Ex Parte Chan et alDownload PDFPatent Trial and Appeal BoardMay 11, 201813724839 (P.T.A.B. May. 11, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. 131724,839 109855 7590 Quest Diagnostics 1311 Calle Batido FILING DATE 12/21/2012 05/15/2018 San Clemente, CA 92673 FIRST NAMED INVENTOR Sum Chan 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 ATTORNEY DOCKET NO. CONFIRMATION NO. 054769-9962 2422 EXAMINER SINGH, SATYENDRA K ART UNIT PAPER NUMBER 1657 NOTIFICATION DATE DELIVERY MODE 05/15/2018 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): ipdocketing@foley.com joshua.e.kim@questdiagnostics.com joel.s.white@questdiagnostics.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte SUM CHAN, QUIBO JIANGO, and RICARD E. REITZ Appeal2017-006849 Application 13/724,839 1 Technology Center 1600 Before RICHARD M. LEBOVITZ, FRANCISCO C. PRATS, and ELIZABETH A. LA VIER, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL This appeal involves claims directed to methods for determining the amount of total thiamine in a body fluid sample utilizing liquid chromatography and mass spectroscopy. The Examiner rejected the claims as obvious under 35 U.S.C. § 103. Appellants appeal the rejections pursuant to 35 U.S.C. § 134. We have jurisdiction under 35 U.S.C. § 6(b). The rejections are affirmed. STATEMENT OF THE CASE Claims 21--45 stand rejected by the Examiner as follows (Ans. 2-3): 1 The Appeal Brief ("Appeal Br.") 1 lists Quest Diagnostics Investments Incorporated as the real-party-in-interest. Appeal2017-006849 Application 13/724,839 1. Claims 21, 23-28, 32-35, 37--41, and 45 under 35 U.S.C. § 103(a), as obvious in view ofMascher et al. (Methods Enzymol. 1997, 279:83-90), Yamanaka et al. (Chromatographia, 1994, 39:91-96), Careri et al. (J. Chromatogr. A, 1998, 794:263-297), and Liu et al. (1981) (Anal. Chem., 1981, 53:109-113). 2. Claims 22 and 36 under 35 U.S.C. § 103(a) as obvious in view of Mascher, Yamanaka, Careri, Liu (1981 ), and Zhao et al. (Am. J Physiol. Cell. Physiol., 2002, 282:Cl512-17). 3. Claims 29-31 and 42--44 are rejected under 35 U.S.C. § 103(a) as obvious in view Mascher, Yamanaka, Careri, Liu (1981 ), and Liu (2006) (J Biol. Chem., 2006, 281:6601---07). Claim 21, which is representative of the appealed claims, is reproduced below: 21. A method for determining the amount of total thiamine in a body fluid sample, comprising: (i) removing soluble protein from the sample; (ii) incubating the sample from step (i) with an acid phosphatase; (iii) performing an organic solvent extraction of the sample from step (ii); (iv) purifying thiamine in the sample from step (iii) by liquid chromatography; and (v) determining the amount of thiamine in the sample from step (iv) by mass spectrometry comprising determining the amount of an ion having a mass/charge ratio of 121.94 ± 1.0, wherein the amount of total thiamine in the sample is determined from step (v). REJECTION 1 The Examiner found that Mascher describes a high-pressure liquid chromatographic (HPLC) method for determining the amount of total 2 Appeal2017-006849 Application 13/724,839 thiamine in a body fluid sample. Final Act. 4. The Examiner found that the method comprises removing soluble protein from the sample as in step (i) of claim 21. Id. The Examiner also found that Mascher's method performs step (ii) of claim 21 of treating the sample with acid phosphatase to convert phosphorylated thiamine to thiamine and step (iv) of purifying thiamine from the liquid chromatography sample. Id. at 5. The Examiner found, however, that Mascher does not teach the organic solvent extraction of step (iii) and the mass spectroscopy of step (v) of the claim. Id. The Examiner cited Yamanaka for teaching determining an amount of thiamine in yeast, where the method comprises an organic extraction step as in step (iii) of claim 21 and obtaining a spectrum of thiamine in the sample using mass spectroscopy as in claim (v) of the claim. Id. at 6. The thiamine ion was determined in Yamanaka's method to have a mass/charge ratio of 265.10, not 121.94 as required byclaim21. Id. However, Appellants' dependent claim 26 determines the amount of