Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Applicant' s amendment filed 12/02/2025 is acknowledged. Claims 1 and 4-6 have been amended. Claims 2 and 8-9 have been cancelled. Claims 1 and 3-7 are pending in the instant application and the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejection
Status of Prior Rejections/Objections:
The drawing, specification, and claim objections are withdrawn in view of the amendments and/or cancellation of claim 8.
The 112(a) enablement rejection of claims 8-9 is withdrawn in view of the cancellation of the claims.
The 112(b) rejection of claim 8 is withdrawn in view of the cancellation of the claim.
The 101 rejection of claims 1-4 and 6-9 is withdrawn in view of the amendment to claim 1 and the cancellation of claims 8-9.
The prior art rejection under 35 USC 102 of claims 1 and 3 as being anticipated by Eldh and claims 1-3 and 6-7 as being anticipated by Lee is withdrawn in view of the amendment to claim 1.
The prior art rejections under 35 USC 103 of claims 4 and 5 are maintained and modified in view of the amendments.
New Ground(s) of Rejections
The new ground(s) of rejections were necessitated by applicant’s amendment of the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP 2111.
Regarding claim 1, the claim recites “wherein, when the composition is used for ... cancer diagnosis, the concentration of the interferon gamma RNA is decreased by ... fold or more compared to a normal control group.”
These limitations are not directed to the structure of the composition comprising a primer set or probes. Accordingly, they are interpreted as intended use and have not been given patentable weight.
Regarding claim 4, the specification recites the “standard material ... as described in Table 1” wherein “a dumbbell structure oligonucleotide primer was designed ... and each PCR condition was constructed for a positive standard material” (para [0053]). The partially palindromic sequences of SEQ ID NO: 1 and 2 shown in Table 1 are therefore interpreted to be inherently dumbbell structure oligonucleotide primers.
Claim Objections
Claim 4 is objected to because of the following informalities: The claim recites “the primer set is a dumbbell structure oligonucleotide primer”. A set is a collective noun; the object should mirror this (i.e., “a dumbbell structure oligonucleotide primer set”). Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
Claims 5 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Regarding claim 5, claim 5 recites “wherein the primer set include SEQ ID NO: 1 and SEQ ID NO: 2”.
Claim 1 recites “a primer or probe set ... wherein the primer set or probe comprises SEQ ID NO: 1 and SEQ ID NO: 2”.
Claim 5 requires no additional limitations beyond what is required in claim 1 or claim 4. The claim does not require the formulation be limited to a primer set (e.g., over an alternative of a probe), nor would it be clear what structural difference would be required by a primer set versus, for example, a probe comprising SEQ ID NO: 1 and SEQ ID NO: 2 under the broadest reasonably interpretation, which may comprise multiple molecules.
For this reason, the claim does not comply with the 112(d) requirements.
Claim Rejections - 35 USC § 103
Claim(s) 1 and 3-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee (WO 2011/132872 A2; published 10/27/2011) in view of Nazarenko (US 2003/0165859 A1; published 09/04/2003).
Regarding claim 1, 3-7, Lee teaches a composition for measuring the concentration of human IFN-γ mRNA expression (claim 9) comprising a primer pair (claim 9). Lee teaches primer pairs for IFN-γ comprising SEQ ID NO: 1 (pg. 30):
SEQ ID NO: 1 of Lee aligns to the instant SEQ ID NO: 1 as follows.
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It is noted that the above sequence has only been aligned with the portion of the downstream of the XXXXX bases (i.e., missing the 5’ portion added to form the dumbbell structure). As the XXXXX represents unknown bases, the sequences of Lee would also align with this segment.
Lee also teaches another pair of IFN-γ primers comprising SEQ ID NO: 7. SEQ ID NO: 7 of Lee aligns to the instant SEQ ID NO: 2 as follows.
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The sequences of Instant SEQ ID NO: 2 also has been trimmed as noted above, and the note regarding the further alignment of the XXXXX portion are reiterated.
Lee teaches such sequences for diagnosis via amplifying IFN-γ (pg. 13, para 1) and a method of measuring levels from RNA (pg. 18, para 1) [i.e., measuring a concentration of interferon gamma RNA].
Therefore, Lee partially teaches the sequences of instant SEQ ID NO: 1 and 2 but fails to fully teach a set comprising the sequences.
Lee teaches its primer set is compatible with measurements of INFG in RNA derived from blood (entire document, e.g., pg. 20; instant claim 3), which would be understood to comprise exosomal RNA. There is no indication that the structures of exosomal RNA different for this gene relative to other known transcripts such that the derivation of the RNA imposes structural differences.
