M. Fernando et al.

Patent Trials and Appeals Board

Mar 21, 2022

2021003268 (P.T.A.B. Mar. 21, 2022)

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. 12/689,370 01/19/2010 M. Rohan Fernando 1251-029 5720 25215 7590 03/21/2022 The Dobrusin Law Firm P.C. 29 W. Lawrence Street Suite 210 Pontiac, MI 48342 EXAMINER POHNERT, STEVEN C ART UNIT PAPER NUMBER 1634 NOTIFICATION DATE DELIVERY MODE 03/21/2022 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): dobrusin_PAIR@firsttofile.com patmail@patentco.com rmasquelier@patentco.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte M. ROHAN FERNANDO and KATE CHAO-WEI CHEN ____________ Appeal 2021-003268 Application 12/689,370 Technology Center 1600 ____________ Before DONALD E. ADAMS, ULRIKE W. JENKS, 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 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 (Appeal Br. 4). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM-IN-PART. 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 “Streck, Inc.” (Appellant’s November 4, 2020, Appeal Brief (Appeal Br.) 2). Appeal 2021-003268 Application 12/689,370 2 STATEMENT OF THE CASE Appellant’s disclosure “relates to prenatal diagnosis of fetal abnormalities and more particularly to the preservation of fetal nucleic acids within a maternal blood sample” (Spec.2 ¶ 2). Appellant’s independent claims 10, 39, 46, and 47 are reproduced below: 10. A method for stabilizing, storing, isolating and analyzing cell-free fetal nucleic acid comprising: drawing a blood sample including a plasma containing donor cellular nucleic acid and cell-free nucleic acid including cell- free fetal nucleic acid directly into an evacuated blood collection tube containing about 0.05 ml to 1.0 ml of a protective agent wherein the protective agent is a solution formed from ingredients including: a) 0.1 to 3 g/ml of imidazolidinyl urea; b) glycine; and c) an EDTA; wherein an amount of imidazolidinyl urea relative to an amount of glycine is 10 parts by weight of imidazolidinyl urea to 1 part by weight glycine; storing the blood sample including the plasma for 1 to 14 days, wherein the protective agent stabilizes the drawn blood sample so that cell-free nucleic acid attributable to apoptosis, cell death and lysis of nucleated maternal blood cells post blood draw is substantially avoided, and so that a fraction of the cell- free nucleic acid that is the cell-free fetal nucleic acid is constant during storage; separating the plasma from the blood sample; isolating the cell-free nucleic acid-from the plasma of the stabilized blood sample; and analyzing at least the cell-free fetal nucleic acid isolated from the plasma of the stabilized blood sample; 2 Appellant’s January 19, 2010 Specification. Appeal 2021-003268 Application 12/689,370 3 wherein the blood sample and the plasma is not frozen prior to the step of isolating. (Appeal Br. 55 (emphasis added).) 39. A method for stabilizing, storing and isolating cell-free fetal nucleic acid comprising: contacting a drawn blood sample containing donor cellular nucleic acid and cell-free nucleic acid including the cell-free fetal nucleic acid with a protective agent that is a solution formed from ingredients including: (i) about 300 g/1 to about 700 g/1 imidazolidinyl urea; (ii) about 20 g/1 to about 60 g/1 glycine; and (iii) about 60 g/1 to about 100 g/1 of an EDTA; wherein the solution includes a solvent; allowing a period of time to lapse; and after the period of time has elapsed, separating a plasma from the drawn blood sample and isolating the cell-free nucleic acid from the plasma, wherein the cell-free nucleic acid is free of cell-free nucleic acid attributable to apoptosis, cell death and lysis of nucleated maternal blood cells post blood draw. (Id. at 56-57 (emphasis added).) 46. A method for stabilizing, storing, isolating and analyzing cell-free fetal nucleic acid comprising: drawing about a 10 ml blood sample containing donor cellular nucleic acid and a plasma comprising cell-free nucleic acid, including a cell-free fetal nucleic acid, directly into an evacuated blood collection tube containing about 0.1 ml to about 0.3 ml protective agent that is formed from a solvent, and ingredients consisting of: (i) about 300 g/1 to about 700 g/1 imidazolidinyl urea; (ii) about 20 g/1 to about 60 g/1 glycine; and (iii) about 60 g/1 to about 100 g/1 EDTA; wherein the protective agent contacts and stabilizes storing the blood sample including the plasma for 1 to 14 days, wherein the Appeal 2021-003268 Application 12/689,370 4 protective agent the drawn blood sample so that cell-free nucleic acid attributable to apoptosis, cell death and lysis of nucleated maternal blood cells post blood draw is substantially avoided, and so that a fraction of cell-free nucleic acid that is the cell-free fetal nucleic acid is constant during the storage; separating the plasma from the stored blood sample; isolating the cell-free nucleic acid, including the cell-free fetal nucleic acid, from the plasma; and amplifying the isolated fetal cell-free nucleic acid by at least 80-fold using whole genome amplification (WGA); wherein the blood sample and the plasma is not frozen prior to the step of isolating. (Id. at 57-58 (emphasis added).) 47. A cell-free fetal nucleic acid based screening procedure utilizing the method of claim 10. (Id. at 58.) Grounds of rejection before this Panel for review:3 I. Claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 stand rejected under the written description provision of 35 U.S.C. § 112, first paragraph. II. Claims 10, 11, 21, 24, 35-37, 39-41, 43, 44, and 47-49 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the 3 Application Nos. 13/766,207 and 14/153,204 were abandoned January 30, 2020 and February 7, 2019, respectively. Therefore, the provisional obviousness rejections over these Applications in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean as moot and will not be further discussed. Appeal 2021-003268 Application 12/689,370 5 combination of Li,4 Ryan ’517,5 Ryan ’417,6 and Garcia- Blanco.7 III. Claims 46, 50, and 51 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Bischoff,8 and Dean.9 IV. Claim 12 stands rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Li, Ryan ’517, Ryan ’417, Garcia-Blanco, and Tropsha.10 V. Claim 52 stands rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Li, Ryan ’517, Ryan ’417, Garcia-Blanco, and Lo.11 VI. Claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 stand provisionally rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over 4 Ying Li et al., Detection of Paternally Inherited Fetal Point Mutations for β-Thalassemia Using Size-Fractionated Cell-Free DNA in Maternal Plasma, 293 JAMA 843-849 (2005). 