Ex Parte 6207372 et al

Patent Trial and Appeal BoardApr 28, 2016

90012838 (P.T.A.B. Apr. 28, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 90/012,838 04/12/2013 10769 7590 04/28/2016 Laboratory Corporation of America Holdings c/o Kilpatrick Townsend & Stockton LLP 1001 West Fourth Street Winston-Salem, NC 27101 FIRST NAMED INVENTOR 6207372 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. LT00791 REX 9573 EXAMINER TURNER, SHARON L ART UNIT PAPER NUMBER 3991 MAILDATE DELIVERY MODE 04/28/2016 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD ESOTERIX GRENETIC LABORATORIES, LLC Patent Owner and Appellant Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl Technology Center 3900 Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and JEFFREY B. ROBERTSON, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL Patent Owner, Esoterix Genetic Laboratories, LLC, 1 appeals from the Patent Examiner's final rejection of claims 1, 33, and 34 in the above- identified ex partes reexamination proceeding of U.S. 6,207,372 Bl. The Board's jurisdiction for this appeal is under 35 U.S.C. Â§Â§ 6(b ), 134(b ), and 306. We affirm. 1 Reel/Frame 25656-581. Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl I. STATEMENT OF CASE This appeal involves U.S. 6,207,372 Bl ("the '372 patent") which issued March 27, 2001. A Request for Ex parte Reexamination under 35 U.S.C. Â§Â§ 301-307 and 37 C.F.R. Â§ 1.510 was filed on behalf of Life Technologies Corporation ("Requester") on April 12, 2013. Reexamination of the '372 patent was subsequently ordered and culminated in a Final Rejection ("Final Rej'n" mailed Aug. 25, 2014). Patent Owner appeals from the Final Rejection. An oral hearing in the appeal was held March 23, 2016. A transcript will be entered into the record in due course. A related appeal (Appeal No. 2015-008320) is pending before the Board and has been decided concurrently to this one. The related appeal is of U.S. Reexamination Control No. 90/012,837, which relates to U.S. Patent No, 5,882,856 ("the '856 patent"). The '372 patent, at issue in this present Reexamination, is a continuation-in-part of the application that issued as the '8 5 6 patent. Claims 1, 33, and 34 stand finally rejected by the Examiner under 35 U.S.C. Â§ 102(e) (pre-AIA) as anticipated by Jeffreys (U.S. Pat. No. 5,811,235, issued Sept. 22, 1998). Final Rej'n 3. Claim 1 is independent and claims 33 and 34 depend from it. Claim 1 is reproduced below (brackets show deletions from original claim): 1. A multiplicity of single-stranded oligonucleotide DNA primers for simultaneous amplification of multiple target DNA sequences under a single set of reaction conditions in a multiplex polymerase chain reaction (PCR), said primers having a 5'X domain and a 3' Y domain, wherein a) each said 5' X domain comprises a sequence that does not hybridize to said multiple target sequences; 2 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl b) the melting temperature of a hybrid between X and its complement in the absence of other sequences is greater than about 60Â° C; and c) Y comprises a sequence contained within or flanking said target sequence or its complement d) each of said primers [being capable of] annealing specifically with it [sic?] cognate target sequence under uniform high stringency annealing conditions during said amplification. CLAIM INTERPRETATION Claim 1 is a composition of matter directed to a "multiplicity of single-stranded oligonucleotide DNA primers." The claim preamble recites that the single-stranded primers are "for simultaneous amplification of multiple target DNA sequences under a single set of reaction conditions in a multiplex polymerase chain reaction (PCR)." The primers have 1) 5 'X and 3 'Y domains and 2) the characteristics recited in limitations a) through d). One of the key issues is this appeal is how the preamble and limitations a) through d) limit the scope of the claim. We begin with the legal principles. The "terms appearing in a [claim] preamble may be deemed limitations of a claim when they 'give meaning to the claim and properly define the invention."' In re Paulsen, 30 F.3d 1475, 1479 (Fed. Cir. 1994). "Conversely, where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation." Rowe v. Dror, 112 F.3d 473, 478 (Fed. Cir. 1997). In Rowe v. Dror, a claim to a "'balloon angioplasty catheter"' was interpreted in view of the application specification to mean a catheter that could be "inflated radially outward to dilate a narrowed region in a blood vessel," 3 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl distinguishing it from the more general class of balloon catheters. Id. at 4 79--80. The phrase "'balloon angioplasty catheter"' breathed "life, meaning, and vitality" into the claim