Alan Handyside

Patent Trials and Appeals BoardJun 15, 2021

2020003999 (P.T.A.B. Jun. 15, 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. 12/093,912 08/25/2008 Alan Handyside 0531.000655US01 6863 143934 7590 06/15/2021 MRG/Illumina c/o Mueting Raasch Group 111 Washington Ave. S., Suite 700 Minneapolis, MN 55401 EXAMINER SISSON, BRADLEY L ART UNIT PAPER NUMBER 1634 NOTIFICATION DATE DELIVERY MODE 06/15/2021 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): illuminadocket@illumina.foundationip.com ptodocketing@mrgs.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte ALAN HANDYSIDE Appeal 2020-003999 Application 12/093,9121 Technology Center 1600 Before FRANCISCO C. PRATS, JOHN E. SCHNEIDER, and TIMOTHY G. MAJORS, Administrative Patent Judges. PRATS, Administrative Patent Judge. DECISION ON APPEAL STATEMENT OF THE CASE Pursuant to 35 U.S.C. § 134(a), Appellant2 appeals from the Examiner’s decision to reject claims 20, 63, 67–72, 76, 79–81, 83, and 85– 92. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 This application has been before the Board in a previous appeal, Appeal 2018-008186. See Appeal Br. 3; see also Decision entered Dec. 11, 2018. 2 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies the real party in interest as the assignee, BlueGnome Limited, a wholly owned subsidiary of Illumina, Inc. Appeal Br. 3. Appeal 2020-003999 Application 12/093,912 2 CLAIMED SUBJECT MATTER Appellant’s invention is directed to methods of “detecting abnormalities of the number of whole chromosomes or chromosome regions (aneuploidy).” Spec. 1. The Specification discloses that high density analysis “of closely adjacent SNPs is capable of positively identifying, inter alia, the presence of two chromosomes derived from one parent and that based on well established assumptions about the frequency and spacing of recombination events between parental chromosomes during meiosis, this will allow accurate detection of trisomy.” Spec. 3. In particular, the Specification explains that when data from SNP analysis of embryonic genomic DNA reveals certain patterns as compared to the SNP patterns from the genomic DNA of the parents, the embryo is likely to have trisomy, rather than the correct set of diploid chromosomes that results from normal chromosomal recombination during meiosis: Multiple chromosomes: if successive informative and semi- informative SNPs alternate repeatedly and\or apparently randomly between the two parental chromosomes, it is highly likely that the test DNA is trisomic rather than a series of double crossover or recombination events (Figure 3; Figure 4). This is because the pattern of normal recombination is non- random and specifically the presence of one crossover physically inhibits another crossover nearby, a phenomenon known as crossover interference (Broman and Weber, 2000).[3] Spec. 7. 3 K.W. Broman & J.L. Weber, Characterisation of human crossover interference, 66 AM. J. HUM. GENET. 1911–1926 (2000) (citation at Spec. 25). Appeal 2020-003999 Application 12/093,912 3 The Specification explains further that statistical analysis may be used to determine the probability of whether the embryonic genotype SNP data is likely to result from normal recombination, or from an embryo likely to have trisomy: In terms of the frequencies of ‘normal’ alternating segments, based on a large experimental data set, Broman and Weber (2000) propose that the probability of a double crossover between two non-recombinant informative polymorphisms can be estimated according to the formula: p = (0.0114d – 0.0154)4 where p is the probability of a double crossover in an interval d measured as genetic distance in centiMorgans (cM) between non-recombinant loci. The probability that one SNP, indicating the presence of the other parental chromosome (or >1 informative SNP with no intervening contradictory informative SNPs) is the result of a double crossover is therefore defined by the probability between adjacent flanking SNPs informative for that chromosome (Figure 2). Thus in one embodiment the statistical likelihood of a double crossover between two SNP alleles is calculated according to the formula: p = (0.0114d- 0.0154)4 where p is the probability of a double crossover in an interval d measured as genetic distance in centiMorgans (cM) between the SNP alleles. Spec. 7–8. Using an average spacing of 0.32cM as an example, “as with the Affymetrix GeneChip 10K system,” the Specification explains that when applying the above formula, “in most cases, the probability of a pattern alternating between the haplotypes of both chromosomes from one parent at successive informative and semi-informative SNPs will be very low Appeal 2020-003999 Application 12/093,912 4 particularly where the density of SNPs analysed is high and generally much lower than the possibility of genotyping error.” Spec. 8. Thus, the Specification explains, “[t]he probability of trisomy is further increased with the number and extent of this alternating pattern which will depend on the number and position of true crossover events on both of the chromosomes.” Spec. 9. As to the preferred method of detecting SNPs in the genomic DNA of the embryo and parents, the Specification discloses as follows: A preferred embodiment employs the Affymetrix GeneChip™ 10K Microarray is designed to analyse 10,000 [SNPs] distributed at an average distance of 0.2Kb across each of 22 chromosomes (see Matsuzaki, H. et al. Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array. Genome Res. 14, 414–425 (2004)). Spec. 14. Claims 63 and 79 are the independent claims on appeal, and read as follows: 63. A method comprising: (a) removing one to five cells from a pre-implantation human embryo resulted from in vitro fertilization (IVF); (b) isolating genomic DNA from at least one human target cell, wherein the at least one human target cell consists of the one to five cells removed from the pre-implantation human embryo resulted from IVF; (c) detecting by oligonucleotide chip or oligonucleotide microarray the genotype of at least 2,500 biallelic single nucleotide polymorphisms (SNPs) in the genomic DNA isolated from the at least one human target cell, wherein detecting by oligonucleotide chip or oligonucleotide microarray the genotype of said at least 2,500 SNPs in the genomic DNA isolated from the at least one human target cell is preceded by whole genome amplification; Appeal 2020-003999 Application 12/093,912 5 (d) isolating maternal genomic DNA, wherein the maternal genomic DNA is from the mother of the pre- implantation human embryo resulted from IVF; (e) detecting by oligonucleotide chip or oligonucleotide microarray the genotype of said at least 2,500 biallelic SNPs in the maternal genomic DNA; (f) isolating paternal genomic DNA, wherein the paternal genomic DNA is from the father of the pre-implantation human embryo resulted from IVF; (g) detecting by oligonucleotide chip or oligonucleotide microarray the genotype of said at least 2,500 biallelic SNPs in the paternal genomic DNA; (h) assessing the statistical likelihood of normal recombination between two SNPs of said at least 2,500 biallelic SNPs in the genomic DNA isolated from the at least one human target cell; and (i) in response to a statistical likelihood of normal recombination, implanting without cryopreservation the pre- implantation human embryo resulted from IVF; wherein the said at least 2,500 biallelic SNPs are distributed on at least 10 human chromosomes. 79. A method comprising: (a) removing one to five cells from a pre-implantation human embryo resulted from in vitro fertilization (IVF); (b) isolating genomic DNA from at least one human target cell, wherein the at least one human target cell consists of the one to five cells removed from the pre-implantation human embryo resulted from IVF; (c) detecting by oligonucleotide chip or oligonucleotide microarray the genotype of at least 2,500 biallelic single nucleotide polymorphisms (SNPs) in the genomic DNA isolated from the at least one human target cell, each biallelic SNP having allele A or allele B, Appeal 2020-003999 Application 12/093,912 6 wherein detecting by oligonucleotide chip or oligonucleotide microarray the genotype of said at least 2,500 SNPs in the genomic DNA isolated from the at least one human target cell is preceded by whole genome amplification; (d) detecting whether the genotype is AA, AB, BB, or absent for each of said at least 2,500 biallelic SNPs in the genomic DNA isolated from the at least one human target cell; (e) isolating maternal genomic DNA, wherein the maternal genomic DNA is from the mother of the pre- implantation human embryo resulted from IVF; (f) detecting by oligonucleotide chip or oligonucleotide microarray the genotype of said at least 2,500 biallelic SNPs in the maternal genomic DNA; (g) detecting whether the genotype is AA, AB, or BB for each of said at least 2,500 biallelic SNPs in the genomic maternal DNA; (h) isolating paternal genomic DNA, wherein the paternal genomic DNA is from the father of the pre-implantation human embryo resulted from IVF; (i) detecting by oligonucleotide chip or oligonucleotide microarray the genotype of said at least 2,500 biallelic SNPs in the paternal genomic DNA; (j) detecting whether the genotype is AA, AB, or BB for each of said at least 2,500 biallelic SNPs in the paternal genomic DNA; (k) assessing the statistical likelihood of normal recombination between two SNPs of said at least 2,500 biallelic SNPs in the genomic DNA isolated from the at least one human target cell; and (l) in response to a statistical likelihood of normal recombination, implanting without cryopreservation the pre- implantation human embryo resulted from IVF; wherein said at least 2,500 biallelic SNPs are distributed on at least 10 human chromosomes. Appeal Br., Claims App., 1–4. Appeal 2020-003999 Application 12/093,912 7 REJECTION(S) The following rejections are before us for review: (1) Claims 20, 63, 67–72, 76, 79–81, 83, and 85–92, rejected under 35 U.S.C. § 112, second paragraph, as being indefinite (Ans. 5–8); and (2) Claims 20, 63, 67–72, 76, 79–81, 83, and 85–92, rejected under 35 U.S.C. § 112, first paragraph, as failing to comply with the written description requirement (Ans. 9–18). INDEFINITENESS The Examiner’s Prima Facie Case The Examiner concludes that independent claims 63 and 79 “are indefinite with respect to just which algorithm(s) is/are encompassed by the act of ‘assessing the statistical likelihood of normal recombination between two SNPs of said at least 2,500 biallelic SNPs in the genomic DNA isolated from the at least one human target cell’.” Ans. 7. The Examiner notes that, “[w]hile the disclosure teaches that a ‘program may’ do a variety of things, including ‘statistically analyze the likelihood’, the algorithm(s) encompassed by the claims are not specified.” Ans. 8 (citing Spec. 18). The Examiner notes further that the Specification expressly states that “the examples provided are non-limiting.” Id. (citing Spec. 18). Summarizing the rationale for the indefiniteness rejection, the Examiner reasons as follows: Given applicant’s assertions as to what it “may” be yet not stating definitely what it is, and that the examples are explicitly “non-limiting”, yet not stating that the claimed method fairly encompasses any and all possible algorithms, it is less than clear as to just which algorithms are encompassed by the Appeal 2020-003999 Application 12/093,912 8 claimed methods wherein one is to be performing the step of “assessing the statistical likelihood”. Ans. 8. Analysis As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992): [T]he examiner bears the initial burden . . . of presenting a prima facie case of unpatentability. . . . After evidence or argument is submitted by the applicant in response, patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument. Appellant persuades us that the preponderance of the evidence does not support the Examiner’s prima facie case of indefiniteness. The language at issue, which appears in both claims 63 and 79, recites the step of “assessing the statistical likelihood of normal recombination between two SNPs of said at least 2,500 biallelic SNPs in the genomic DNA isolated from the at least one human target cell.” Appeal Br., Claims App. 2 (claim 63); id. at 4 (claim 79). As seen in the summary of the Specification set forth above, Appellant’s invention involves the observation that, when data from SNP analysis of embryonic genomic DNA reveals certain patterns as compared to the SNP patterns from the genomic DNA of the parents, the embryo is likely to have trisomy, rather than the correct set of diploid chromosomes that results from normal chromosomal recombination during meiosis. Spec. 7. As noted above, the Specification also discloses that statistical analysis may be used to determine the probability of whether the results of embryonic genotype SNP analysis is likely to result from normal recombination, or from an embryo likely to have aneuploidy, such as trisomy. Id. at 7–9 Appeal 2020-003999 Application 12/093,912 9 (citing the Broman and Weber equation). Thus, when the language at issue is properly interpreted in light of the Specification, claims 63 and 79 encompass using any method of statistical analysis capable of determining the likelihood that two of the detected embryonic SNPs represent a genotype resulting from normal recombination during meiosis, as opposed to recombination from an embryonic genotype likely to have aneuploidy, such as trisomy. Therefore, although the language at issue might be broad, we are not persuaded that claims 63 and 79, when properly viewed in light of the Specification, fail to inform a skilled artisan of the claims’ scope with reasonable certainty. See In re Miller, 441 F.2d 689, 693 (CCPA 1971) “[B]readth is not to be equated with indefiniteness.”); see also Nautilus, Inc. v. Biosig, Insts., Inc., 572 U.S. 898, 908–10 (2014) (“[A] patent’s claims, viewed in light of the specification and prosecution history, [must] inform those skilled in the art about the scope of the invention with reasonable certainty. The definiteness requirement, so understood, mandates clarity, while recognizing that absolute precision is unattainable.”). The Examiner argues that the claims are indefinite because they encompass using equations or formulae other than the equation provided in the Specification as an example. See Ans. 20. At best, however, the Examiner has merely established that claims 63 and 79 encompass any method of statistical analysis capable of determining the likelihood that two of the detected embryonic SNPs represent a genotype resulting from normal recombination. That is, the Examiner has at best shown that the scope of the language at issue is fairly broad. As noted above, however, it is well settled Appeal 2020-003999 Application 12/093,912 10 that “breadth is not to be equated with indefiniteness.” Miller, 441 F.2d at 693. In sum, we are not persuaded, for the reasons discussed, that the Examiner has shown that Appellant’s claims are indefinite. We therefore reverse the Examiner’s rejection of claims 20, 63, 67–72, 76, 79–81, 83, and 85–92, rejected under 35 U.S.C. § 112, second paragraph. WRITTEN DESCRIPTION The Examiner’s Prima Facie Case The Examiner determines that, because independent claims 63 and 