with a pair of nucleic acid primers that define a locus to produce a first population of amplicons each comprising said polynucleotide segment; (b) clonally amplifying each member of said first population of amplicons Appeal 2020-005906 Application 14/089,517 6 to produce a plurality of populations of second amplicons wherein each population of second amplicons derives from one member of said first population of amplicon . . .[;] bridge amplification involving annealing of the appropriate primer molecule immobilized on a solid support . . .[; and] amplification in an emulsion that is sprayed into microparticles, which would necessarily involve dilution as solutions are added to the amplicons. (Ans. 9 (citing Leamon claim 1; 24:15–25:2).) ANALYSIS Based on the combination of Van Dongen, Arstila, Miqueu, and Leamon, Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to modify the method suggested by the combination Van Dongen, Arstila and Miqueu to utilize a primer, in a first amplification step, that comprises additional nucleotides that provide a binding sequence for a common (universal) primer and, then, dilute the first amplification composition prior to performing a second amplification step using a common (universal) primer (see Ans. 9–10). “Appellant appeals the present rejection by arguing exclusively with regard to Leamon. No other reference is addressed” (Ans. 11). “Appellant’s argument to distinguish the present claims from Leamon . . . is . . . that the separate emulsions of Leamon constitute separate reactions whereby each separate emulsion contains a distinct bead to allow amplification of a single target in each emulsion” (Appeal Br. 7). “In contrast, [Appellant contends that] the present claims disclose the simultaneous amplification of amplicons in a single reaction” (id.). We are not persuaded. As Examiner explains, Appellant’s “claims do not exclude the use of emulsion-based amplification in any way, and . . . contrary to [A]ppellant’s arguments, the instant application clearly contemplates such emulsion-based Appeal 2020-005906 Application 14/089,517 7 methods of amplification, wherein said emulsion comprises amplification upon microbeads suspended therein” (Ans. 15). In this regard, Examiner finds that Appellant “appears to rely upon a definition of ‘emulsion’ that is not consistent with the use of this term in either the instant [S]pecification or the prior art” (Ans. 13; see id. at 14 (Examiner finds that “[t]he notion that each of the amplification reactions of Leamon are made up of multiple separate emulsions, and that each separate emulsion constitutes a separate reaction is simply not consistent with how an ‘emulsion’ is defined by or used in the prior art.”)). Examiner further finds that Leamon discloses that “‘[t]he emulsion may contain millions of individual reactions. The emulsion may contain microparticles with which the amplification products become associated in a clonal fashion.’ . . . Thus, Leamon teaches a single emulsion comprising millions of amplification reactions” (Ans. 15 (citing Leamon 24–25: bridging paragraph) (emphasis omitted); cf. Ans. 15 (citing Spec. 23) (Examiner finds that Appellant discloses “an ‘emulsion PCR’ reaction, (a semisolid gel like environment) the diluted PCR products are amplified by primers . . . on the surface of the microbeads”)). Examiner explains that an emulsion as disclosed by Leamon is analogous to an emulsion “‘system (such as fat in milk) consisting of a liquid dispersed . . . in an immiscible liquid usually in droplets of larger than colloidal size’” (Ans. 14). Stated differently, Leamon’s emulsion contains a plurality of microparticles dispersed in the emulsion, like fat droplets are dispersed in milk. For the foregoing reasons, we are not persuaded by Appellant’s contention that “Leamon requires isolation of each primer, in contrast to the present claims. Unlike the multiplex amplification methods disclosed by Appeal 2020-005906 Application 14/089,517 8 Appellant, Leamon instead discloses a method that requires a series of discrete, physically-separated single-plex amplifications running in parallel” (Reply Br. 5). Only those arguments timely made by Appellant in the briefs have been considered; arguments not so presented are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015); see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) (“Any bases for asserting error, whether factual or legal, that are not raised in the principal brief are waived.”). CONCLUSION The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. The rejection of claim 20 under 35 U.S.C. § 103(a) as unpatentable over the combination of Van Dongen, Arstila, Miqueu, and Leamon is affirmed. Claims 21–27 and 29–31 are not separately argued and fall with claim 20. DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 20–27, 29– 31 103 Van Dongen, Arstila, Miqueu, Leamon 20–27, 29–31 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv) (2019). AFFIRMED