Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
This is a continuation of applicant’s earlier Application Nos. 13/210331, in which Applicants appealed the Examiner’s rejection, but the Examiner was AFFIRMED; and 17/732384 in which this same claim set was presented and rejected as below. All claims are drawn to the same invention claimed in the earlier application and could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the earlier application. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action in this case. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
Once again, Applicants are encouraged to amend the claims to require specific “rescue” procedure of the single example in the specification and any additional step(s) and/or elements that yield supposed unexpected results over the broad range of their claimed invention. The Office welcomes objective evidence compared to the closest prior art and reasonably commensurate with the claimed invention to overcome the prima facie case of obviousness.
Claim Notes
The full scope of the very broad claims are directed to any target nucleic acid, using any reaction mixture(s), any cycling protocol, any primers and any collection technique. The specification provides only a single example in which only a very narrow range of conditions worked. Specifically, Applicants used the specific primers in Tables 1-2 in very specific concentrations (pgs. 19-21) to amplify a single target (Campylobacter jejuni). Applicants never disclose the components of the reaction mixture such as buffer, magnesium concentration, Taq, etc. Moreover, only the very specific cycling parameters of page 20 were ever used. Only luminex-based streptavidin-biotin capture of amplicons was used as the collection technique (pgs. 16 & 20-21). Finally, only 10 pg/uL or 1 pg/uL template concentration worked with high or low concentration primers (Table 3). In other words, only very specific conditions worked for the claimed method. Clearly, these very specific conditions fail to support the broad scope of the claim directed to generic target nucleic acid, reaction mixture(s), cycling protocol, primers and collection technique.
In fact, “only one target template, Campylobacter jejuni, was included” (para. 0031). No other target, sample types, reaction conditions, cycling parameters, primers, rescue steps, or any other conditions were tried. Yet, the claims are directed to any target, any sample type, any reaction conditions, any primers, any rescue technique, any detection technique, etc. with no explanation as to which conditions and components were essential. Even more, the claimed invention “TEM-PCR” is never defined such that a skilled artisan would recognize what TEM-PCR means as far as reaction conditions, primers, primer concentrations, cycling parameters, sample type, rescue technique, detection technique, etc. (TEM-PCR is mentioned once; para. 0034). Thus, when Applicant compares their single example to arm-PCR prior art (Table 3), it is unclear exactly what is compared (even more confusing, Applicant describes the example as “arm-PCR,” not TEM-PCR; para. 0029).
Claim Rejections - 35 USC § 103 - Maintained
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-7 are rejected under 35 U.S.C. § 103(a) as being unpatentable over Brownie et al. (The elimination of primer-dimer accumulation in PCR, Nucleic Acids Research, 1997, Vol. 25, No. 16 3235–3241), Heath et al. (Universal primer quantitative fluorescent multiplex (UPQFM) PCR: a method to detect major and minor rearrangements of the low density lipoprotein receptor gene, J Med Genet. 2000 Apr;37(4):272-80) and UHLEN (US 5,629,158, issued 05/13/1997) as evidenced by TAO (US 2007/0059700, published 03/15/2007), in view of Haff (Improved Quantitative PCR Using Nested Primers, in PCR Methods and Applications, 1994, pgs. 332-337) and VON KALLE (US 6,514,706, issued 02/04/2003), in further view of WHO, WHO Informal Consultation on the Application of Molecular Methods to Assure the Quality, Safety and Efficacy of Vaccines, Geneva, Switzerland, 4/8/2005, Heinemeyer et al., A sensitive method for the detection of murine C-type retroviruses, J Virol Methods. 1997 Jan;63(1-2):155-65, Kramer et al. (Enzymatic Amplification of DNA by PCR: Standard Procedures and Optimization, in Current Protocols in Molecular Biology (2001) 15.1.1-15.1.14, 2001), Sachse et al. (Specificity and Performance of Diagnostic PCR Assays, in Methods in Molecular Biology, vol. 216: PCR Detection of Microbial Pathogens: Methods and Protocols, 2003, pgs. 3-19) and Grunenwald et al. (Optimization of Polymerase Chain Reactions, in Methods in Molecular Biology, Vol. 226: PCR Protocols, Second Edition Edited by: J. M. S. Bartlett and D. Stirling, 2003).