5 Ryan, US 5,849,517, issued Dec. 15, 1998. 6 Ryan, US 2004/0137417 A1, published July 15, 2004. 7 Garcia-Blanco et al., US 2004/0014107 A1, published Jan. 22, 2004. 8 Bischoff, US 2007/0243549 A1, published Oct. 18, 2007. 9 Dean et al., Comprehensive human genome amplification using multiple displacement amplification, 99 PNAS 5261-5266 (2002). 10 Tropsha et al., US 5,654,054, issued Aug. 5, 1997. 11 Y. M. Dennis Lo et al., Quantitative Analysis of Fetal DNA in Maternal Plasma and Serum: Implications for Noninvasive Prenatal Diagnosis, 62 Am. J. Hum. Genet. 768-775 (1998). Appeal 2021-003268 Application 12/689,370 6 claims 54-60 and 62-74 of 12/850,26912 in view of Swarup,13 Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean. VII. Claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 stand provisionally rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 17, 21-25, 29, 30, and 32-50 of co-pending Application 15/937,44614 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean. VIII. Claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 stand rejected under the judicially created doctrine of obviousness- type double patenting as being unpatentable over claims 1-20 of Fernando ’22715 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean. IX. Claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 stand rejected under the judicially created doctrine of obviousness- type double patenting as being unpatentable over claims 1-108 of Fernando ’59016 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean. 12 See Ryan, US 2010/0317107 A1, published Dec. 16, 2010. 13 Vishnu Swarup & M. R. Rajeswari, Circulating (cell-free) nucleic acids - A promising, non-invasive tool for early detection of several human diseases, 581 FEBS Letters 795-799 (2007). 14 See Fernando, US 2018/0216165 A1, published Aug. 2, 2018. 15 Fernando, US 9,657,227 B2, issued May 23, 2017. 16 Fernando, US 9,926,590 B2, issued Mar. 27, 2018. Appeal 2021-003268 Application 12/689,370 7 X. Claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 stand rejected under the judicially created doctrine of obviousness- type double patenting as being unpatentable over claims 1-20 of Fernando ’95517 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean. XI. Claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 stand rejected under the judicially created doctrine of obviousness- type double patenting as being unpatentable over claims 1-19 of Fernando ’98418 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean. Written Description: ISSUE Does the preponderance of evidence on this record support Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for the claimed invention? FACTUAL FINDINGS (FF) FF 1. Appellant discloses: The stabilizing of the nucleated blood cells within a blood sample makes it no longer necessary to separate plasma immediately after blood draw. The present invention may further allow for blood samples to be stored at room temperature for up to about 14 days without compromising the integrity of the cell-free nucleic acids present in the plasma and without contaminating the sample with cellular nucleic acids originating from lysed cells. The present invention may also 17 Fernando, US 10,144,955 B2, issued Dec. 4, 2018. 18 Fernando et al., US 10,091,984 B2, issued Oct. 9, 2018. Appeal 2021-003268 Application 12/689,370 8 make it possible to avoid any freezing of the plasma and/or contact with any formaldehyde. (Spec. ¶ 12.) FF 2. Appellant discloses: Either or both of the isolating or analyzing steps may occur at least 2 hours, 7 days, or even 14 days after the blood sample is drawn. Either or both of the isolating or analyzing steps may occur without and/or prior to any freezing the blood sample or any of its constituents (e.g.[,] to a temperature colder than about -30°C (more preferably colder than about -70°C)). (Id. ¶ 16; see also id. ¶ 48 (Appellant discloses “[i]ncubation may occur on ice or at any temperature between -30°C and 70°C. For example, a sample may be incubated at about -20°C. A sample may also be stored at room temperature and thus substantially free of freezing upon blood draw.”).) FF 3. Appellant discloses: [I]t is possible that a lapse of time of at least about 2 hours, more preferably at least about 6 hours, at least about 24 hours, at least about 7 days or even at least about 14 days can elapse between the time of blood draw . . . and the time of any testing or screening of the sample, and/or isolation of the nucleic acids. (Id. ¶ 34 (emphasis added).) FF 4. Appellant discloses WGA “enrichment in fetal cell-free DNA by at least about . . . 80 fold from maternal plasma that had been stored in a device containing the protective agent of the present teachings at ambient temperature” (id. ¶ 69). FF 5. Appellant discloses that its “nucleic acid protective agent may include a formaldehyde releaser preservative agent such as . . . imidazolidinyl urea” (id. ¶ 15; see id. (Appellant discloses that “[t]he concentration of the preservative agent prior to the contacting step may be between about 0.1 g/ml and about 3 g/ml.”)). Appeal 2021-003268 Application 12/689,370 9 FF 6. Appellant discloses that “[t]he amount of active ingredient or fixative (e.g.[,] the formaldehyde releaser) relative to the amount of EDTA may be about 1 to about 10 parts (more preferably about 2 to about 8 parts) by weight of fixative to about 1 part by weight EDTA” (id. ¶ 37; see also id. ¶ 50 (Appellant discloses “a range of about 300 to about 700 g/L [imidazolidinyl urea (IDU)] . . . from about 60 to about 100 g/L Tripotassium EDTA, and about 20 to about 60 g/L glycine,” wherein “[t]he protective agent may include roughly about 6 parts by weight IDU per about 1 part by weight EDTA, and roughly about 10 parts by weight IDU per about 1 part glycine.”)). FF 7. Appellant’s Figure 6 is reproduced below: Appellant discloses: FIG. 6 is an illustrative graphic representation showing the relative amounts of plasma DNA over time in a blood sample drawn into a device of the present teachings. In each box-plot, the total amount of cell-free plasma DNA is represented as genome equivalents per milliliter of plasma (GE/ ml). The line inside of the box indicates the median value. The limits of the box represent the 75th and 25th percentiles. The upper and lower Appeal 2021-003268 Application 12/689,370 10 error bars indicate the 10th and 90th percentiles, respectively. The uppermost and lowermost dots indicate the maximum and minimum values. The y-axis is in logarithmic scale. (Spec. ¶ 24.) FF 8. Appellant’s Figure 8 is reproduced below: Appellant