because it enabled the catheter to be used in the context of an angioplasty procedure. See Bell Comm. Res., v. Vitalink Com., 55 F.3d 615, 620 (Fed. Cir. 1995). The intended use of the primers is for multiplex PCR "under a single set of reaction conditions," but the claim is not a method claim and does not require that multiplex PCR be carried out. For this reason, we construe the claim preamble to impose the requirement only that the primer structure be capable of being utilized in a multiplex PCR process. Limitations a) through d) recite additional characteristics of the primers. Limitation b) specifies that the melting temperature between X and its complement is greater than about 60Â°C. Limitation d) recites that each of the primers is "annealing specifically with it cognate target sequence under uniform high stringency annealing conditions during said amplification." Both requirements are functional limitations in that they define the structure of the primer by a function, i.e., the primer's function to melt and anneal at the recited conditions. See In re Schreiber, 128 F.3d 1473, 1478 (Fed. Cir. 1997) ("[a] patent applicant is free to recite features of an apparatus either structurally or functionally.") To satisfy these claim limitations, it has to be shown that primers possess the claimed functionality. However, because the claim is a composition, and not a method, it is not necessary that the primers were actually utilized in the prior art at the recited melting and annealing conditions. 4 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl There are two phrases in the claim whose interpretation is in dispute: "multiplex" and "high stringency annealing conditions." During reexamination of an unexpired patent, the PTO must give claims their broadest reasonable construction consistent with the specification. In re Am. Acad. of Sci. Tech Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004); In re Suitco Surface, Inc., 603 F.3d 1255, 1259 (Fed. Cir. 2010); In re Abbott Diabetes Care Inc., 696 F.3d 1142, 1148 (Fed. Cir. 2012). Patent Owner contends that "a multiplex" PCR reaction as recited in the claim means the presence of three or more pairs of single-stranded primers, each pair targeting a different nucleic acid sequence. We first look to the '372 patent to determine whether the words in the claim are defined. The '372 patent defines "'Multiplex PCR"' as a reference "to the simultaneous amplification of multiple DNA targets in a single polymerase chain reaction (PCR) mixture." '372 patent, col. 4, 11. 14--16. The ordinary meaning of "multiple" as defined in general purpose dictionary is "1: consisting of, including, or involving more than one ."2 Thus, by its ordinary definition, "multiplex" means more than one. The '372 patent describes problems with "employing more than a single pair of oligonucleotide primers" in a standard PCR reaction. '372 patent, col. 4, 11. 47-57. The patent states at the end of this description that "[ c ]learly, these problems are magnified when it is desired to use multiple primer pairs (>3-4) in a single reaction." Id. at col. 4, 11. 57-59. This statement indicates that more than three (">3") is at least an example of "multiple," and if read narrowly to define "multiple" as more than three (i.e., 2 http://www.merriam-webster.com/dictionary/multiple 5 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl multiple is another word for "> 3 "), would be inconsistent with Patent Owner's position that "multiple" means three or more(= 3) and the examples in the '372 patent. Appeal Br. 8. To support their position that "multiplex" means more than 2 (i.e., >2), Patent Owner cites the declaration of Anthony P. Shuber, 3 the sole inventor of the '372 patent, who states that it is his "belief that one of skill in the art would not consider the term multiplex to be a biplex assay, i.e., attempted amplification of two targets." Shuber Deel., p. 2. However, Mr. Shuber did not provide a factual basis for this opinion. Mr. Shuber's statement can also be seen to be inconsistent with the '372 patent which defines "multiplex" as meaning "multiple" targets, a term whose ordinary meaning is more than one. Patent Owner also cites the Jeffreys patent which refers to "duplex or multiplex reactions" as if distinguishing between two (duplex) and more than two (multiplex). Jeffreys, col. 13, 1. 34; col. 55, 11. 1-2. However, the term "multiplex" as used in the '372 patent claims is interpreted in view of the written description of the '372 patent, which does not necessarily use the term in the same way as in the Jeffreys patent. Moreover, Jeffreys also describes the "use of ARMS [Amplification Refractory Mutation System] to detect more than one suspected variant nucleotide in the same sample is conveniently referred to as multiplex ARMS." Id. at col. 14, 11. 