The prior art as a whole demonstrates that attogram target DNA (0.01 pg/uL, or 10 attogram/uL, or less) was regularly used in PCR, including nested PCR to increase sensitivity. Stated simply, every element of the claims (primer concentration, target nucleic acid amounts, nested PCR, primer location and annealing temperatures) is routinely used in the PCR art to detect nucleic acids with high sensitivity. Applicants fail to provide any evidence (e.g. secondary evidence of unexpected results) that the combination of familiar PCR techniques leads to anything other than familiar results.
It would have been prima facie obvious at the time of the invention to use familiar nested amplification in familiar two-stage universal-primer multiplex amplification techniques because a skilled artisan would have been motivated to take advantage of the increased sensitivity and specificity of nested amplification in the familiar two-stage universal-primer multiplex amplification techniques with a reasonable expectation of success. See KSR Int'l v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”).
As to familiar two-stage universal-primer multiplex amplification techniques, both Brownie and Heath teach the elements and benefits thereof.
As to claims 8-12 and 18-30, Brownie and Heath teach a first amplification with 10-50 nucleotide primers separated by 1-1,000bp (primers of Tables 1-2 such as K1T1 and K2T1 used at 5µM and 60°C annealing; pg. 3238) (P1 PCR reaction using 3-8 pmol primer and 46°C annealing; pg. 274 and Table 1), wherein a primer includes a universal sequence for second-round amplification (id.); reducing the concentration of primers from first round (“After PCR, reaction mixes for each PD were pooled and the whole of each sample was electrophoresed on a 1.5% Nusieve agarose preparative gel. PDs were extracted and purified using a Qiaex II Agarose Gel Extraction Kit (Qiagen), ethanol precipitated and resuspended in 10 mM Tris–HCl pH 8.5 (30 ml)”; pg. 3238) (“Two ml of the P1 product was immediately removed and added to the appropriate P2 reaction”; id.); then using universal primers at lower concentration and an annealing temperature that is higher than the first-round amplification (T1 at 0.5µM and >60°C annealing; id.) (universal primers at 4 pmol and 57°C annealing; id.).
As to claims 9-11, both Brownie and Heath teach to use clinical samples from various sources such as humans (id.) (id.).
Neither Brownie nor Heath explicitly teaches to use nested amplification; nor magnetic bead separation of first reaction amplicons.
However, a skilled artisan at the time of the invention would have been motivated to apply nested amplification to the methods of Brownie and Heath in order to yield increased sensitivity and specificity. For example, Haff teaches that non-specific products can be removed to increase sensitivity and specificity in amplification by using nested PCR and magnetic separation of amplicons between steps (Abstract, pg. 333 and Fig. 1). In fact, “[a] widely accepted and generally effective solution to PCR nonspecificity is nested primer PCR. . . . [b]ecause the discriminatory power of nested primer PCR is so high[ such that] a single PCR product can often be obtained with low target concentrations” (pg. 332, col. 3). Similarly, VAN KALLE teaches that nested amplification and magenetic separation of amplicons increased sensitivity and specificity (col. 3, ll. 1-8, col. 6, ll. 57-64 and Fig. 1). Such techniques were “known to a skilled person” (col. 4, ll. 43-44). Finally, UHLEN teaches the same principles and benefits: “the nested primer technique greatly enhances the specificity of the method and reduces background 'noise' caused by non-specific binding” (col. 5, ll. 48-51); and magnetic separation between amplifications yields fast, easy and less damaging collection (col. 6, ll. 30-67). In sum, a skilled artisan at the time of the invention would have been motivated to apply familiar magnetic separation of nested amplicons to the familiar two-stage universal-primer multiplex amplification techniques of Brownie and Heath to yield even more sensitivity and specificity.