discloses: FIG. 8 is an illustrative graphic representation showing the relative amounts of fetal cell-free DNA over time in a blood sample drawn into a device of the present teachings. In each box plot, the percentage of cell-free plasma DNA is represented as genome equivalents per milliliter of plasma (GE/ ml). The line inside of the box indicates the median value. The limits of the box represent the 75th and 25th percentiles. The upper and lower error bars indicate the 10th and 90th percentiles, respectively. The upper most and lower most dots indicate the maximum and minimum values. The y-axis is in logarithmic scale. Over time, a statistically significant decrease in the percentage of fetal cell-free DNA is seen only in K3EDTA tubes (*P< 0.05, **P < 0.01 by paired Student’s t test). (Spec. ¶ 26.) Appeal 2021-003268 Application 12/689,370 11 ANALYSIS Storage for 1 to 14 days without freezing: Appellant discloses that its “invention may . . . allow for blood samples to be stored at room temperature for up to about 14 days without compromising the integrity of the cell-free nucleic acids present in the plasma and without contaminating the sample with cellular nucleic acids originating from lysed cells” (FF 1). Appellant specifically identifies a number of time points within the range of “up to about 14 days” including “at least about 24 hours . . . or even at least about 14 days” (FF 1, 3). In addition, Appellant discloses that “[e]ither or both of the isolating or analyzing steps may occur without and/or prior to any freezing the blood sample or any of its constituents (e.g.[,] to a temperature colder than about -30°C (more preferably colder than about -70°C))” (FF 2). Therefore, we are not persuaded by Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for “the 1 day end point of [Appellant’s] . . . claim” or “the range of 1 to 14 days without freezing” (Ans.19 5; cf. Appeal Br. 22-25). At least 80-fold amplification: Appellant discloses WGA “enrichment in fetal cell-free DNA by at least about . . . 80 fold from maternal plasma that had been stored in a device containing the protective agent of the present teachings at ambient temperature” (FF 4). Therefore, we are not persuaded by Examiner’s finding that Appellant’s Specification lacks written descriptive support for 19 Examiner’s February 22, 2021, Answer. Appeal 2021-003268 Application 12/689,370 12 the range of “at least 80[-]fold” (Ans. 6 (emphasis omitted); cf. Appeal Br. 25-26). The concentrations of imidazolidinyl urea; glycine; EDTA; and solvent: Appellant’s claim 46 requires, inter alia, a “protective agent that is formed from a solvent, and ingredients consisting of: (i) about 300 g/1 to about 700 g/1 imidazolidinyl urea; (ii) about 20 g/1 to about 60 g/1 glycine; and (iii) about 60 g/1 to about 100 g/1 EDTA” (Appeal Br. 57-58). The specific ranges set forth in Appellant’s claim 46 are expressly disclosed in Appellant’s Specification (see FF 6). Appellant’s claim 10 requires, inter alia: the protective agent is a solution formed from ingredients including: a) 0.1 to 3 g/ml of imidazolidinyl urea; b) glycine; and c) an EDTA; wherein an amount of imidazolidinyl urea relative to an amount of glycine is 10 parts by weight of imidazolidinyl urea to 1 part by weight glycine. (Appeal Br. 55). The specific imidazolidinyl urea range set forth in Appellant’s claim 10 is expressly disclosed in Appellant’s Specification (see FF 5). The claimed ratio of imidazolidinyl urea to glycine is also expressly disclosed in Appellant’s Specification (see FF 6). Appellant’s Specification further discloses a specific weight range of an EDTA and a ratio of imidazolidinyl urea to EDTA (id.). For the foregoing reasons, we are not persuaded by Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for “a combination of 3 reagents at an infinite number of Appeal 2021-003268 Application 12/689,370 13 combination of concentrations of the 3 regents and solvent” (Ans. 7; cf. Appeal Br. 27-28). To be complete, to the extent this portion of Examiner’s written description rejection (see Ans. 6-7) relates to the requirement in Appellant’s claims 10 and 46 relating to “a fraction of the cell-free nucleic acid that is the cell-free fetal nucleic acid is constant during storage,” we address this specific limitation below. The cell-free fetal nucleic acid is constant during storage: Appellant’s claims 10 and 46 require, inter alia, “that a fraction of the cell-free nucleic acid that is the cell-free fetal nucleic acid is constant during storage” (see Appeal Br. 55, 57-58). Appellant’s Specification, however, illustrates that the cell-free fetal nucleic acid is not constant during storage (see FF 7-8). Thus, we agree with Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for the limitation of Appellant’s claims 10 and 46, and their dependents, that requires “a fraction of the cell-free nucleic acid that is the cell-free fetal nucleic acid is constant during storage” (Ans. 5). We recognize Appellant’s contention “that the term ‘constant’, in view of the specification, would be interpreted by a skilled artisan to mean ‘does not change significantly’” (Appeal Br. 29 (emphasis added); see also Reply Br. 5-9). We also acknowledge Appellant’s contentions regarding the phrase “statistically significant” (Appeal Br. 29; see also id. at 27-30; Reply Br. 9). We are, however, not persuaded by Appellant’s contentions that Appellant’s disclosed variability in the cell-free fetal nucleic acid during storage provides written descriptive support for the term “constant” (see id. Appeal 2021-003268 Application 12/689,370 14 at 27-30). The Specification does not provide a definition for the term “constant.” The inclusion of error bars in Figures 3, 6, and 8 (Reply Br. 5- 9) is not a definition. Moreover, Appellant’s figures show change over time, which the Specification confirms, albeit also noting that the changes may not be considered by one of ordinary skill in the art as significant in a statistical sense. (Spec. ¶ 62 (referring to Figure 3 and noting “little if any decline” as being a consistent relative percentage); id. ¶ 66 (referring to Figure 6 and noting the concentration “does not increase significantly throughout the entire 14 day experimental period”); id. ¶ 68 (referring to Figure 8 and noting the percentage “does not change significantly” at the measured time periods).) Appellant also does not provide evidence in support of its assertion that one of ordinary skill in the art would understand the term “constant” to include variability, even statistically insignificant variability. In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of evidence.”). CONCLUSION