5-7 (emphasis added). Thus, Jeffreys could also be read as consistent with the interpretation of multiplex as more than one. 3 Declaration of Anthony P. Shuber, dated April 24, 2014. 6 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl In sum, the preponderance of the evidence does not support Patent Owner's position that "multiplex" as utilized in the '372 patent means only 3 or more, absent an express definition in the patent's written description or persuasive fact-based testimony of such meaning. The proper interpretation of the phrase "high stringency annealing conditions" is also disputed. Patent Owner contends that such conditions require an annealing temperature of 60Â°C, and would not include a temperature as low as 54Â°C. Appeal Br. 10. Patent Owner's support for this interpretation is that the '372 patent "disclose[s] testing of a range from 50- 650C (column 8, lines 43-48) in single amplifications and subsequent use of the optimized temperature 60Â°C in further multiplex reactions (column 9, lines 12-18)." Id. Patent Owner also relied on testimony by inventor Shuber that it is his "belief ... based upon reading the '856 and '372 patents, one of skill in the art would consider high stringency annealing conditions to be greater than 54Â°C, e.g., about 60Â°C." Shuber Deel., p. 2. The '372 patent does not provide a definition of "high stringency annealing conditions." The '372 patent discloses that "the annealing temperatures and primer concentrations may be calculated to some degree, conditions generally have to be empirically determined for each multiplex reaction." '372 patent, col. 1, 11. 61-63. The patent also discloses: each primer pair is evaluated independently to confirm that all primer pairs to be included in a single multiplex PCR reaction require the same amplification conditions (i.e., temperature, duration of annealing and extension steps). It was found (see example below) that all chimeric primers containing the M13 derived UPS as the 5' half of their sequence could be used at a broad range of annealing temperatures (i.e., 50-60Â° C.). Id. at col. 7, 11. 20-27. 7 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl The patent further states that "an annealing temperature of 60Â° C. was determined to be optimal for PCR amplification using UPS-tagged primers." Id. at col. 9, 11. 16-19. In addition, the '372 patent discloses: The SS#l ... and SS#3 ... primers, for example, were noticeably inefficient at annealing temperatures above 60Â° C. The primer pair designated SS#3 ... -UPS, which corresponds to the SS#3 ... primers having the M13 UPS ... sequence on their 5' termini, was highly efficient in priming at all temperatures tested; furthermore, few spurious amplification products were detected in reactions containing SS#3 ... -UPS primers. By contrast, SS#2 ... primers gave spurious amplification products at all three temperatures below 65Â° C [50Â°, 55Â°, and 60Â°]. Id. at col. 9, 11. 28-38. First, none of these disclosures characterize the annealing temperatures at "high stringency annealing conditions" as recited in the claims. Second, the temperature range, including the optimal temperature of 60Â°C, is for UPS-tagged primers, which are specific universal primer sequence. Id. at col. 5, 1. 16 to col. 6, 1. 16. The claims, however, are not limited to the sequences. Further, the '372 patent specifically teaches that not all primers worked at 60Â°C (see above at col. 9, 11. 28-38, primer SS#2), inconsistent with Patent Owner's contention that 60Â°C is optimal and "high stringency annealing conditions." One of ordinary skill reading the '372 patent would not have discerned that 60Â°C constituted "high stringency annealing conditions" because a temperature range is disclosed and not all primers even worked in this range. 8 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl Mr. Shuber's statements about the high-stringency temperature are not supported by evidence nor does he explain why "one of skill in the art would consider high stringency annealing conditions to be greater than 54Â°C, e.g., about 60Â°C." Shuber Deel., p. 2. On the other hand, another scientist with 14 years of research and development in the area of PCR assays testified that an annealing step of 54 Â°C constitutes "'uniform high stringency annealing conditions."' Broomer Deel. 4 i-f 10. In sum, we do not find any persuasive factual support for limiting high stringency conditions to above 54 Â°C or 60Â°C. ANTICIPATION The Examiner found that Example 15, col. 35, 1. 45 to col. 36, 1. 30, of Jeffreys anticipates claim 1. Final Rej 'n 3--4. The example utilizes two pairs of tagged gene-specific primers, one pair to the normal CFTR gene and the second pair to a mutant APC gene sequence. Jeffreys, col. 35, 1. 