In fact, TAO demonstrates that nested amplification was routinely performed in multiplex amplifications to increase sensitivity, and primer concentration was also routinely optimized to adjust sensitivity and specificity in multiplex amplifications. For example, TAO explicitly teaches to optimize such parameters in multiplex amplifications based on familiar principles, and even provides guidelines as to how to do so (Figs. 1-2 and paras. 0036-0045 and claims 25-27, as examples). Thus, at the least, nested amplification was a familiar technique to drastically increase specificity and sensitivity, and optimizing primer concentrations was a familiar result-effective variable.
Thus, it would have been prima facie obvious to one having ordinary skill in the art at the time of the invention to apply the familiar magnetic separation of amplicons and nested amplification techniques of Haff, VAN KALLE and UHLEN to the familiar two-stage universal-primer multiplex amplification techniques of Brownie and Heath to yield even more sensitivity and specificity with a reasonable expectation of success. See KSR Int'l v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”).
As to “5 to 50 pmol per primer,” this is taught in Brownie (0.5-5uM in 100 uL= 2-20 pmol) and Heath (3-8 pmol). These are standard concentrations routinely used in the art and cannot be the basis for allowability.
As to “no more than about 0.01pg/ul” target nucleic acid, this is routinely optimized in the art. For example, WHO states what a skilled artisan would expect from PCR: “qPCR assay has an exceptionally sensitive limit of detection of 1-10 attograms” (pg. 10). Similarly, Heinemeyer states that “[t]he PCR method is ultrasensitive, which enables the detection of 100 attogram of MoMuLV proviral DNA” and uses nested PCR for “ultrasensitive detection” (Abstract). Kramer teaches to optimize template DNA according to the application (15.1.1, 15.1.5 & 15.1.9). Sachse also teaches that template concentration is routinely optimized (pgs. 12-16), even down to 0.04 pg/uL (Table 7). Grunenwald states that for multiplex PCR, .22 pg – 5 ng of target nucleic acid should be used (pg. 91 (“For a typical PCR, 104 to 107 molecules of template DNA [104 to 107 = 0.11 pg – 1ng of 10kb template DNA] is recommended. . . . For amplification from genomic DNA, use 100 to 500 ng of template DNA. In multiplex PCR, two- to fivefold more DNA template than what is needed for a typical PCR should be used [2*0.11 pg – 1ng of 10kb template DNA= 0.22 pg – 5 ng].”)). Assuming 20-100 uL PCR mix, this equates to 0.001 pg/uL – 50 pg/uL Even more, standard curves (e.g. down to attogram concentrations to determine r-value/amplification efficiency or limit-of-detection) are routinely created with success for PCR. Finally, it is noted that the claims do not require any particular treatment of the target nucleic acid before PCR (e.g. purification) or any particular type of target nucleic acid (e.g. plasmid, blood sample, etc.). In other words, the claims encompass any target nucleic acid type however derived. Thus, it was prima facie obvious to an ordinarily-skilled artisan of common sense to optimize the target nucleic acid concentration according to the application.
In fact, Aller specifically held that such a limitation, absent secondary evidence to the contrary, constitutes routine optimization. Thus, the holding in Aller is pertinent here:
[n]ormally, it is to be expected that a change in temperature, or in concentration, or in both, would be an unpatentable modification. Under some circumstances, however, changes such as these may impart patentability to a process if the particular ranges claimed produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. Such ranges are termed ‘critical’ ranges, and the applicant has the burden of proving such criticality. However, even though applicant's modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art. More particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
In re Aller, 220 F.2d 454, at 456 (CCAP 1955) (emphases added) (citations omitted).
The discovery of an optimum value of a result-effective variable in a known process is prima facie obvious. In re Antonie, 559 F.2d 618, 620 (CCPA 1977); see also In re Boesch, 617 F.2d 272, 275 (CCPA 1980) (“This accords with the rule that discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.”)
Applicants use such vague language that it is impossible to determine what may be incorporated:
One embodiment of the invention allows the direct detection of cell changes in response to ion channel regulators as they occur in real time with a colorimetric resonant reflectance biosensor and without the need to incorporate radiometric, colorimetric, or fluorescent labels. Changes in cells can be detected as the cells are probed with test reagents, agonists, and antagonists. The cellular changes can then be detected in real time using a high speed instruments such as the BIND Scanner™ (i.e., a colorimetric resonant reflectance biosensor system), and corresponding algorithms to quantify data. See, e.g., U.S. Pat. No. 6,951,715 and U.S. Pat. Publ. 2004/0151626. . . .