The preponderance of evidence on this record supports Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for the claimed invention. Rejection I: The rejection of claims 10 and 46 under the written description provision of 35 U.S.C. § 112, first paragraph is affirmed. Claims 11, 12, 21, 24, 35-37, 41, 43, 47-51 are not separately argued and fall with claims 10 and 46, respectively. The preponderance of evidence on this record fails to support Examiner’s finding that Appellant’s Specification fails to provide written descriptive support for the claimed invention set forth in claims 39, 40, 44, Appeal 2021-003268 Application 12/689,370 15 and 52. Rejection I: The rejection of claims 39, 40, 44, and 52 under the written description provision of 35 U.S.C. § 112, first paragraph is reversed. Obviousness: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 9. Li discloses the detection of paternally inherited fetal point mutations for β-thalassemia using size-fractionated cell-free DNA in maternal plasma (Li, Title; see also Ans. 8). FF 10. Li discloses the collection of 18 ml of maternal blood samples “into two 9-ml EDTA blood collection tubes” (Li 844; see also Ans. 8). FF 11. Li discloses “[i]nitially, 21 samples were sent as whole blood by overnight commercial express courier service. Because of concern that this 24-hour delay before processing of the maternal plasma sample might be detrimental, the remaining 11 samples were processed directly on- site . . . and the plasma was shipped frozen” (Li 844; see id. (Li discloses “[p]lasma was prepared from the maternal blood samples by high-speed centrifugation . . . and stored at -70ºC before analysis.”); see also Ans. 8). FF 12. Li discloses that “[c]irculatory DNA was extracted from 5- to 10-ml maternal plasma . . . separated by agarose gel . . . electrophoresis . . .[, wherein] DNA was extracted from . . . gel slice” (Li 844). FF 13. Li discloses the amplification of specific regions of the isolated DNA using PCR (see Li 844, see also Ans. 8 (Examiner finds that “Li teaches PCR amplification using an enzyme to detect fetal nucleic acids”)). Appeal 2021-003268 Application 12/689,370 16 FF 14. Examiner finds that although Li recognizes “that delay in processing may be detrimental to the samples[,] Li does not specifically teach how to address this issue . . . [or] the protective agent of . . . [Appellant’s] claims” (Ans. 8). FF 15. Ryan ’517 “relates to compositions useful for the stabilization and fixation of cells and tissues and, more particularly, to compositions for the stabilization and fixation of cells and tissues that preserve antigenic sites and nucleic acids for a useful period of time” (Ryan ’517 1:34-38; see id. at 3:21-24 (Ryan discloses “a fixative solution for tissues and cells that preserves tissues and cells and their cellular detail and, in particular, does not alter cell surface antigens, cytoplasmic antigens, RNA or DNA); Ans. 8). FF 16. Ryan ’517 discloses “[a] highly preferred fixative solution . . . compris[ing] imidazolidinyl urea (IDU), polyethylene glycol and EDTA, preferably in a buffered physiological salt solution,” wherein The preferred concentration of IDU is from about 4% to about 6% by weight, and most preferably about 5% by weight. The preferred concentration of polyethylene glycol is up to about 1% by weight and the most preferred concentration is about 0.5% by weight. The preferred concentration of EDTA is up to about 0.2% by weight and the most preferred concentration is about 0.1 % by weight. (Ryan ’517 4:23-36; see Ans. 8-9.) FF 17. Ryan ’517 discloses: [T]he addition of glycine, or other formaldehyde reactive compounds, is useful in removing any free formaldehyde which may be an equilibrium component of the compositions of [its] . . . invention. It should be noted, however, that the preferred compositions of [its] . . . invention contain only trace amounts of formaldehyde in equilibrium. (Ryan ’517 5:54-60.) Appeal 2021-003268 Application 12/689,370 17 FF 18. Ryan ’517 discloses treating patient samples “by mixing them directly with a preferred fixative solution,” wherein, “[f]or example, 1 ml peripheral blood is added to a vial containing 1 ml fixative solution, mixed and stored at 4º C. for up to seven days” (Ryan ’517 8: 35-40; see id. at 8:58 (Ryan ’517 discloses storing samples “at 2º-8º C. for 0-7 days until use.”); see also Ans. 9). FF 19. Ryan ’417 discloses: [A] method and a collection device that are capable of maintaining the cells in their original unaltered morphology; preserving the cell antigenic sites; and allowing the cells to be transported at ambient temperature, to be handled in a low toxicity and non-flammable environment, and to be directly analyzed by flow cytometry without further dilution and/or treatment. (Ryan ’417 ¶ 7; see id. ¶ 16 (Ryan ’417 discloses that “a typical size for the container . . . may have an internal volume of between 100 μl to 10 ml” and “can be constructed using art-disclosed methods and is commercially available.”); see also Ans. 10-12.) FF 20. Ryan ’417 discloses a composition for preserving “(e.g., fixation, stabilization and the like)” cells comprising “an anticoagulant agent,” “a fixative agent,” such as “imidazolidinyl urea,” and optionally a polyacrylic acid . . . or any suitable acid having a pH ranging from about one to about seven, wherein the compounds are in a sufficient amount to preserve the collected cells’ original morphology and antigenic sites without significant dilution of the cells . . ., and thereby allowing the cells . . ., stored with the compounds . . ., to be directly analyzed by a flow cytometer. (Ryan ’417 ¶ 17; see id. ¶ 18 (Ryan ’417 discloses the use of “[a] suitable amount of any art-disclosed anticoagulant agent such as . . . [EDTA] and its Appeal 2021-003268 Application 12/689,370 18 salts,” wherein, “[f]or example, in a preferred embodiment, K3EDTA is the anticoagulant agent . . . and its concentration weight/volume is preferably less than about 0.3 g/ml.”); id. ¶ 19 (Ryan ’417 discloses that “in a preferred embodiment, diazolidinyl urea is the fixative agent . . . and its concentration weight/volume is preferably about less than about 1 g/ml.”); see also Ans. 10-12.) FF 21. Ryan ’417 discloses that a number of additional compounds may optionally be added to its composition including glycine, RNAse inhibitors, and nucleic acid stabilizers (Ryan ’417 ¶ 21; see also Ans. 10). FF 22. Ryan ’417 discloses: To avoid significant dilution, the compounds . . . (comprising of the anticoagulant agent . . ., the fixative agent . . ., and optionally, the acid . . .) are in concentrated forms, preferably in a ratio