a thiamine ion having a 265.10 ion mass/charge ratio. To meet the ion mass/charge ratio of 121.94 of claim 21, the Examiner cited Liu (1981) as describing "thiamine parent as well as daughter fragmentation ions having m/z ratio of 265 for the parent ion, and 144, 122 and 123 for the daughter ions depending on the conditions of mass spectrometry and specific matrices used for mass analyses." Final Act. 7. The Examiner also cited Careri for teaching ionization and fragmentation of thiamine using liquid chromatography with mass spectrometry (LC-MS). Id. at 6-7. Thus, the Examiner determined it was known in the art to perform liquid chromatography and mass spectroscopy as claimed to determine the amount of thiamine in a sample. 3 Appeal2017-006849 Application 13/724,839 The Examiner determined it would have been obvious to one of ordinary skill in the art to have modified the method of Mascher with the teachings in Yamanaka, Liu ( 1981 ), and Careri of improved mass spectroscopy systems, the motivation "being the extraordinary selectivity, sensitivity and high throughput capability of such combination of chromatographic systems as specifically disclosed." Final Act. 8. The Examiner further found that "each or any one of [the identified ions] ... can be used by an artisan in the art to detect, analyze and/or determine the amount of thiamine in a given sample under appropriate conditions of mass spectrometry. Id. at 9. The Examiner also stated that Appellants "have not shown and/or demonstrated on the record ... as to why the use of m/z ratio of 121.94 ± 1.0 alone is critical to the determination of 'total thiamine'" in a body fluid sample. Id. at 10. Appellants contend that the cited references cannot be combined because the combination would "render the prior art invention being modified unsatisfactory for its intended purpose." Appeal Br. 7. Appellants contend that Liu (1981) teaches: Thiamine is one of nonvolatile organic samples that are "difficult samples" to analyze, which traditionally required special techniques such as field desorption, laser desorption, plasma desorption, and ele[ c ]trohydrodynamic ionization. See Liu 1981 at p. 109, right column. Liu 1981 explicitly discloses that its analysis was achieved only by a salt reaction with thiamine using ammonium chloride, resulting in thiamine chloride. See Liu 1981 at p. 109, right column. Liu 1981 teaches that samples that omit the salt "have not been successfully analyzed." See Liu 1981 at p. 109, right column. Appeal Br. 8. In contrast, Appellants argue that the Mascher and Yamanaka describe the analysis of free thiamine. Id. Appellants state that Liu (1981) teaches 4 Appeal2017-006849 Application 13/724,839 that "omitting the salt (i.e., free thiamine) did not yield successful analyses of thiamine." Appeal Br. 8. Discussion The evidence does not support Appellants' contention that Liu (1981) teaches that "omitting the salt (i.e., free thiamine) did not yield successful analyses of thiamine." Appeal Br. 8; see also Reply Br. 1 asserting that Liu ( 1981) teaches that "quantifying free thiamine did not work." The relevant passage in Liu (1981) by Appellants to support their statements is reproduced below: We now show that the capabilities or SIMS [secondary ion mass spectroscopy] are enhanced if the organic sample is mixed with ammonium chloride and that protonated or metal- cationized molecular ions can be observed for intact mononucleotides, peptides, sugars, and other nonvolatile and thermally labile compounds. Several of these samples have not been successfully analyzed by SIMS by use or preparation methods which omit the salt. Liu (1981) 109 (column 2) (emphasis added). Thus, while Appellants argue that Liu ( 1981) teach that free thiamine could not be successfully analyzed in its free form, Liu ( 1981) made no such statement about thiamine, only mentioning that "[ s ]everal" samples could not be successfully analyzed by SIMS, without identifying thiamine as one of these samples. Accordingly, the teaching that Appellants rely upon in challenging the obviousness rejection was not accurately stated and therefore undermines their arguments of nonobviousness based on changing "the principle of operation of the disclosure being modified" and of a "teaching away from the claimed subject matter. Appeal Br. 7-9; see also Reply Br. 1-2. 