[]
Biosensors of the invention can be colorimetric resonant reflectance biosensors. See e.g., Cunningham et al., “Colorimetric resonant reflection as a direct biochemical assay technique,” Sensors and Actuators B, Volume 81, p. 316-328, Jan. 5 2002; U.S. Pat. Publ. No. 2004/0091397. . . .
[]
A colorimetric resonant reflectance biosensor comprises, e.g., an optical grating comprised of a high refractive index material, a substrate layer that supports the grating, and optionally one or more specific binding substances or linkers immobilized on the surface of the grating opposite of the substrate layer. The high refractive index material has a higher refractive index than a substrate layer. See, e.g., U.S. Pat. No. 7,094,595; U.S. Pat. No. 7,070,987. . . .
[]
With embodiments of the instant invention modulation of ion channels or lack thereof can be detected as it occurs, thus circumventing the need to incorporate radiometric, colorimetric, fluorescent labels or microscopy for evaluation. Changes in cells that occur due to modulation of ion channels can be expediently monitored in real time, in a label free manner. For cell changes to be detected in real time, the BIND Biosensor™, BIND Reader™, and BIND Scanner™ (e.g., a colorimetric resonant reflectance biosensor system) were designed and corresponding algorithms were created to quantify data. See, e.g., U.S. Pat. No. 6,951,715, U.S. Patent Appl. Publ. 2004/0151626
(paras. 0034, 0035, 0043 & 0091). Thus, it is not clear the scope of “colorimetric resonant reflectance optical biosensor.”
Claim Rejection - Double Patenting - Maintained
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Instant claims 1-7 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over conflicting claims 1-39 of US 7,851,148, in view of Haff, VAN KALLE and UHLEN, in further view of Heath (as evidenced by Shuber), in further view of Kramer, Sachse and Grunenwald.
The following is a representative conflicting claim of US 7,851,148:
1. A method for multiplex primer-based amplification of a target sequence from a plurality of agents, said target sequence being different for each agent, said method comprising:
a. carrying out a first amplification reaction for each target sequence to be amplified using
i) as a template, a nucleic acid from each of said plurality of agents, said nucleic acid containing said target sequence;
ii) a first pair of target enrichment primers hybridizing to said nucleic acid and bracketing said target sequence;
iii) a second pair of target enrichment primers hybridizing to said nucleic acid and bracketing said target sequence, said second pair of target enrichment primers being located proximate to said target sequence and one of the second pair of target enrichment primers comprising at its 5′ end a binding tag corresponding to the sequence of one of a pair of target amplification primers and the other of the second pair of target enrichment primers comprising at its 5′ end a binding tag corresponding to the sequence of the other of said pair of target amplification primers, wherein the second pair of target enrichment primers binds to the inside of the first set of target enrichment primers; and
iv) amplification reagents and conditions for said first amplification reaction such that the first amplification reaction generates a plurality of first amplification products, wherein at least a portion of the first amplification products contain said target sequence and at least one complement of the binding tag for one of said target enrichment primers thereby forming at least one binding site for at least one of said target amplification primers; and
b. carrying out a second amplification reaction for each target sequence to be amplified using
i) as a template, said portion of the first amplification products containing said at least one binding site for at least one of said target amplification primers;
ii) at least one of said first pair of target amplification primers binding to its corresponding binding sites on said portion of said first amplification products; and
iii) amplification reagents and conditions for said second amplification reaction such that the second amplification reaction generates a plurality of second amplification products containing the target sequence.
The above claims teach all elements of the instant claims except lower concentration of primers in the second round of amplification using common primers and magnetic separation of amplicons.
However, in light of the arguments made above, instant claims 1-7 would have been prima facie obvious to one having ordinary skill in the art at the time of the invention because adjusting primer concentrations constitutes routine optimization; and magnetic separation of amplicons was familiar in the art to yield increased sensitivity and specificity.