45 to col. 36, 1. 30. Each of the primers has a TAG sequence. The Examiner found that the CFTR and APC sequences meet the limitation of the "3 'Y domain," where "c) Y comprises a sequence contained within or flanking said target sequence or its complement." Final Rej'n 4. The Examiner found that the TAG sequence meets the limitation of "a) each said 5' X domain comprises a sequence that does not hybridize to said multiple target sequences." Id. Consequently, each of the primers has "a 5 'X domain and a 3 'Y domain" as required by the claim. 4 Declaration of Adam Broomer, dated April 11, 2013. 9 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl For limitation "b) the melting temperature of a hybrid between X and its complement in the absence of other sequences is greater than about 60Â° C," the Examiner calculated the TAG's melting temperature and determined it to be above 60Â°C (72Â°C and 66.1Â°C, depending on the formula utilized). Id. at 4--5. The claim also requires that "d) each of said primers [being capable of] annealing specifically with it cognate target sequence under uniform high stringency annealing conditions during said amplification." Example 15 of Jeffreys does not disclose a temperature at which annealing is accomplished. The Examiner found the declaration by Adam Broomer reproduced Jeffreys's multiplex PCR and demonstrated that specific amplification products occurred under a single set of art standard high stringency annealing conditions. Final Rej 'n. 5. The PCR assay carried out by Mr. Broomer performed annealing at 54 Â°C (Broomer Deel. i-f 1 O; Answer 10), which is within the effective PCR range mentioned in the '372 patent for multiplex PCR ('372 patent, col. 7, 11. 20-27). Patent Owner contends that the Examiner erred in finding that Jeffreys anticipates claim 1. Specifically, Patent Owner contends that Jeffreys fails to disclose (1) a multiplicity of primers for multiplex PCR; and (2) primers that anneal specifically with their cognate target "under uniform high stringency annealing conditions." Appeal Br. 20-21. "multiplex" Patent Owner contends that Jeffreys does not anticipate the claim because it only describes two primer pairs, where one is for detecting a 10 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl control sequence (CFTR) and the other is for detecting a target sequence (APC). Appeal Br. 22-23. Patent Owner states that the primers are "designed, at best, for use in a biplex reaction." Id. at 23. Patent Owner also argues that Jeffreys needed to use a two-step method, because no PCR products would be detected in the first step. Id. According to Patent Owner, "detectable products are not observed after step 1 because it is a primer extension reaction and amplification is not carried out for a sufficient number of rounds to produce detectable products." Id. at 24. Based on the Declaration by Parker, 5 Patent Owner further argues that "when step 1 is carried out for a sufficient number of rounds of amplification, only the APC primer product is detectable given the high concentration of primers used." Id. To begin with, we have interpreted "multiplex" PCR to read on PCR assay utilizing two primer pairs, each to a target sequence. Since Jeffreys describes two primer pairs - one to the CFTR target gene and the other to the APC gene - we conclude that the claim limitation of"[ a] multiplicity of single-stranded oligonucleotide DNA primers for simultaneous amplification of multiple target DNA sequences under a single set of reaction conditions in a multiplex polymerase chain reaction (PCR)" is met. While one primer set is utilized as a "control," it still satisfies the claim because it comprises a "sequence contained within or flanking said target sequence," where the target is the CFTR gene. Patent Owner's argument that the first step of Jeffreys's two-step assay would not produce PCR product improperly focuses on Jeffreys' s 5 Declaration of Scott Parker, dated December 17, 2014. 