79 recite the step (the same step at issue above) of assessing the statistical likelihood of normal recombination between two SNPs of the at least 2,500 biallelic SNPs in the genomic DNA isolated from an embryo, “one must be able to detect not only the normal, non-mutated sequence, but any and all manner of mutations that may occur within each gene of the genome” to practice the full scope of claims 63 and 79. Ans. 13; see also id. at 14 (finding that claims 63 and 79 encompass “determining the genotype of any segment or gene anywhere in the human genome”). The Examiner determines, however, that at the time the present application was filed, the human genome had not been fully sequenced. Ans. 14. The Examiner determines, moreover, that the claimed step of assessing the likelihood of normal recombination based on two SNPs detected in the embryonic genomic DNA encompasses detecting sequences from human hybrids such as Neanderthals and Denisovans, as well as other archaic species. Id. at 14–15. The Examiner determines that the Specification does not disclose materials critical to practicing the full scope of the claimed invention Appeal 2020-003999 Application 12/093,912 11 because the Specification includes “no disclosure of any nucleotide sequence” and because the Specification does not disclose a primer to be used in the whole genome amplification recited in claims 63 and 79. Ans. 16. The Examiner determines further that, while the Specification provides an example of an equation to perform the statistical analysis recited in claims 63 and 79, the claims are not limited to using that equation, and therefore encompass non-disclosed methods of performing the claimed statistical analysis. Ans. 17. The Examiner determines, moreover, that the Specification “has not provided any reference sequence, much less provide a listing of the different forms of ‘normal’ sequences or each what are ‘normal recombinations’ versus abnormal, but not disease, versus SNPs that are both abnormal and disease-associated.” Ans. 17. Analysis To meet the initial burden of establishing a prima facie case of unpatentability based on a lack of written description, the Examiner must “present[] evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the invention defined by the claims.” In re Alton, 76 F.3d 1168, 1175 (Fed. Cir. 1996). The test for determining whether a specification is sufficient to support a particular claim “is whether the disclosure of the application relied upon ‘reasonably conveys to the artisan that the inventor had possession at that time of the later claimed subject matter.’” Ralston Purina Co. v. Far- Mar-Co, Inc., 772 F.2d 1570, 1575 (Fed.Cir.1985) (quoting In re Kaslow, 707 F.2d 1366, 1375 (Fed.Cir.1983)). Appeal 2020-003999 Application 12/093,912 12 Thus, “[i]t is not necessary that the application describe the claim limitations exactly, . . . but only so clearly that persons of ordinary skill in the art will recognize from the disclosure that appellants invented processes including those limitations.” In re Wertheim, 541 F.2d 257, 262 (CCPA 1976) (citation omitted). Our reviewing court has explained further: A claim will not be invalidated on section 112 grounds simply because the embodiments of the specification do not contain examples explicitly covering the full scope of the claim language. That is because the patent specification is written for a person of skill in the art, and such a person comes to the patent with the knowledge of what has come before. Placed in that context, it is unnecessary to spell out every detail of the invention in the specification; only enough must be included to convince a person of skill in the art that the inventor possessed the invention and to enable such a person to make and use the invention without undue experimentation. Falkner v. Inglis, 448 F.3d 1357, 1366 (Fed. Cir. 2006) (internal quotations omitted). In the present case, we agree with Appellant that the Specification reasonably conveys to a skilled artisan that Appellant possessed processes encompassed by claims 63 and 79. Like the indefiniteness rejection discussed above, the language upon which the Examiner primarily bases the written description rejection recites the step of “assessing the statistical likelihood of normal recombination between two SNPs of said at least 2,500 biallelic SNPs in the genomic DNA isolated from the at least one human target cell.” Appeal Br., Claims App. 2 (claim 63); id. at 4 (claim 79). Appeal 2020-003999 Application 12/093,912 13 As discussed above, when the language in the claimed assessing step is properly interpreted in light of the Specification, claims 63 and 79 encompass using any method of statistical analysis capable of determining the likelihood that two of the detected embryonic SNPs represent a genotype resulting from normal recombination during meiosis, as opposed to recombination resulting in an embryonic genotype likely to have aneuploidy, such as trisomy. Thus, when viewed in light of the Specification, rather than requiring a specific “normal” reference gene sequence as the Examiner contends, the