For example, Heath (which cites Shuber for the basis of its “QFM-PCR” at pg. 273) demonstrates that preferential amplification in a first PCR allows the use of lower primer concentration in a second round of PCR (pg. 274). In fact, Heath specifically points to Shuber’s teaching that “[h]ighly specific and efficient amplification of multiple target sequences was achieved easily and reproducibly by simple adjustment of the individual primer concentrations, with no additional modification of either the reaction components or annealing temperatures” (pg. 273). Therefore, at the least, Heath and Shuber/SHUBER demonstrate that preferential amplification in a first PCR allows the use of lower primer concentration in a second round of PCR.
As to magnetic separation, Haff teaches that non-specific products can be removed to increase sensitivity and specificity in amplification by using nested PCR and magnetic separation of amplicons between steps (Abstract, pg. 333 and Fig. 1). In fact, “[a] widely accepted and generally effective solution to PCR nonspecificity is nested primer PCR. . . . [b]ecause the discriminatory power of nested primer PCR is so high[ such that] a single PCR product can often be obtained with low target concentrations” (pg. 332, col. 3). Similarly, VAN KALLE teaches that nested amplification and magenetic separation of amplicons increased sensitivity and specificity (col. 3, ll. 1-8, col. 6, ll. 57-64 and Fig. 1). Such techniques were “known to a skilled person” (col. 4, ll. 43-44). Finally, UHLEN teaches the same principles and benefits: “the nested primer technique greatly enhances the specificity of the method and reduces background 'noise' caused by non-specific binding” (col. 5, ll. 48-51); and magnetic separation between amplifications yields fast, easy and less damaging collection (col. 6, ll. 30-67). In sum, a skilled artisan at the time of the invention would have been motivated to apply familiar magnetic separation of nested amplicons to the familiar two-stage universal-primer multiplex amplification techniques of Brownie and Heath to yield even more sensitivity and specificity.
Thus, it would have been prima facie obvious to one having ordinary skill in the art at the time of the invention to apply the familiar magnetic separation of amplicons and nested amplification techniques of Haff, VAN KALLE and UHLEN to the familiar universal-primer multiplex amplification techniques of the conflicting claims to yield even more sensitivity and specificity with a reasonable expectation of success. See KSR Int'l v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”).
As to “5 to 50 pmol per primer,” this is taught in Brownie (0.5-5uM in 100 uL= 2-20 pmol) and Heath (3-8 pmol). These are standard concentrations routinely used in the art and cannot be the basis for allowability.
As to “no more than about 0.01pg/ul” target nucleic acid, this is routinely optimized in the art. For example, Kramer teaches to optimize template DNA according to the application (15.1.1, 15.1.5 & 15.1.9). Sachse also teaches that template concentration is routinely optimized (pgs. 12-16). Grunenwald states that for multiplex PCR, .22 pg – 5 ng of target nucleic acid should be used (pg. 91 (“For a typical PCR, 104 to 107 molecules of template DNA [0.11 pg – 1ng of 10kb template DNA] is recommended. . . . For amplification from genomic DNA, use 100 to 500 ng of template DNA. In multiplex PCR, two- to fivefold more DNA template than what is needed for a typical PCR should be used [2*0.11 pg – 1ng of 10kb template DNA= 0.22 pg – 5 ng].”)). Assuming 20-100 uL PCR mix, this equates to 0.001 pg/uL – 50 pg/uL Even more, standard curves (e.g. femtogram to nanogram concentrations to determine r-value/amplification efficienecy or limit-of-detection) are routinely created for PCR. Brownie even uses .1 pg/uL (10 ng in 100 ul). Thus, it was prima facie obvious to an ordinarily-skilled artisan of common sense to optimize the target nucleic acid concentration according to the application.
Previous Response to Arguments
The Examiner finds Applicant’s arguments dated 04/20/2017 unpersuasive because the Specification is not relevant to the broadly-worded claims which form the basis of the obvious-type double patenting rejection.