with the final composition . . . that is less than about 2:100, more preferably less than about 1.5:100, and most preferably less than about 1:100. (Ryan ’417 ¶ 22; see also Ans. 10-11.) FF 23. Ryan ’417 discloses that its cell maintaining composition allows cell transport “in ambient temperature” and “[t]hereafter, it is preferred that the final composition . . . be stored at temperature less than about 40° C,” wherein “cells . . . stored in the final composition . . . have more than about 3 days, preferably more than about 5 days, more preferably more than about 7 days stability” and the cells can “be directly analyzed by a flow cytometer without further dilution and/or treatment” (Ryan ’417 ¶ 22; see also Ans. 12.) FF 24. Garcia-Blanco “relates to a method of identifying an RNA, or specific region thereof, to which a protein of interest binds” (Garcia-Blanco ¶ 2). Appeal 2021-003268 Application 12/689,370 19 FF 25. Garcia-Blanco discloses a “method compris[ing] crosslinking cells with [formaldehyde or other] . . . reversible crosslinking agent, lysing the cells, immunoprecipitating from the lysate a target protein complexed to an RNA using an antibody specific for the target protein, reversing the crosslinks and analyzing the resulting RNA and/or protein” (Garcia-Blanco ¶¶ 12-13). FF 26. Garcia-Blanco discloses that “[u]pon completion of the crosslinking step, the reaction can be quenched” with “[g]lycine or other appropriate compound with a primary amine can be used as the quencher when crosslinking is effected using formaldehyde” (Garcia-Blanco ¶ 15; see also Ans. 13 (citing Garcia-Blanco ¶ 15) (Examiner finds that Garcia-Blanco discloses that “‘[c]rosslinking reactions were quenched by the addition of glycine (pH 7.0) to a final concentration of 0.25 M followed by incubation at room temperature for 5 min.’,” wherein “[t]he 0.25M glycine is about 20 g/L.”). FF 27. Examiner finds that the combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco does “not specifically teach whole genome amplification of isolated fetal nucleic acids about 80[-]fold” and relies on the combination of Bischoff and Dean to make up for this deficiency (Ans. 17-18). FF 28. Examiner finds that the combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco does “not specifically teach a polymeric coated evacuated blood collection tube” and relies on Tropsha to make up for this deficiency (Ans. 19). FF 29. Examiner finds that the combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco does “not specifically teach the fetal nucleic acids are Appeal 2021-003268 Application 12/689,370 20 3.4%-6.2% of cell free nucleic acids” and relies on Lo to make up for this deficiency (Ans. 20). ANALYSIS Rejection II: Appellant’s independent claims 10, 39, and 47 are reproduced above. Appellant’s claims 11, 21, 24, 35-37, 40, 41, 43, 44, 48, and 49 depend directly or indirectly from Appellant’s independent claims 10 and 39, respectively. We recognize that Li discloses that a 24-hour delay in the processing of a “maternal plasma sample might be detrimental” and, therefore, discloses the processing of samples “directly on-site” and then shipping frozen plasma to a test center (see FF 11; see also Ans. 8 (Examiner finds that “Li teaches that delay in processing may be detrimental to the samples”); see generally FF 9-13). Examiner, however, fails to identify, and we do not find, a disclosure in Li relating to the precise “detriment” posed by such a 24-hour processing delay (see generally FF 14 (Examiner finds that “Li does not specifically teach how to address this issue” or “the protective agent of [Appellant’s] . . . claims”)). By failing to identify the particular detriment generically mentioned in Li, Examiner failed to establish a reason, i.e. motivation, to look to: (a) methods and compositions for stabilizing or maintaining cells and nucleic acid that may be contained in the cells as disclosed by Ryan ’517 and Ryan ’471 and (b) a formaldehyde, or other reversible crosslinker, based “method of identifying an RNA, or specific region thereof, to which a protein of interest binds” as disclosed by Garcia-Blanco (see FF 15-26; see Appeal Br. 34 (Appellant contends that “[t]he Final Office Action provides Appeal 2021-003268 Application 12/689,370 21 no reasoning why a skilled artisan would modify the teachings of Li, which employs cell-free fetal nucleic acid, with the teachings of Ryan [’517], which does not employ cell-free fetal nucleic acid,” “the Final Office Action does not adequately support a prima facie case of obviousness,” and “stabilization methods suitable for stabilization of blood samples does not necessarily translate into suitable stabilization methods for cell-free fetal nucleic acids”); see generally Appeal Br. 31-33, 37-38, 40-43). See In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006) (“[R]ejections on obviousness grounds cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.”). For the foregoing reasons, we are not persuaded by Examiner’s conclusion that, at the time Appellant’s invention was made, it would have been prima facie obvious to optimize the amount of glycine, IDU and EDTA in a nucleic acid protective agent comprising or consisting of imidazolidinyl urea (IDU), . . . [EDTA], glycine and a solvent with concentrations of IDU between about 300g/L and about 700g/L, glycine between about 20g/L and about 60g/L and EDTA between about 60g/L and about 100g/L or the ratios of [Appellant’s] claim 10 as suggested by Ryan [’517] and Ryan [’417] in a tube to draw 10 ml blood samples into a evacuated blood tube with about 0.05 to 1 ml of protective agent from a pregnant female, storing up to at least 7 days at room temperature, isolate nucleic acids from plasma of the stabilized sample, and analyze fetal nucleic acids . . . [and] optimize the ratio glycine to remove free formaldehyde which is dependent on the amount of IDU and glycine obvious in view of the teach[ings] of Garcia-Blanco with respect to 0.5M glycine being used to quench [formaldehyde]. (Ans. 15-16.) Appeal 2021-003268 Application 12/689,370 22 In addition, we note that Examiner’s statement of the rejection does not refer to a Chung document (see Ans. 8). As Examiner makes clear, although Appellant’s “brief . . . provide[s] arguments to the teachings of Chung, which the brief asserts is attached as attachment 1. First the teachings of Chung are not attached and cannot be reviewed or refuted by the [E]xaminer” and “this appears to be the first time arguments to Chung can be found in the record” (Ans. 119 (emphasis added)). Thus, we are not persuaded by Examiner’s assertion that “[t]he art recognizes IDU and glycine as art result effective variables” and, thus, the method would merely be substituting the specific nucleic acid protective agent of . . . [Ryan ’517 and Ryan ’417] for formaldehyde of Chung or alternatively the specific maternal blood sample of Chung for the generic blood sample of [Ryan ’517 and Ryan ’417] . . . and optimizing the amounts of IDU, glycine, and EDTA suggested by the prior art. (Ans. 16 (emphasis added); see also Final Act.20 24). Having found that Examiner failed to establish an evidentiary basis on this record to support a prima facie case of obviousness, we do not address the First Hunsley Declaration21 or Second Hunsley Declaration22 relied upon by Appellant to overcome a prima facie case of obviousness. Rejection III: Appellant’s independent claim 46 is reproduced above. Appellant’s claims 50 and 51 depend directly or indirectly from Appellant’s independent claim 46. 