11 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl method steps. Claim 1 is a composition of matter claim. As discussed already, the claim has several functional requirements, including: â€¢ "simultaneous amplification of multiple target DNA sequences under a single set of reaction conditions in a multiplex polymerase chain reaction (PCR)" â€¢ "each of said primers annealing specifically with it [sic?] cognate target sequence under uniform high stringency annealing conditions during said amplification" Along with the initial Request for Reexamination, a declaration under 37 C.F.R. Â§ 1.132 by Adam Broomer was filed as evidence that Jeffreys's primers possess the recited functional properties. Request 16-1 7. Mr. Broomer, a staff scientist at Life Technologies - the Third Party Requester - performed a multiplex PCR reaction using the two primer pairs in Jeffreys's Example 15 directed to the CFTR and APC genes. Broomer Deel. i-f 6. Mr. Broomer used final concentrations of the CFTR and APC primers of 200 nM and 250 nM, respectively (id. at i-f 7), and genomic DNA for the CFTR gene and a synthetic gene fragment for the APC gene (id. at i-f 8). Mr. Broomer stated that he used standard PCR concentrations for the PCR reagents. Id. at i-f 9. The annealing step was carried out at 54 Â°C for thirty seconds, which Mr. Broomer stated were "'uniform high stringency annealing conditions"' based on his experience and disclosure in the 'patent. Id. at i-f 10. Mr. Broomer performed multiplex PCR with both primer pairs and template DNA. Gel electrophoresis was used to detect the PCR reaction products. Id. at i-f 11. Mr. Broomer described the presence of reaction products corresponding to the CFTR and APC genes. Id. at i-f 15. Mr. Broomer 12 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl concluded that "the PCR reactions with Jeffreys' primers . . . yielded PCR amplification products of the expected size(s) and were virtually free of any spurious products, and that each primer annealed specifically with its cognate target sequence under uniform stringency annealing conditions." Id. at i-f 16 (footnote omitted). The Examiner found that Mr. Broomer's experiment established that Jeffreys's primers meet the functional limitations of claim 1. Patent Owner argues that step 1 of Jeffreys's Example 15 does not produce detectable PCR product and therefore cannot anticipate the claim. This argument is not persuasive since Broomer's declaration shows that there are conventional PCR conditions in which the primers amplify "multiple target DNA sequences under a single set of reaction conditions" as required by claim 1. Claim 1 is not a method claim so it is not necessary that the primers be utilized in the same way and concentrations as they are in Example 15 as long as the primers have the properties recited in the claim, which Mr. Broomer established they do. See Appeal Br. 27 attempting to distinguish Broomer based on the differences in concentration between the Broomer experiment and Jeffreys' Example 15. To rebut Mr. Broomer's declaration, Patent Owner provided a declaration by their own technical expert, Scott Parker ("Parker Deel."). Mr. Parker performed PCR reactions using Jeffreys' s CFTR and APC primer pairs. Parker Deel. i-f 7. Two PCR reactions were carried out, at annealing temperatures of 60Â°C (Figs. 1 and 2) and 54Â°C (Fig. 3), respectively. Id. at i-fi-15---6. For the PCR reaction as 60Â°C (Figs. 1 and 2), the concentrations of primers were the same as those in Broomer's experiment; for the reaction at 13 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl 54Â°C (Fig. 3), primer concentrations were those described in Jeffreys's Example 15. Id. at i-f 9. The PCR products for each reaction were analyzed by gel electrophoresis and fluorescent dye staining. Id. at i-f 11. Mr. Parker found that at an annealing temperature of 60Â°C, and using the primer concentrations in the Broomer experiment, CFTR control primers did not produce an amplification product and non-specific amplification was observed. Id. at i-f 13. At an annealing temperature of 54Â°C, and using the primer concentrations in Example 15 of Jeffreys, Mr. Parker found that the PCR reaction failed "to produce a detectable amplification product for CFTR and may result in non-specific amplification of the wild-type APC gene." Id. at i-f 14. Patent Owner contends that the Parker Declaration shows that the primer pairs of Jeffreys are distinguishable from the claimed primers (Appeal Br. 22-23) because simultaneous amplification of both primer pairs were not observed at either temperature and thus each of Jeffreys's primers are not "d) ... annealing specifically with it cognate target sequence under uniform high stringency annealing conditions during said amplification" as required by claim 1. Patent Owner concludes: the Parker Declaration demonstrates that the Jeffreys primers are structurally different from the primers of claim 1 because [spurious amplification products and a lack of CFTR primer product are] observed using the Jeffreys primers under high stringency annealing conditions. [Furthermore], Parker used the primer concentrations disclosed by Jeffreys whereas Broomer did not. The difference in outcome in the Parker experiments versus Broomer [experiments] in fact proves the very point the Appellants seek to make: the Jeffreys primers do not inherently have the characteristics of the claimed primers, even