determination of the likelihood of normal recombination (in contrast to recombination resulting in aneuploidy), as described and claimed, only requires a comparison between the SNP genotype of the embryo, and the SNP genotypes of both parents, as Appellant contends. The Examiner does not persuade us, therefore, that the claims omit critical subject matter, or that the Specification fails to provide it. As noted above, moreover, the Specification discloses that methods of performing multi-chromosome analysis of over 2,500 SNPs, as recited in Appellant’s claims, were known in the art. See Spec. 14 (disclosing preferred embodiment using Affymetrix GeneChip™ 10K Microarray designed to analyze 10,000 SNPs distributed at an average distance of 0.2Kb across each of 22 chromosomes) (citing “Matsuzaki, H. et al. Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array. Genome Res. 14, 414–425 (2004)”). We are not persuaded on this record, therefore, that the Examiner has explained sufficiently why the Specification would have failed to convey to a skilled artisan that Appellant possessed the claimed SNPs-based analytical methods, or a primer required to perform that analysis. See Falkner v. Inglis, 448 F.3d Appeal 2020-003999 Application 12/093,912 14 at 1366 (“[T]he patent specification is written for a person of skill in the art, and such a person comes to the patent with the knowledge of what has come before. Placed in that context, it is unnecessary to spell out every detail of the invention in the specification.”). As noted above, moreover, the Specification discloses an example of a formula capable of determining the likelihood of normal recombination based on SNPs analysis of the embryo and parents, and applies that formula to an example of a nucleotide array. See Spec. 8 (citing Broman and Weber formula and providing an example of the operation of the formula with the Affymetrix GeneChip 10K system). Despite these disclosures, other than the breadth of the claims, the Examiner fails to explain why, through sufficient evidence or reasoning, the exemplary embodiments are inadequate to demonstrate that Appellant was in possession of a process that includes the assessing step recited in claims 63 and 79. We are not persuaded that, by itself, the allegedly large breadth of the claims is sufficient to demonstrate a lack possession by the Appellant, when the Specification provides a working example undisputedly encompassed by the claims. The Examiner argues that, in view of the Natesan4 reference cited in the First Handyside Declaration,5 Appellant has effectively conceded that it was not in possession of an algorithm capable of determining through SNPs analysis the likelihood of normal recombination in an embryo. Ans. 23–24. 4 Senthilkumar A. Natesan et al., Genome-wide karyomapping accurately identifies the inheritance of single-gene defects in human preimplantation embryos in vitro, 16 GENETICS IN MEDICINE 838–845 (2014). 5 Declaration under 37 C.F.R. § 1.132 of Alan H. Handyside (signed May 8, 2017). Appeal 2020-003999 Application 12/093,912 15 We are not persuaded. As an initial matter, the Examiner points to nothing in the Natesan reference that mentions the particular statistical methodology disclosed in Appellant’s Specification for assessing the likelihood of normal recombination in an embryo based on SNPs analysis. The Examiner’s argument in relation to Natesan therefore fails to explain specifically why the particular disclosures in the Specification are insufficient to demonstrate possession of the claimed assessing step. Moreover, while we acknowledge the isolated passage in Natesan identified by the Examiner, Natesan ultimately teaches that microarray- based SNPs analysis is useful for detecting chromosomal abnormalities: The advantage of using a microarray platform to genotype a defined set of SNP loci for karyomapping is that there are no incidental findings at the sequence level. Nevertheless, because the SNP density is high, even relatively small partial chromosome deletions may be detected, some of which may have serious clinical consequences. The partial deletions detected in this study were relatively large, and further work will be needed to validate the limits of resolution and clinical significance of these chromosome abnormalities. Natesan 845. In sum, for the reasons discussed, we are not persuaded that the Examiner has shown sufficiently that a skilled artisan would have failed to recognize that Appellant was in possession of the full scope of the claimed subject matter. We therefore reverse the Examiner’s rejection of claims 63 and 79, and their dependent claims, for failure to comply with the written description requirement. Appeal 2020-003999 Application 12/093,912 16 DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 20, 63, 67– 72, 76, 79– 81, 83, 85– 92 112, second paragraph Indefiniteness 20, 63, 67– 72, 76, 79– 81, 83, 85– 92 20, 63, 67– 72, 76, 79– 81, 83, 85– 92 112, first paragraph Lack of Written Description 20, 63, 67– 72, 76, 79– 81, 83, 85– 92 Overall Outcome 20, 63, 67– 72, 76, 79– 81, 83, 85– 92 REVERSED