20 Examiner’s June 4, 2020, Final Office Action. 21 Declaration of Brad Hunsley, signed November 16, 2015. 22 Declaration of Brad Hunsley, signed April 12, 2017. Appeal 2021-003268 Application 12/689,370 23 Examiner finds that the combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco does “not specifically teach whole genome amplification of isolated fetal nucleic acids about 80[-]fold” and relies on the combination of Bischoff and Dean to make up for this deficiency (FF 27). The combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco suffers the same deficiency, with respect to Appellant’s independent claim 46, as discussed above with respect to Rejection II. In addition, Examiner failed to establish an evidentiary basis on this record to support a finding that the combination of Bischoff and Dean makes up for the deficiencies in the combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco (see FF 27). For the foregoing reasons, we are not persuaded by Examiner’s conclusion that, at the time Appellant’s invention was made, it would have been prima facie obvious in view of the combination of Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Bischoff, and Dean, to perform whole genome and select conditions to amplify the genome to a level of at least 80 fold. The artisan would be motivated to have increased amount of fetal nucleic acids to examine for fetal abnormalities. The level of amplification is merely a design choice. The artisan would have a reasonable expectation of success as the artisan is merely using known methods to amplify known nucleic acids. (Ans. 18; see generally Appeal Br. 45.) Rejection IV: Appellant’s claim 12 depends from and further limits Appellant’s independent claim 10 to require that the evacuated blood collection tube into which the blood sample is drawn includes a polymeric coating on an interior of the tube (see Appeal Br. 55). Appeal 2021-003268 Application 12/689,370 24 Examiner finds that the combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco does “not specifically teach a polymeric coated evacuated blood collection tube” and relies on Tropsha to make up for this deficiency (FF 28). Examiner, however, failed to establish an evidentiary basis on this record to support a finding that Tropsha makes up for the deficiencies in the combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco discussed above. For the foregoing reasons, we are not persuaded by Examiner’s conclusion that, at the time Appellant’s invention was made, it would have been prima facie obvious in view of the combination of Li, Ryan ’517, Ryan ’417, Garcia-Blanco, and Tropsha, “to use an evacuated blood tube with a polymeric coating as taught by Tropsha in the method of Li, [Ryan ’517, Ryan ’417], and Garcia-Blanco” (Ans. 19; cf. Appeal Br. 45-46). Rejection V: Appellant’s claim 52 depends from and further limits Appellant’s independent claim 39 to require that from 3.4% to 6.2% of the cell-free nucleic acid in the plasma is the cell-free fetal nucleic acid (see Appeal Br. 59). Examiner finds that the combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco does “not specifically teach the fetal nucleic acids are 3.4%- 6.2% of cell free nucleic acids” and relies on Lo to make up for this deficiency (FF 29). Examiner, however, failed to establish an evidentiary basis on this record to support a finding that Lo makes up for the deficiencies in the combination of Li, Ryan ’517, Ryan ’417, and Garcia- Blanco discussed above. Appeal 2021-003268 Application 12/689,370 25 For the foregoing reasons, we are not persuaded by Examiner’s conclusion that, at the time Appellant’s invention was made, it would have been prima facie obvious in view of the combination of Li, Ryan ’517, Ryan ’417, Garcia-Blanco, and Lo, “that 3.4-6.2% of the cell free plasma DNA is fetal DNA” (Ans. 20; cf. Appeal Br. 46). CONCLUSION The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness. Rejection II: The rejection of claims 10, 11, 21, 24, 35-37, 39-41, 43, 44, and 47-49 under 35 U.S.C. § 103(a) as unpatentable over the combination of Li, Ryan ’517, Ryan ’417, and Garcia-Blanco is reversed. Rejection III: The rejection of claims 46, 50, and 51 under 35 U.S.C. § 103(a) as unpatentable over the combination of Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Bischoff, and Dean is reversed. Rejection IV: The rejection of claim 12 under 35 U.S.C. § 103(a) as unpatentable over the combination of Li, Ryan ’517, Ryan ’417, Garcia- Blanco, and Tropsha is reversed. Rejection V: The rejection of claim 52 under 35 U.S.C. § 103(a) as unpatentable over the combination of Li, Ryan ’517, Ryan ’417, Garcia- Blanco, and Lo is reversed. Obviousness-type Double Patenting: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness-type double patenting? Appeal 2021-003268 Application 12/689,370 26 FACTUAL FINDINGS (FF) FF 30. Amended claim 70 of Appellant’s co-pending Application 12/850,269 is reproduced below: 70. A method comprising: a) providing a device including: i) a tube having an open end and a closed end, a closure inserted in the open end of the tube, and a vacuum drawn to a predetermined level inside the tube; and ii) preloaded compounds loaded into an interior portion of the tube prior to insertion of the closure and the vacuum draw, such that in an upright position the majority of the interior portion of the tube is substantially free of contact with the preloaded componentscompounds, wherein the preloaded compounds include diazolidinyl urea and/or imidazolidinyl urea and ethylenediamine tetraacetic acid (EDTA); b) drawing a blood sample into the tube such that the blood sample contacts the preloaded compounds to yield a final composition, wherein a ratio of a volume of the preloaded compounds including