Lee teaches that a diagnostic kit comprising the diagnostic composition (instant claim 6) and an RT-PCR kit (instant claim 7) comprising the same are provided (pg. 12, para 7; see also pg. 25, para 2: “composition for diagnosing…is provided, comprising a primer that specifically binds to a human IFN-γ gene to measure the mRNA expression level of the gene…the diagnostic kit may be a…diagnostic kit characterized by including essential elements necessary for performing a reverse transcription polymerase reaction. The reverse transcription polymerase chain reaction kit may include each primer pair specific for the human IFN-γ gene”).
Lee fails to teach the full sequence of the IFNG binding-portion of the primers or the palindromic portion.
Nazarenko rectifies this by teaching hairpin primers (Fig. 38), wherein bases are added to the 5’ termini of the oligo nucleotide selected to be complementary to the 3’ termini of the oligonucleotide, such that they assume a hairpin [i.e., dumbbell] structure (para [0253]: “In a preferred embodiment, ... about 10 nucleotides ... [or] ... about 5 nucleotides are added to the 5'-end of the oligonucleotide, the nucleotides selected such that they are complementary to the at least one to about 10 contiguous nucleotides present in the 3'-end of the oligonucleotide.”).
Nazarenko teaches that the number of bases added to the 5'-end is selected such that the oligonucleotide forms a hairpin at temperatures below the annealing temperature and assumes a linear form at or near the annealing temperature, wherein those skilled in the art can readily determine the number of nucleotides to be added to the 5'-end of the primer so as to control the temperature at which the primer assumes a linear form (para [0255]). Nazarenko further teaches primer design using the existence of a C or G as the terminal 3’ nucleotide of the primer, the delta-G of the stem, and standard characteristics comprising length and Tm that are utilized as design rules by proprietary software to output numerous primer pairs located throughout a user-chosen target or template sequence (para [0568]). Nazarenko provides the example that the software outputs 94 primer pairs for GAPDH (para [0568]), and amplicons of various sizes were chosen for testing (para [0575]).
Nazarenko further teaches the use of a pair of hairpin primers (instant claim 4), wherein, in contrast to the linear version of the primers that “generated various mis-priming products and primer-dimers”, the corresponding hairpin primers produced the expected size amplification product with very little incorrect product (para [0481]). Nazarenko further teaches another experiment wherein “the hairpin primers gave more and cleaner amplification products of the appropriate size than linear primers of the same gene specific sequence” (para [0482]). See also para [0031].
Nazarenko teaches use of the oligonucleotides in diagnosis methods (para [0340]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the IFNG primers of Lee to be hairpin/dumbbell primers as taught by Nazarenko. In adopting the primers of Lee for the dumbbell/hairpin structure in light of Nazarenko, it would have been obvious under MPEP 2144.05(II) to optimize the start locations and length of the linear portion of primers in the composition, wherein the artisan reasonably would have arrived at the pair of claimed sequences (instant claims 1 and 5) through routine optimization, particularly in light of the sequences being partially claimed by Lee and in view of the numerous stated characteristics of Nazarenko upon which such hairpin/dumbbell primers are designed (i.e., to control the temperature at which the primers linearize; to include the C or G as the terminal 3’ nt; to optimize standard considerations of length and Tm, as taught by Nazarenko) in the software of Nazarenko based on the starting sequence(s) and the template of INFG of Lee. The artisan would have been so motivated to improve specificity of the amplification possible using the composition, as taught by Nazarenko, as the application of a primer design technique to improve an analogous product in a predictable way.
It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the primer composition in a kit, motivated by the desire to include essential elements necessary for performing an RT reaction to the artisan, as taught by Lee.
The artisan would have found the results predictable as Nazarenko teaches the necessary additions to apply the modification of primer design of standard linear primers and to design primers based on a target sequence and Lee teaches performing a kit, wherein each is directed to primers including for diagnosis.
Response to Arguments
Applicant's arguments filed 12/02/2025 have been fully considered but they are not persuasive.
Applicant argues on pgs. 9 and 10 that Lee’s SEQ ID NO: 1 and 7 are completely different from SEQ ID NO: 1 and 2 of claim 1. Applicant alleges that primer sets having superficially similar binding relationships constitutes hindsight bias and is not scientifically valid. Applicant argues that Lee explicitly describes primer pairs consisting of SEQ ID NO: 1 and SEQ ID NO: 2 or SEQ ID NO: 7 and SEQ ID NO: 8. Applicant also alleges that there is no motivation or indication of a reasonable expectation of success in the combination of the two embodiments of Lee.