Specifically, Applicants argue that “the specification of the '148 Patent specifically describes the method as a ‘multiplex amplification reaction... used to amplify pre-determined target sequences from the nucleic acid through one amplification reaction in one vial’” (Reply, pg. 10). However, the broad language of the claimed invention encompasses “carrying out a second [separate] amplification reaction for each target sequence to be amplified using [] as a template, said portion of the first amplification products containing said at least one binding site for at least one of said target amplification primers” using “[separate] amplification reagents and conditions for said second amplification reaction such that the second amplification reaction generates a plurality of second amplification products containing the target sequence.” Even more, the conflicting claims recite two separate amplifications using “a” and “b” as listing notations: “a. carrying out a first amplification reaction . . .”; and “b. carrying out a second amplification reaction . . . .” In fact, if Applicants wish to rely on the Specification, then the Specification cuts both ways: not only does the Specification disclose single-tube reactions, but also multi-tube reactions in which the “detection means” includes a second reaction with labeled primers (see, e.g., Fig. 1). Thus, this arguments is not convincing.
Applicants also argue that the cited prior art is irrelevant because “PCR optimization protocols do not apply to all forms of PCR, particularly multiplex PCR” (Reply, pg. 11). The Office disagrees with this bald assertion, for which Applicants provide no evidence. PCR optimization principles apply to all PCRs. Furthermore, a skilled artisan reading the combination of familiar PCR information disclosed in the prior art would have been motivated to apply such information to other common amplification techniques. Thus, this arguments is not convincing.
In sum, the obvious-type double patenting rejections are maintained.
Previous Response to Arguments (10/21/2016)
The Examiner finds Applicant’s arguments dated 10/07/2016 unpersuasive because Applicants fail to address the facts that both Heath and Shuber teach to reduce or minimize universal primer in the second round of amplification (see Non-Final Office Action dated 04/08/2016, at pgs. 13-14). See In re Keller, 642 F.2d 413,425 (CCPA 1981) ("The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in anyone or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art".); see also In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986) ("Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references . . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.").
Instead, Applicants cite Elnifro to argue that multiplex amplification are susceptible to spurious amplification products (Reply, pgs. 7-8). However, this was known in the cited prior art and overcome with familiar amplification techniques (see Brownie, Heath, Shuber, etc.). It is also noted that “‘[o]bviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success.’” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (quoting In re O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988)). Furthermore,
obviousness must be determined in light of all the facts, and there is no rule that a single reference that teaches away will mandate a finding of nonobviousness. Likewise, a given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine. See id. at 1349 n. 8 (“The fact that the motivating benefit comes at the expense of another benefit, however, should not nullify its use as a basis to modify the disclosure of one reference with the teachings of another. Instead, the benefits, both lost and gained, should be weighed against one another.”). Where the prior art contains ‘apparently conflicting’ teachings (i.e., where some references teach the combination and others teach away from it) each reference must be considered “for its power to suggest solutions to an artisan of ordinary skill.... consider[ing] the degree to which one reference might accurately discredit another.’ In re Young, 927 F.2d 588, 591 (Fed.Cir.1991).”
Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006). Elnifro is one reference in a vast amount of references that overwhelmingly demonstrate that multiplex amplifications worked and worked well, even considering the “disadvantages” of possible spurious amplifications, which were largely overcome by know techniques.
Finally, Applicants argue that the obvious-type double patenting rejection is improper because “[t]he '148 Patent was originally owned by Genaco Biomedical, sold to Qiagen, and is now owned by Diatherix (Huntsville, AL)” (Reply, pg. 8). However, first, the exception to obvious-type patenting only applies when the conflicting patent and the pending application are not commonly owned. See MPEP § 804. Applicants have not provided evidence that the instant application was never owned by Genaco Biomedical, Qiagen, or Diatherix. Second, even if the assignees/owners are different, yet “[d]ouble patenting may exist between an issued patent and an application filed by the same inventive entity.” MPEP § 804(I)(A); see MPEP § 2136.04 (I) (“’Another’ means other than applicants, In re Land, 368 F.2d 866, 151 USPQ 621 (CCPA 1966), in other words, a different inventive entity. The inventive entity is different if not all inventors are the same.”). Here, the inventive entity is the same: Jian Han. Thus, the obvious-type rejections are proper, even if the assignees/owners are different.