5 Appeal2017-006849 Application 13/724,839 Nevertheless, the evidence does not support Appellants' contentions that combining Liu (1981) or Yamanaka with Mascher would change the principle of operation ofMascher and constitute a teaching away. Yamanaka teaches that thiamine "having a tetra-ammonium ion and other amino groups in the structure, forms an ion-pair complex." Yamanaka 94. Yamanaka also teaches that "thiamine hydrochloride is a tetra- ammonium salt in structure ... [which] complexes with ion-pair reagents." Id. at 91. Yamanaka further teaches utilizing thiamine hydrochloride in its liquid chromatography. Id. at 92, 93. Yamanaka also teaches taking the HPLC sample and mixing it with hydrochloric acid. Id. at 93. Liu ( 1981) shows that "Thiamine hydrochloride analyzed from a silver-supported ammonium chloride matrix produce ion fragment ions at m/z 122, m/z 123, m/z 144, and an intact cation C+ at m/z 265." Liu (1981) 111 (1981) (legend to Figure 4). Thus, both Yamanaka and Liu (1981) use thiamine hydrochloride as part of its process, contrary to Appellants' contention that these references utilized "free thiamine." Mascher also performed several experiments using a thiamine chloride salt. Mascher 83 ("Materials"). Accordingly, we are not persuaded that the evidence establishes that one of ordinary skill in the art would not have had reason to apply the teachings of Liu (1981) and Yamanaka to Mascher. To the contrary, the evidence shows that it was known that a thiamine salt could be measured by mass spectroscopy (i.e., Lu (1981) and Yamanaka). Appellants state that "Yamanaka does not teach that any salt reaction of thiamine was used as in Liu 1981." Reply Br. 2. As explained above, Yamanaka teaches a salt. The Examiner stated: 6 Appeal2017-006849 Application 13/724,839 The presence of ammonium chloride in the matrix [as described in Liu ( 1981)] helps to enhance the ionization detection of nonvolatile and thermally labile compounds using such secondary ion mass spectrometry methods. However, it is to be noted that prior art reference of Yamanaka et al already discloses the fact that final thiamine-salt containing organic extracts used for HPLC-MS are dissolved in 0.1 N hydrochloric acid solution (see Yamanaka et al, page 93, right column, section "Sample Preparation for HPLC/APCI-MS", in particular). Thus, under the conditions of detection and analysis of total thiamine in the aqueous extract using HPLC in combination with MS as taught by the combined disclosure form Mascher et al and Yamanaka et al, a person of ordinary skill in the art would have fully contemplated the use of aqueous salt solutions for separation and detection of thiamine using suitable HPLC-mass spectrometry. Ans. 4. Appellants have not identified an error in the Examiner's analysis and we find it to be supported by preponderance of the evidence. Do "superior results" rebut prima facie obviousness? Appellants provided a declaration by Michael Caulfield, Ph.D. ("Caulfield Deel."). Dr. Caulfield was an employee of the real-party-in- interest at the time the declaration was executed. Caulfield Deel. i-f 1. Dr. Caulfield stated that he submitted the declaration "to demonstrate superiority of determining the amount of thiamine with mass spectrometry as described in" the application involved in this appeal. Id. at i-f 2. Dr. Caulfield states that both plasma and whole blood samples containing thiamine were analyzed using the mass spectrometry assay according to the present claims. 7 Appeal2017-006849 Application 13/724,839 Id. at 4. The most pertinent paragraphs2 of the declaration are reproduced below: 5. Exhibit A demonstrates that the limit of detection of the presently claimed assay was 2.3 nmol/L (0.69 ng/ml) for plasma and 2.2 nmol/L (0.66 ng/ml) for whole blood. 