In response to applicant's arguments against the references individually (i.e., that Lee does not teach the entire sequence of either the individual primers or the pair), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Specifically, while it is agreed that the INFG-binding portions of the sequences are not fully shared with the sequences of Lee, as shown in the alignments in the 103 rejection above, SEQ ID NO: 1 and SEQ ID NO: 7 do show Lee targeting the approximate regions of IFNG RNA. It further is noted that the 5’ XXXXX bases of SEQ ID NO: 1 and SEQ ID NO: 2 would encompass a larger portion of the primers of Lee than is shown. Nazarenko teaches forming pairs of hairpin sequences for primers, adding 5 or 10 bases from the 3’ to the 5’, and generating numerous primer pair sets across a target sequence range. Nazarenko teaches the conditions under which the artisan would desire to optimize, which have been further clarified in the rejection above. Accordingly, the length of the binding regions of the sequences and the positions of the sequences have been determined to be routinely optimizable characteristics of such primers.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
As discussed above, Lee teaches compositions for diagnosis using primers targeting IFGN RNA and the regions thereof amplified (via the primer). Nazarenko teaches the sequence modifications and optimization characteristics and routine practices (e.g., generating 94 sequences with design software for an entire gene with and choosing a particular number of sets from among them) through which an ordinary artisan would have derived the claimed sequences for such a composition based off of the targeting IFNG RNA of Lee, particularly one or both of the regions already targeted by Lee. Nazarenko motivates the combination with Lee and of the “embodiments” of the target(s) represented by the primers and the routine optimization that flows from the combination by teaching that the use of pairs of hairpin primers improve the specificity of the amplification possible with such compositions. The expectation of success is likewise addressed by Nazarenko, which teaches the necessary conditions for applying the hairpin modifications, i.e., designing and testing such primers. Both the motivation and expectations for success of the combination of Lee and Nazarenko were addressed in the rejection of claim 4 in the Office action dated 05/23/2025 and the optimization rejection has been clarified in the amended claim here.
It also is noted for the sake of compact prosecution that that the composition does not preclude the combination of both sets of primers of Lee (i.e., “comprises”) and that both the combinations of equivalents or substitutions of equivalents (e.g., a particular direction of primer for the same purpose of diagnosis using the same template) would be obvious under MPEP 2144.06.
Regarding the allegations that derivation of primer sets through optimization would not be scientifically valid in the biomedical field, the applicant has provided no supporting evidence. MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)). Therefore, as Nazarenko teaches designing primers based on a target sequence, wherein the sequence of the primers would be optimized based on the conditions taught, and Lee teaches teach particular targeted sequence regions via the primer binding, the argument is unpersuasive. The prior art made of record in the Conclusion teaching design optimization based on target sequences and redesign as a standard part of troubleshooting for such hairpin primers is also noted.
Applicant appears to argue unexpected results due to the sensitivity and specificity values in the arguments on pg. 11.
Claim 1 is directed to the product. The paragraph makes clear that the sensitivity and specificity is a “clinical sensitivity” for cancer identification (para [0075]) rather than the ability of the claimed primers/probes themselves to correctly identify true positives and false negatives if a template is present or not, for example. Secondary considerations must have a nexus to the claimed invention. Because the evidence presented is directed to the performance of a prediction method, there is no nexus to the claimed composition.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Invitrogen (Invitrogen. LUX Fluorogenic Primers [Internet]. Carlsbad, CA: Invitrogen Corporation; 2002. Available from: https://www.gene-quantification.de/invitrogen-luxprimers-manual.pdf) teaches LUX primers have 4-6 nucleotides on the 5’ end complementary to the 3’ end of the primer (pg. 1, Overview). Invitrogen teaches that LUX primers are easy to use, highly sensitive, and efficient with high specificity and multiplex capability (pg. 1, Overview).
Invitrogen teaches a web-based design for generating primers based on provided sequences that assigns rankings to generated designs (pg. 3, LUX Designer Web-based Design Software). Invitrogen teaches optimal amplicon lengths and the influence of target amplicon choice in optimal primer design likelihood (pg. 3, Submitting a Target Sequence). Invitrogen teaches optimizing an efficiency of a reaction based on the choice of a penalty score and a Tm, which are also dependent on the target amplicon selection choice (pg. 3, Submitting a Target Sequence).
Invitrogen teaches redesigning primers if there is low or no signal or if there is signal in controls with no template, including redesigning one primer to save costs (pg. 14, Troubleshooting).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 Emma R Hoppe whose telephone number is (703)756-5550. The examiner can normally be reached Mon - Fri 11:00 am - 7:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571) 272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636