In sum, the claims remain rejected for the reasons explained before because a skilled artisan would have found it prima facie obvious to apply lower concentration primers in the second round of amplification using common primers and magnetic separation of amplicons with a reasonable expectation of success.
Previous Note on Applicants’ Arguments
Applicants’ arguments in the Reply filed 01/21/2016 were unpersuasive because Applicants rely on unclaimed differences between the conflicting claims and instant claims (“gene-specific nested primers are very low” in tem-PCR versus “the primer concentrations are high” in arm-PCR; “with tem-PCR, the universal [common] primers are included in the initial reaction together with the nested gene-specific primers, but with arm-PCR, the universal primers are not included in the initial reaction”) (Reply, pg. 12); and “significant differences” are not enough because the differences must be different in kind and degree. See Bristol-Myers Squibb Co., v. Teva Pharma. USA, Inc., 752 F.3d 967, 976-77 (Fed. Cir. 2014) (“And ‘differences in degree’ of a known and expected property are not as persuasive in rebutting obviousness as differences in ‘kind’—i.e., a new property dissimilar to the known property. . . . When assessing unexpected properties, therefore, we must evaluate the significance and ‘kind’ of expected results along with the unexpected results.”) (citations omitted); Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1362 (Fed. Cir. 2012) (“Evidence that a combination of known components results in an effect greater than the predicted additive effect of the components can support a finding of nonobviousness.”) (Emphasis added). Applicants fail to provide convincing evidence of unexpected results that are reasonably commensurate in scope with the claimed invention; thus, the obvious-type rejection are maintained.
Previous Response to Arguments
The Examiner finds Applicant’s arguments dated 03/30/2015 unpersuasive because: at the least the evidence presented fails to demonstrate unexpected results reasonably commensurate with the full scope of the claims; and Applicants still fail to explain how the proffered evidence is commensurate in scope with the claims directed to any target, any primer combination and as few as two primer pairs, much less the broad range of primer concentrations and any additional elements in the amplifications that were known to increase sensitivity and specificity. See Bristol-Myers Squibb Co., v. Teva Pharma. USA, Inc., 752 F.3d 967, 976-77 (Fed. Cir. 2014) (explaining requirements for secondary consideration evidence).
For example, according to the presented evidence, at the least tem-PCR still works better than or just as well as arm-PCR at template concentrations of 1-10 pg/µL.
In addition, the proffered evidence fails to explain which variables (e.g. primer concentration, other additional components and/or steps, cycle and/or amplification parameters and steps, etc.) were held constant, what target sequences were used, or even the number of primer pairs (i.e. multiplexing level such as 5-plex, 10-plex, etc.).
Furthermore, contrary to Applicants’ attempt to distinguish the claimed invention over the prior art claimed method, the instant claims do not require “gene-specific primers,” or universal primers “included in the initial reaction” (Reply at pg. 8).
Thus, the Obvious-type double-patenting rejection is maintained for the reasons stated above and before.
Response to Arguments from Office Action Dated 05/19/2014
The Examiner finds Applicant’s arguments dated 05/19/2014 unpersuasive because: (1) Applicant did not explain how the results were unexpected in light of the prior art as a whole; (2) and the evidence presented is not reasonably commensurate in scope with the broad claims.
Applicant must explain how the results were unexpected in light of the prior art as a whole, which teaches amplicon “rescue,” followed by amplification (e.g. emulsion PCR in WOUDENBERG and LEAMON, or QFM-PCR in Heath).
In addition, Applicant has not ruled out other elements of the instant broad claims that could “provide[] better results when template is available at lesser concentrations and therefore provides better sensitivity than does the previously-described method” and allow “[r]esults [to be] be obtained in a shorter time (fewer amplification cycles)” (Reply at pg. 6). For example, cycle numbers during the first amplification, emulsion PCR, certain polymerases, buffer components, specific primers, cycling conditions, isothermal amplification, etc. could all cause “better results when template is available at lesser concentrations and therefore provides better sensitivity than does the previously-described method” and allow “[r]esults [to be] be obtained in a shorter time (fewer amplification cycles).”