in a biplex PCR instead of a multiplex PCR. 14 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl Id. at 20. We do not agree that the weight of the evidence supports the conclusion that Jeffreys' s primers do not meet the properties of the claimed primers. The three experiments described in the declarations are summarized in the table below: Annealing CFTR APC temperature concentration concentration Broomer 54Â°C for 30 sec 200nM 250nM Parker (Fig 3) 54Â°C for 30 sec lOnM 1 ÂµM Parker (Figs 1 60Â°C for 30 sec 200nM 250nM and2) Broomer's experiment was said to show that Jeffreys's primers meet all the claimed limitations. Parker's experiments were said to show the primers do not have all the characteristics of the claimed primers. However, as the table shows, Parker did not reproduce Broomer's experiment since the primer concentrations at 54 Â°C were different. The data, taken together, show that different PCR conditions can produce different results. Nonetheless, Broomer's conditions show that Jeffreys's primers meet the claimed limitation of "simultaneous amplification of multiple target DNA sequences under a single set of reaction conditions in a multiplex polymerase chain reaction (PCR)." Contrary to Patent Owner's contention (Appeal Br. 20), Mr. Broomer did not have to carry out the same primers concentrations as in step 1 of Example 15 because the claim does not require it. 15 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl "uniform high stringency annealing conditions" Patent Owner contends that 54 Â°C is not "uniform high stringency annealing conditions." We have already determined that Patent Owner did not provide adequate evidence to establish that 54Â°C is excluded from the scope of the claim. Consequently, the argument made by Mr. Shuber that the loss of signal at 54 Â°C in the Broomer experiments is evidence that specific annealing at 60Â°C would not occur is moot. Appeal Br. 17, 27. Patent Owner also argues that Jeffreys teaches that the primer pairs do not anneal at high stringency conditions. Jeffreys' primers contain a TAG sequence (the 5'X domain of claim 1 which does not hybridize to target sequences) and gene-specific sequence (the 3 'Y domain of claim 1 which contains the target sequences). Jeffreys describes a two-step process. In the Step 1, a "multiplex PCR reaction" containing the CFTR and APC primers is carried out. Jeffreys, col. 35, 11. 59---65. No temperatures are disclosed. In Step 2, the products of the PCR reaction are used to seed a second PCR reaction. Id. at col. 35, 11. 66---67. The reaction contains only the TAG primer-the 5 'X domain of claim 1. Jeffreys states: This second PCR reaction is performed at a high annealing temper[ a ]ture which prevents the action of any carried-over control PCR primers. The TAG primers, however, are able to efficiently amplify the control and ARMS PCR products at the elevated annealing temper[ a ]ture. Therefore, the presence of the somatic mutation will lead to the formation of an ARMS and a control PCR product after step 2 PCR whereas in its absence only the control PCR product will be detected. Id. at col. 36, 11. 4--10. 16 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl Patent Owner contends that Jeffreys's statements establish that "the control PCR primers are unable to work at a high annealing temperature." Appeal Br. 15. Jeffreys's example appears to be prophetic. There is no disclosure at what temperatures the PCR reactions is conducted. Jeffreys also does not disclose the "high annealing" temperature mentioned in the second PCR reaction. Mr. Broomer provides evidence that carrying out step 1 with both primer pairs at 54 Â°C in standard PCR conditions resulted in amplification of the CFTR and APC targets. While this temperature may not be the "high annealing" temperature contemplated by Jeffreys, we have not been directed to sufficient evidence that 54 Â°C is disqualified as a "high stringency annealing" temperature within the scope of the claim. Consequently, Jeffreys teaching has not been established to be inconsistent with Mr. Broomer' s experiment. For the foregoing reasons, we affirm the rejection of claim 1 and dependent claims 33 and 34 which were grouped with the arguments for claim 1. TIME PERIOD FOR RESPONSE Requests for extensions of time in this ex parte reexamination proceeding are governed by 37 C.F.R. Â§ 1.550(c). See 37 C.F.R. Â§ 41.50(f). AFFIRMED 17 Appeal2015-007789 Reexamination Control 90/012,838 U.S. Patent 6,207,372 Bl PATENT OWNER: LABORATORY CORPORATION OF AMERICA HOLDINGS C/O KILPATRICK TOWNSEND & STOCKTON LLP 1001 West Fourth Street Winston-Salem, NC 27101 THIRD PARTY REQUESTER: LIFE TECHNOLOGIES CORPORATION ATTN: IP DEPARTMENT 5791 Van Allen Way Carlsbad, CA 92008 18