diazolidinyl urea and ethylenediamine tetraacetic acid (EDTA) to a volume of the final composition is from about 1:100 to about 2:100; c) transporting, at ambient temperature, the device including the blood sample to an analysis site; d) puncturing the closure, wherein the puncturing takes place at least three days after the blood sample draw; e) handling the blood sample in a low-toxicity environment wherein the preloaded compounds have an inhalation toxicity amount of zero; and f) transferring at least a portion of the blood sample from the device to another substrate and analyzing cells and cellular components present in the transferred blood sample for disease diagnosis; and Appeal 2021-003268 Application 12/689,370 27 wherein the preloaded compounds prevent in vitro cell clumping of the cells in the blood sample; and wherein the method is free of diluting the final composition. (Co-pending Application 12/850,269, March 7, 2022, Claim Amendment.) FF 31. Claim 21 of Appellant’s co-pending Application 15/937,446 is reproduced below: 21. A direct blood draw tube comprising: a composition formulated for stabilizing a direct drawn blood sample having cell-free nucleic acids within the blood sample while the blood sample is within the tube including: a) a formaldehyde releaser preservative agent selected from one or both of 2-bromo-2-nitropropane-1,3-diol and imidazolidinyl urea (IOU); b) ethylenediam inetetraacetic acid (EOTA); c) water; d) formaldehyde as a result of the formaldehyde releaser preservative agent; and wherein an amount of the formaldehyde releaser preservative agent within the direct blood draw tube prior to blood draw is an amount of about 50 to about 500 grams per liter; wherein an amount of the composition is in an amount so that any consequential dilution of the blood sample is substantially avoided, and cell-free nucleic acids in the blood sample are not materially diluted; and wherein at least about 7 days can elapse between a time of blood draw and a time of any testing or screening of a drawn blood sample, and or isolation of the cell-free nucleic acids. (Co-pending Application 15/937,446, March 27, 2018, Claim Amendment.) FF 32. Claim 1 of U.S. Patent No. 9,657,227 is reproduced below: 1. A direct blood draw tube for stabilization of cell-free nucleic acid within a plasma sample comprising: Appeal 2021-003268 Application 12/689,370 28 a composition including: a) one or more preservative agents including imidazolidinyl urea; b) one or more enzyme inhibitors; and c) one or more solvents; and wherein the one or more enzyme inhibitors are selected from the group consisting of EDTA, aurintricarboxylic acid, and combinations thereof; wherein an amount of the one or more preservative agents relative to an amount of the one or more enzyme inhibitors is about 3 to about 6 parts by weight of preservative agent to about 2 parts by weight of enzyme inhibitors; wherein the composition contains less than, or about 30% by weight of the one or more enzyme inhibitors; wherein the composition includes some formaldehyde but less than 500 parts per million of formaldehyde; and wherein a concentration of the preservative agent is less than, or about 1000 g/1 of the composition; and wherein the direct blood draw tube including the composition and a blood sample located therein is storable at room temperature. (U.S. Patent No. 9,657,227 13:20-43.) FF 33. Claim 1 of U.S. Patent No. 9,926,590 is reproduced below: 1. A direct blood draw tube comprising: a composition formulated for stabilizing cell-free nucleic acids within a blood sample including: a) one or more formaldehyde releaser preservative agents; b) ethylenediaminetetraacetic acid (EDTA); c) one or more solvents; d) about 1 % formaldehyde; Appeal 2021-003268 Application 12/689,370 29 wherein the composition is free of separately added formaldehyde but contains the formaldehyde as a result of the one or more formaldehyde releaser preservative agents; wherein an amount of composition within the direct blood draw tube prior to blood draw is less than, or about 1000 g/liter and is in an amount sufficiently small so that any consequential dilution of the blood sample is avoided; and wherein the direct blood draw tube including the composition: facilitates storage of the blood sample collected in the direct draw blood tube at room temperature for at least, or about 14 days without cell lysis and without cell-free nucleic acid degradation of the blood sample due to DNase and RNase activity after blood draw. (U.S. Patent No. 9,926,590 13:20-44.) FF 34. Claim 1 of U.S. Patent No. 10,144,955 is reproduced below: 1. A method comprising: preparing a blood collection tube including at least, or about, 200 grams per liter of a composition formulated for stabilizing cell-free nucleic acids within a blood sample, the composition including: a) about 50 to about 500 grams per liter of at least one formaldehyde releaser preservative agent; b) ethylenediaminetetraacetic acid (EDTA); and c) one or more solvents; wherein the presence of the at least one formaldehyde releaser preservative agent results in release of at least some formaldehyde and up to, or about, 1% formaldehyde into the composition; and sending the blood collection tube and composition located therein to a remote location for collection of a blood sample that contains cell-free nucleic acids that are stabilized by the composition. (U.S. Patent No. 10,144,955 13:23-39.) Appeal 2021-003268 Application 12/689,370 30 FF 35. Claim 1 of U.S. Patent No. 10,091,984 is reproduced below: 1. A method for blood sample treatment comprising: locating about 50 μl to about 400 μl of a protective agent into a tube, the protective agent including imidazolidinyl urea, EDTA and glycine; drawing a blood sample having a first circulating tumor cell concentration into the tube, whereby it contacts the protective agent; isolating circulating tumor cells from the contacted blood sample at least 24 hours after the blood draw, the contacted blood sample having a second circulating tumor cell concentration, wherein the second circulating tumor cell concentration is not lower or higher than the first circulating tumor cell concentration by any statistically significant value; and wherein the concentration of the imidazolidinyl urea after the contacting step is greater than 5 mg/ml; wherein the concentration of the glycine after the contacting step is below about 0.03 g/ml; wherein the protective agent is present in an amount that is less than about 5% of an overall mixture volume of the protective agent and the drawn blood sample; wherein the method is free of any step of refrigerating the contacted