9. Thus, these results show that the presently claimed mass spectrometric assay is highly sensitive for determining the amount of thiamine in both plasma and whole blood. The results are significantly more sensitive than the prior art assays. From these results, the ordinary skilled in the art would readily understand that the claimed subject matter provides superior assay that is not disclosed or suggested in the prior art. To establish unexpected results, the claimed subject matter must be compared with the closest prior art. In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) ("[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art"). Dr. Caulfield did not identify the prior art assay compared to which the claimed assay is purportedly "more sensitive." Dr. Caulfield did not establish that the stated improved sensitivity and superiority is with respect to the closest prior art, let alone to any of the assays cited in the rejection. In the Appeal Brief, Appellants state: Mascher discloses that its limit of detection (LOD) was 2 ng/ml. See Mascher at p. 87, 1st paragraph. As such, the presently claimed assay is at least 3 times more sensitive than the prior art assay measuring free thiamine. Appeal Br. 9. 2 Paragraph numbering goes from 5 directly to 9; there are no numbered paragraphs 6, 7, and 8 in the declaration. 8 Appeal2017-006849 Application 13/724,839 Even if Mascher is the closest prior art, and the three-fold difference is significant, such results must be surprising or unexpected to a person of ordinary skill in the art. In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) ("One way for a patent applicant to rebut a prima facie case of obviousness is to make a showing of 'unexpected results,' i.e., to show that the claimed invention exhibits some superior property or advantage that a person of ordinary skill in the relevant art would have found surprising or unexpected."). In this case, Appellants did not provide evidence that the results obtained by Dr. Caulfield as compared to those from Mascher are surprising or unexpected to one of ordinary skill in the art when considered in the context of the closest prior art. Dr. Caulfield made no such statement. 3 For this reason, we find the declaration insufficient. Furthermore, it has not been established that Mascher is the closest prior art. As discussed by the Examiner, Mascher utilizes only HPLC, while Yamanaka, Careri, and Liu (1981) each use liquid chromatography and mass spectroscopy. Final Act. 19. Appellants state: Although the Examiner compares the sensitivity disclosed in Liu 1981, it cannot be fairly compared because of the differences in the analytes and technology used (thiamine chloride vs. free thiamine), as discussed above. Appeal Br. 9. This argument is not persuasive. It does not appear that the argued differences are claimed, e.g., the claim is not limited to a particular form of thiamine. In addition, even if Liu ( 1981) is not considered the closest prior 3 The related statement in the Appeal Brief is unpersuasive because it is unsupported attorney argument. See Knorr v. Pearson, 671F.2d1368, 1373 (CCPA 1982) ("However, arguments of counsel cannot take the place of evidence lacking in the record."). 9 Appeal2017-006849 Application 13/724,839 art, each of Yamanaka and Careri use both liquid chromatography and mass spectroscopy to measure thiamine as required by claim 21. Appellants did not explain why Mascher, which only uses liquid chromatography, is closer prior art than Yamanaka or Careri. Summary For the foregoing reasons, the obviousness rejection of claim 21 is affirmed. Claims 23-28, 32-35, 37--41, and 45 fall with claim 21 because their separate patentability was not argued. 37 C.F.R. § 41.37(c)(l)(iv). REJECTIONS 2 AND 3 Appellants contend that the rejections are "overcome based on the above argument regarding the independent claims, which the dependent claims incorporate all limitations thereof." Appeal Br. 10. The arguments for independent claim 21 were not persuasive. The rejections are thus affirmed for the same reasons. TIME PERIOD No time period for taking any subsequent action in connection with this appeal may be extended under 3 7 C.F .R. § 1.13 6( a )(1 )(iv). AFFIRMED 10 Copy with citationCopy as parenthetical citation