Finally, obvious-type double-patenting is proper where the patent and application share inventor(s) but do not share owners. In re Hubbell, No. 11-1547, Slp op. at 12 (Fed. Cir. Mar. 7, 2013) (“[A]lthough Hubbell argues that we should create a specific exception barring application of obviousness-type double patenting in instances where the conflicting claims share only common inventors, rather than common ownership, we see no valid basis for doing so.”).
Previous Response to Arguments
The Office is not persuaded of error by Applicants’ response filed 8/15/2018 because Applicants merely restate their previous arguments, which were not found persuasive in the previous office actions. Thus, this rejection is maintained.
Response to Arguments
The Office is not persuaded of error by Applicants’ response filed 04/12/2019 because Grunewald, as clearly explained by the Office (Final Office Action, 10/12/2018, pgs 16-19), discloses to optimize primer concentrations, including down to 0.01pg/uL. Thus, Grunewald, in view of the other references cited, and consistent with what any skilled artisan would have done, suggests to optimize primer concentration, even down to 0.01pg/uL.
Prior Art
The following prior art is considered pertinent but not cited in the above rejections: BARANY (US 7,097,980); Sotlar et al. (Detection and Typing of Human Papillomavirus by E6 Nested Multiplex PCR, JOURNAL OF CLINICAL MICROBIOLOGY, July 2004, p. 3176–3184); Lam et al. (Rapid Multiplex Nested PCR for Detection of Respiratory Viruses, JOURNAL OF CLINICAL MICROBIOLOGY, Nov. 2007, p. 3631–3640); HAN (US 2007/0141575); TAO (US 2007/0059700); Belgrader et al. (A Multiplex PCR-Ligase Detection Reaction Assay for Human Identity Testing, GENOME SCIENCE & TECHNOLOGY, Volume 1, Number 2, 1996, pgs. 77-87); Lin et al. (Multiplex genotype determination at a large number of gene loci, Proc. Natl. Acad. Sci. USA Vol. 93, pp. 2582-2587, March 1996).
The following prior art is also considered pertinent: Shuber et al. (A Simplified Procedure for Developing Multiplex PCRs, Genome Res. 1995 5: 488-493)); Jou et al. (Single-Tube, Nested, Reverse Transcriptase PCR for Detection of Viable Mycobacterium tuberculosis, JOURNAL OF CLINICAL MICROBIOLOGY, May 1997, p. 1161–1165); Henegariu et al. (Multiplex PCR: Critical Parameters and Step-by-Step Protocol, BioTechniques 23:504-511, September 1997); Aoyagi (PCR, in Molecular Biology Problem Solver: A Laboratory Guide, Edited by Alan S. Gerstein, 2001); Roux (Optimization and Troubleshooting in PCR, in PCR Methods and Applications, Cold Spring Harbor Laboratory, 1995) and BELL (US 2006/0147959, published 7/6/2006); Dieffenbach et al. (General concepts for PCR primer design, Genome Res. 1993 3: S30-S37), at pgs. S34-S35; Yourno (A method for nested PCR with single closed reaction tubes, Genome Res. 1992 2: 60-65), at pg. 60, col. 2; Dear (Single Molecule PCR – Basic Protocols and Applications, in PCR Technology, 2004, pgs. 245-57); WOUDENBERG (US 2006/0269934).
Conclusion
No claims are allowed.
Application Nos. 13/210331, in which Applicants appealed the Examiner’s rejection, but the Examiner was AFFIRMED; and 17/732384 in which this same claim set was presented and rejected as above. All claims are identical to, patentably indistinct from, or have unity of invention with the invention claimed in the earlier application (that is, restriction (including lack of unity) would not be proper) and could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the earlier application. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action in this case. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aaron Priest whose telephone number is (571)270-1095. The examiner can normally be reached 8am-6pm.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681
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