blood sample to a temperature below room temperature after it has been contacted with the protective agent composition; and wherein as a result of metabolic inhibition of the circulating tumor cells in the treated blood sample, apoptotic and necrotic pathways are inhibited and the circulating tumor cells are protected from cell degradation. (U.S. Patent No. 10,091,984 14:21-49.) FF 36. Examiner relies on Swarup to disclose that “circulating cell free nucleic acids are found in the blood of subjects with cancer as well as fetal Appeal 2021-003268 Application 12/689,370 31 derive[d] DNA in maternal plasma” (Ans. 34 (citing Swarup 795); see also Ans. 55, 66, 76, 87, 98). ANALYSIS Appellant’s independent claims 10, 39, 46, and 47 are reproduced above. Appellant’s claims 11, 12, 21, 24, 35-37, 40, 41, 43, 44, and 48-52 depend directly or indirectly from Appellant’s independent claims 10, 39, and 46, respectively. Rejection VI-XI: Examiner finds that “[t]he claims of . . . [co-pending Application 12/850,269, co-pending Application 15/937,446, U.S. Patent No. 9,657,227, U.S. Patent No. 9,926,590, U.S. Patent No. 10,144,955, U.S. Patent No. 10,091,984] do not specifically teach fetal nucleic acids in maternal blood or the specific concentration/ratios of . . . [Appellant’s] claims (Ans. 34, 55, 65, 76, 87, 98; cf. FF 30-35). Examiner, therefore, relies on the combination of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean to make up for the foregoing deficiencies (see Ans. 33-107; see also FF 9-29, 30-36). Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean are discussed above (see Analysis of Rejections II-V). As discussed above, Examiner failed to establish a reason, i.e. motivation, to look to: (a) methods and compositions for stabilizing or maintaining cells and nucleic acid that may be contained in the cells as disclosed by Ryan ’517 and Ryan ’471 and (b) a formaldehyde, or other reversible crosslinker, based “method of identifying an RNA, or specific region thereof, to which a protein of interest binds,” as disclosed by Garcia-Blanco, to determine the Appeal 2021-003268 Application 12/689,370 32 specific concentrations/ratios of reagents for Appellant’s claimed methods presented on this record (see e.g., FF 24). As further discussed above, Lo, Tropsha, Bischoff, and Dean also fail to make up for the foregoing deficiencies. Examiner’s reliance on Swarup disclose that “circulating cell free nucleic acids are found in the blood of subjects with cancer as well as fetal derive[d] DNA in maternal plasma” also fails to make up for the foregoing deficiencies (see FF 36). In sum, Examiner failed to establish an evidentiary basis on this record to support a conclusion that Appellant’s claims on this record are not patentably distinct from those of co-pending Application 12/850,269, co- pending Application 15/937,446, U.S. Patent No. 9,657,227, U.S. Patent No. 9,926,590, U.S. Patent No. 10,144,955, U.S. Patent No. 10,091,984 (see generally Appeal Br. 47-54). To be complete, for the same reasons discussed above, we are not persuaded by Examiner’s assertions regarding Chung (see, e.g., Ans. 42). CONCLUSION The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness-type double patenting. Rejection VI: The provisional rejection of claims 10-12, 21, 24, 35- 37, 39-41, 43, 44, and 46-52 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 54-60 and 62-74 of co-pending Application 12/850,269 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean is reversed. Rejection VII: The provisional rejection of claims 10-12, 21, 24, 35- 37, 39-41, 43, 44, and 46-52 under the judicially created doctrine of Appeal 2021-003268 Application 12/689,370 33 obviousness-type double patenting as being unpatentable over claims 17, 21-25, 29, 30, and 32-50 of co-pending Application 15/937,446 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean is reversed. Rejection VIII: The rejection of claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,657,227 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean is reversed. Rejection IX: The rejection of claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-108 of U.S. Patent No. 9,926,590 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean is reversed. Rejection X: The rejection of claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,144,955 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean is reversed. Rejection XI: The rejection of claims 10-12, 21, 24, 35-37, 39-41, 43, 44, and 46-52 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,091,984 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, and Dean is reversed. Appeal 2021-003268 Application 12/689,370 34 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 112 Written Description 10-12, 21, 24, 35-37, 41, 43, 46-51 39, 40, 44, 52 10, 11, 21, 24, 35-37, 39-41, 43, 44, 47-49 103(a) Li, Ryan ’517, Ryan ’417, Garcia- Blanco 10, 11, 21, 24, 35-37, 39-41, 43, 44, 47-49 46, 50, 51 103(a) Li, Ryan ’517, Ryan ’417, Garcia- Blanco, Bischoff, Dean 46, 50, 51 12 103(a) Li, Ryan ’517, Ryan ’417, Garcia- Blanco, Tropsha 12 52 103(a) Li, Ryan ’517, Ryan ’417, Garcia- Blanco, Lo 52 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 Provisional Obviousness-type Double Patenting over co-pending Application 12/850,269 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia- Blanco, Lo, Tropsha, Bischoff, Dean 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 Appeal 2021-003268 Application 12/689,370 35 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 Provisional Obviousness-type Double Patenting over co-pending Application 15/937,446 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia- Blanco, Lo, Tropsha, Bischoff, Dean 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 Obviousness-type Double Patenting over Fernando ’227 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, Dean 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 Obviousness-type Double Patenting over Fernando ’590 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, Dean 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 Obviousness-type Double Patenting over Fernando ’955 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, Dean 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 Appeal 2021-003268 Application 12/689,370 36 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 Obviousness-type Double Patenting over Fernando ’984 in view of Swarup, Li, Ryan ’517, Ryan ’417, Garcia-Blanco, Lo, Tropsha, Bischoff, Dean 10-12, 21, 24, 35-37, 39-41, 43, 44, 46-52 Overall Outcome 10-12, 21, 24, 35-37, 41, 43, 46-51 39, 40, 44, 52 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 IN PART